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- Elhai, M, et al.
(author)
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Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study
- 2019
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 979-987
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Journal article (peer-reviewed)abstract
- To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice.MethodsWe performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab.Results254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83–9.62]; p=0.019 as compared with controls vs 3 [0.66–5.35]; p=0.012).ConclusionRituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.
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- Barghouth, Mohammad, et al.
(author)
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The structure of insulin granule core determines secretory capacity being reduced in type-2 diabetes
- 2022
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Other publication (other academic/artistic)abstract
- Exocytosis in excitable cells is essential for their physiological functions. Although the exocytotic machinery controlling cellular secretion has been well investigated, the function of the vesicular cargo, i.e. secretory granular content remains obscure. Here we combine dSTORM imaging and single-domain insulin antibody, to dissect the in situ structure of insulin granule cores (IGCs) at nano level. We demonstrate that the size and shape of the IGCs can be regulated by the juxta-granular molecules Nucleobindin-2 and Enolase-1, that further contribute to the stimulated insulin secretion. IGCs located at the plasma membrane are larger than those in the cytosol. The IGCs size is decreased by ∼20% after glucose stimulation due to the release of the peripheral part of IGCs through incomplete granule fusion. Importantly, the reduction of the IGCs size is also observed in non-stimulatory pancreatic β-cells from diabetic db/db mice, Akita (Ins2+/-) mice and human Type-2 diabetic donors, in accordance with impaired secretion. These findings overall highlight the structure of exocytotic insulin cores as a novel modality amenable to targeting in the stimulated exocytosis in β-cells with impaired insulin secretion.Competing Interest StatementThe authors have declared no competing interest.
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| 8. |
- Bergholdt, R, et al.
(author)
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Transcriptional profiling of type 1 diabetes genes on chromosome 21 in a rat beta-cell line and human pancreatic islets
- 2007
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In: Genes and Immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 8:3, s. 232-238
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Journal article (peer-reviewed)abstract
- We recently finemapped a type 1 diabetes (T1D)-linked region on chromosome 21, indicating that one or more T1D-linked genes exist in this region with 33 annotated genes. In the current study, we have taken a novel approach using transcriptional profiling in predicting and prioritizing the most likely candidate genes influencing beta-cell function in this region. Two array-based approaches were used, a rat insulinoma cell line (INS-1 alpha beta) overexpressing pancreatic duodenum homeobox 1 (pdx-1) and treated with interleukin 1 beta (IL-1 beta) as well as human pancreatic islets stimulated with a mixture of cytokines. Several candidate genes with likely functional significance in T1D were identified. Genes showing differential expression in the two approaches were highly similar, supporting the role of these specific gene products in cytokine-induced beta-cell damage. These were genes involved in cytokine signaling, oxidative phosphorylation, defense responses and apoptosis. The analyses, furthermore, revealed several transcription factor binding sites shared by the differentially expressed genes and by genes demonstrating highly similar expression profiles with these genes. Comparable findings in the rat beta-cell line and human islets support the validity of the methods used and support this as a valuable approach for gene mapping and identification of genes with potential functional significance in T1D, within a region of linkage.
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| 11. |
- Harbo, HF, et al.
(author)
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Two genome-wide linkage disequilibrium screens in Scandinavian multiple sclerosis patients
- 2003
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In: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 143:1-2, s. 101-106
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Journal article (peer-reviewed)abstract
- We report the first two genome-wide screens for linkage disequilibrium between putative multiple sclerosis (MS) susceptibility genes and genetic markers performed in the genetically homogenous Scandinavian population, using 6000 microsatellite markers and DNA pools of approximately 200 MS cases and 200 controls in each screen. Usable data were achieved from the same 3331 markers in both screens. Nine markers from eight genomic regions (1p33, 3q13, 6p21, 6q14, 7p22, 9p21, 9q21 and Xq22) were identified as potentially associated with MS in both screens. (C) 2003 Elsevier B.V. All rights reserved.
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| 12. |
- Kappos, L., et al.
(author)
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Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS
- 2006
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In: Neurology. - 1526-632X. ; 67:6, s. 944-953
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Journal article (peer-reviewed)abstract
- Objective: To conduct systematic long-term follow-up (LTFU) of patients in the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis ( PRISMS) study to provide up to 8 years of safety, clinical and MRI outcomes on subcutaneous (SC) interferon (IFN) beta-1a in relapsing-remitting multiple sclerosis (RRMS). Methods: The original cohort of 560 patients was randomized to IFN beta-1a, 44 or 22 mu g three times weekly (TIW) or to placebo; after 2 years, patients on placebo were rerandomized to active treatment and the blinded study continued for a further 4 years. The LTFU visit was scheduled 7 to 8 years after baseline. Results: LTFU was attended by 68.2% of the original PRISMS study cohort ( 382/560 patients). 72.0% (275/382) were still receiving IFN beta-1a SC TIW. Patients originally randomized to IFN beta-1a 44 mu g SC TIW showed lower Expanded Disability Status Scale progression, relapse rate and T2 burden of disease up to 8 years compared with those in the late treatment group. Brain parenchymal volume did not show differences by treatment group. Overall, 19.7% of patients progressed to secondary progressive MS between baseline and LTFU (75/381). No new safety concerns were identified and treatment was generally well tolerated. Conclusions: Despite the limitations inherent in any long-term study ( for example, potential differences between returning and nonreturning patients), these results indicate that patients with relapsing-remitting multiple sclerosis can experience sustained benefit over many years from early interferon beta-1a subcutaneous therapy three times weekly compared with patients whose treatment is delayed. This effect was more apparent in the patients receiving the higher dose.
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- Polman, C, et al.
(author)
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Treatment with laquinimod reduces development of active MRI lesions in relapsing MS
- 2005
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In: Neurology. - 1526-632X. ; 64:6, s. 987-991
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Journal article (peer-reviewed)abstract
- Background: Laquinimod is a novel immunomodulatory substance developed as an orally available disease modifying treatment in multiple sclerosis ( MS). The purpose of this study was to evaluate safety, tolerability, and efficacy on MRI lesions of two different doses of laquinimod compared with placebo in patients with relapsing MS. Methods: In this multicenter, double-blind, randomized trial, patients with relapsing MS received 0.1 mg or 0.3 mg laquinimod or placebo as three daily tablets for 24 weeks. Gadolinium- enhanced brain MRI scans were performed at screening, every eighth week during treatment, and 8 weeks after end of treatment. The primary efficacy variable was the cumulative number of active lesions over 24 weeks. Safety measures included adverse events, physical examination, and laboratory variables. Results: Of 256 screened patients, 209 were randomized (67 to 74 patients per group) in 20 centers. There was a significant difference between laquinimod 0.3 mg and placebo for the primary outcome measure ( mean cumulative number of active lesions reduced by 44%). In the subgroup of patients with at least one active lesion at baseline the reduction was slightly more pronounced (52%). No differences with respect to clinical variables (relapses, disability) were found. The safety profile was favorable; there were no clinical signs of undesired inflammatory manifestations. Conclusion: Oral laquinimod in a dosage of 0.3 mg daily was well tolerated and effective in suppressing development of active lesions in relapsing multiple sclerosis.
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- Scheja, A, et al.
(author)
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Computer based quantitative analysis of capillary abnormalities in systemic sclerosis and its relation to plasma concentration of von Willebrand factor
- 1996
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In: Annals of the Rheumatic Diseases. - 0003-4967. ; 55:1, s. 6-52
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To evaluate an objective and quantitative method for assessment of capillary abnormalities in systemic sclerosis (SSc).METHODS: Nailