| 1. |
- Dahlén, Eva, et al.
(författare)
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Development of interleukin-1 receptor antagonist mutants with enhanced antagonistic activity in vitro and improved therapeutic efficacy in collagen-induced arthritis.
- 2008
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Ingår i: Journal of Immunotoxicology. - : Informa UK Limited. - 1547-6901 .- 1547-691X. ; 5:2, s. 189-199
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of the pro-inflammatory interleukin-1-mediated activation of the interleukin-1 receptor (IL-1R). Although wild-type IL-1Ra is used for treatment of inflammatory diseases, its effect is moderate and/or short-lived. The objective of this study was to generate IL-1Ra mutants with enhanced antagonistic activity for potential therapeutic use. Using a directed evolution approach in which libraries of IL-1Ra gene mutants were generated and screened in functional assays, mutants with desired properties were identified. Initially, diversity was introduced into the IL-1Ra using random mutagenesis. Mutations resulting in enhanced antagonistic activity were identified by screening in a reporter cell assay. To further enhance the antagonistic activity, selected mutations were recombined using the DNA recombination technology Fragment-INduced Diversity (FIND). Following three rounds of FIND recombination, several mutants with up to nine times enhanced antagonistic activity (mean IC50 +/- SEM value: 0.78 +/- 0.050 vs. 6.8 +/- 1.1 ng/ml for mutant and wild-type, respectively) were identified. Sequence analysis identified the mutations D47N, E52R and E90Y as being most important for this effect, however, the mutations P38Y, H54R, Q129L and M136N further enhanced the antagonistic function. Analysis of identified mutations in protein models based on the crystal structure of the IL-1Ra/IL-1R complex suggested that mutations found to enhance the antagonistic activity had a stabilizing effect on the IL-1Ra mutants or increased the affinity for the IL-1R. Finally, the therapeutic effect of one mutant was compared to that of wild-type IL-1Ra in collagen-induced arthritis in mice. Indeed, the enhanced antagonistic effect of the mutants observed in vitro was also seen in vivo. In conclusion, these results demonstrate that directed evolution of IL-1Ra is an effective means of generating highly potent therapeutic proteins.
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| 2. |
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| 3. |
- Eriksson, Jonas, 1984, et al.
(författare)
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Update of prevalence of self-reported allergic rhinitis and chronic nasal symptoms among adults in Sweden
- 2012
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Ingår i: The Clinical Respiratory Journal. - 1752-699X .- 1752-6981. ; 6:3, s. 159-168
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Tidskriftsartikel (refereegranskat)abstract
- Background: Allergic rhinitis (AR) is the most common immunologic disease, and it renders a considerable burden on both sufferers and society. The prevalence of AR has been increasing worldwide over the past century. The aim of this study was to assess the present prevalence, risk factor patterns and comorbidity of self-reported AR and chronic nasal symptoms in different age groups in Stockholm, Sweden. Methods: A postal questionnaire was sent on two occasions, in 2006 to a population aged 30-80 years, randomly selected 10 years previously, and in 2007 to a randomly selected sample of subjects aged 20-69 years. The response rates were 83% and 68%, respectively, and in total, 9792 subjects participated. The questionnaire included questions on self-reported AR, asthma, respiratory and nasal symptoms and possible determinants. Results: The prevalence of self-reported AR was 28.0% (men 26.6%, women 29.1%, P<0.01) similar to 10 years previously and 33.6% in ages 30-40 years. Allergic heredity [odds ratio (OR) 4.76, confidence interval (CI) 95% 4.25-5.33], physician-diagnosed asthma (OR 5.29, CI 95% 4.49-6.24) and occupational exposure to dust, gases and fumes (OR 1.49, CI 95% 1.30-1.72) were determinants for AR. Prevalence of chronic nasal congestion was 16.1% and of chronic rhinorrhea 14.1%. Conclusions: As a basis for understanding the disease, as well as in planning and prioritising health-care resources, the study provides information about the current prevalence and determinants of self-reported AR and chronic nasal symptoms. Further, comparing with previous studies, the present study suggests that a plateau in the prevalence of AR may have been reached in Sweden. Please cite this paper as: Eriksson J, Ekerljung L, Rönmark E, Dahlén B, Ahlstedt S, Dahlén S-E and Lundbäck B. Update of prevalence of self-reported allergic rhinitis and chronic nasal symptoms among adults in Sweden
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| 4. |
- Yasinska, Valentyna, et al.
(författare)
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Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids
- 2023
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Ingår i: ERJ Open Research. - : European Respiratory Society. - 2312-0541. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Patients with severe asthma are dependent upon treatment with high doses of inhaled corticosteroids (ICS) and often also oral corticosteroids (OCS). The extent of endogenous androgenic anabolic steroid (EAAS) suppression in asthma has not previously been described in detail. The objective of the present study was to measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure.Methods: Urine collected at baseline in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcomes) study of severe adult asthmatics (SA, n=408) was analysed by quantitative mass spectrometry. Data were compared to that of mild-to-moderate asthmatics (MMA, n=70) and healthy subjects (HC, n=98) from the same study.Measurements and main results: The concentrations of urinary endogenous steroid metabolites were substantially lower in SA than in MMA or HC. These differences were more pronounced in SA patients with detectable urinary OCS metabolites. Their dehydroepiandrosterone sulfate (DHEA-S) concentrations were <5% of those in HC, and cortisol concentrations were below the detection limit in 75% of females and 82% of males. The concentrations of EAAS in OCS-positive patients, as well as patients on high-dose ICS only, were more suppressed in females than males (p<0.05). Low levels of DHEA were associated with features of more severe disease and were more prevalent in females (p<0.05). The association between low EAAS and corticosteroid treatment was replicated in 289 of the SA patients at follow-up after 12–18 months.Conclusion: The pronounced suppression of endogenous anabolic androgens in females might contribute to sex differences regarding the prevalence of severe asthma.
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| 5. |
- Alerby, Eva, et al.
(författare)
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Ömsesidig samverkan mellan pedagogisk forskning och pedagogisk praktik
- 2010
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Ingår i: Utbildning på vetenskaplig grund. - Stockholm : Lärarförbundet. - 9789197808835 ; , s. 22-32
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Vad innebär det i praktiken att skolans och förskolans verksamhet skall vila på vetenskaplig grund och beprövad erfarenhet? Det vi tycker är intressant att lyfta fram är på vilket sätt forskningen bedrivs, hur forskningsfrågorna kommer till och hur resultaten kommer den pedagogiska praktiken tillgodo. I denna artikel diskuterar och problematiserar vi relationen mellan den pedagogiska forskningen och förskolans och skolans verksamhet. Diskussionerna exemplifieras från ett konkret forsknings- och samverkansprojekt, där forskning och praktik har gått hand i hand. Vidare ger en forskare, en doktorand, en lärarutbildare, en skolledare och en lärare sin personliga syn på samverkan mellan pedagogisk forskning och praktik.
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| 6. |
- Bornefalk, Eva, et al.
(författare)
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Age-dependent effect of oral glucocorticoids on markers of bone resorption in patients with acute asthma
- 1998
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 63:1, s. 9-13
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Tidskriftsartikel (refereegranskat)abstract
- It is generally accepted that bone formation is depressed during corticosteroid treatment, but the effects of glucocorticoids on bone resorption are less well characterized. We have investigated the effects of short-term treatment with high-dose oral glucocorticoids on biochemical markers of bone turnover in 20 consecutive patients with asthma who sought help for acute respiratory obstruction in our emergency department. Serum concentrations of the carboxy-terminal cross-linked telopeptide of type 1 collagen (1CTP), reflecting bone resorption, and the carboxy-terminal propeptide of type 1 procollagen (P1CP), reflecting bone formation, were measured by radioimmunoassay. Changes of the circulating levels of the bone resorption marker 1CTP after treatment were age dependent with a significant negative correlation (r = -0.54, P = 0.01). The dependency on age remained when correcting, in a multiple linear regression analysis, for 1CTP levels at admission, weight, sex, and daily maintenance dose of inhaled glucocorticoids. Circulating levels of P1CP were suppressed in the whole group 1 week after initiation of glucocorticoid therapy, from 123.3 +/- 10.2 ng/ml at admission to 88.1 +/- 6.3 ng/ml after 1 week (P < 0.01). The changes in P1CP levels were not related to age. Our data indicate that bone formation is suppressed by glucocorticoids in all age groups, whereas the effect of glucocorticoids on markers of bone resorption is dependent on age.
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| 7. |
- Börve, Alexander, et al.
(författare)
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Smartphone Teledermoscopy Referrals: A Novel Process for Improved Triage of Skin Cancer Patients.
- 2015
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Ingår i: Acta dermato-venereologica. - : Medical Journals Sweden AB. - 1651-2057 .- 0001-5555. ; 95:2, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- In this open, controlled, multicentre and prospective observational study, smartphone teledermoscopy referrals were sent from 20 primary healthcare centres to 2 dermatology departments for triage of skin lesions of concern using a smartphone application and a compatible digital dermoscope. The outcome for 816 patients referred via smartphone teledermoscopy was compared with 746 patients referred via the traditional paper-based system. When surgical treatment was required, the waiting time was significantly shorter using teledermoscopy for patients with melanoma, melanoma in situ, squamous cell carcinoma, squamous cell carcinoma in situ and basal cell carcinoma. Triage decisions were also more reliable with teledermoscopy and over 40% of the teledermoscopy patients could potentially have avoided face-to-face visits. Only 4 teledermoscopy referrals (0.4%) had to be excluded due to poor image quality. Smartphone teledermoscopy referrals allow for faster and more efficient management of patients with skin cancer as compared to traditional paper referrals.
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| 8. |
- Dahlén, Eva
(författare)
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Antigen presenting cells in autoimmune diabetes: phenotype, function and modulation by Linomide
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to better understand the role of antigen presenting cells (APC) in the development of diabetes in the nonobese diabetic (NOD) mouse. We have shown that DC and Mphi that infiltrate the islets of Langerhans produce tumour necrosis factor-a (TNF-a), a cytokine known to contribute to the pathogenesis in the early stages of diabetes development. TNF-a is produced from the early stages of insulitis development and occurs independently of T cells. Furthermore, we have found that NOD APC express relatively low levels of the costimulatory molecule CD86 (B7-2) and therefore have a poor T cell stimulatory capacity. This gives rise to a reduced T cell activation as well as an impaired upregulation of the negative T cell regulator CTLA-4, suggesting that APC defects contribute to disease development. The immunomodulator Linomide inhibits diabetes in NOD mice. We found that this is accompanied by a reduced lymphocyte and dendritic cell infiltration into the islets of Langerhans. In addition, Linomide treatment results in a reduced production of TNF-a whereas instantly, following the initiation of Linomide treatment the production of IL-12 p40 and IFN-g is increased. IFN-g is known to upregulate MHC class II as well as adhesion and costimulatory molecules that are important in antigen presentation. In analogy, we found that Linomide treatment of SJL/J mice results in the upregulation of MHC class II, CD11a, CD54 and CD80 on Mphi, indicating an improved T cell stimulatory capacity. In addition, the ability of several Linomide analogues to inhibit experimental autoimmune encephalomyelitis correlates with their ability to upregulate MHC class II on Mphi, suggesting that APC activation may indeed inhibit autoimmune disease. In summary, APC are required for the induction of T cell activation and therefore also for the induction of autoimmunity. However, given that the development of regulatory T cell responses could be dependent on optimal antigen presentation, autoimmune disease may be due to ineffective APC function. Therefore, improving APC capacity, e.g. by Linomide treatment, may indeed inhibit autoimmune disease.
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| 9. |
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| 10. |
- Dahlén, Elin, et al.
(författare)
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Sibship and dispensing patterns of asthma medication in young children : a population based study
- 2019
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Ingår i: Pharmacoepidemiology & Drug Safety. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 1053-8569 .- 1099-1557.
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Our aim was to study the association between sibship and dispensing patterns of asthma medication in young children, focusing on incidence and persistence, and taking sibship status, asthma diagnoses, and siblings’ medication into account. Methods: A register-based cohort study including all children (n=50,546) born in Stockholm, Sweden 2006–2007, followed up during 2006–2014. Exposure was sibling status; outcome was incidence of dispensed asthma medication and persistence over time. A Cox-model was used to study the association between sibship and asthma medication. Persistence was defined using two different time windows (4- and 18-months) in a refill sequence model including siblings’ and unrelated control children’s medication. Results: After one year of age, the adjusted hazard ratio of dispensed asthma medication was 0.85 (95%CI 0.80–0.90) among children with siblings compared to singletons. The estimated proportion of children with persistent controller medication was 7.2% (4-month model) and 64.5% (18-month model). When including the siblings’ controller medication, the estimated proportion was 8.8% (4-months) and 7.8% for control children (relative risk, RR 0.89, 95%CI 0.81-0.98). The persistence was lower for those with siblings compared to singletons (adj. RR 0.72, 95%CI 0.62-0.85 for 4-months) with similar estimates for older, younger, and full siblings and regardless of asthma diagnoses. Conclusions: Siblings have different dispensing patterns of asthma medications compared to singletons regardless of asthma diagnoses. After including the siblings’ asthma medication and compared with control children, the proportion of children with persistent medication increased which may indicate that siblings share asthma medications.
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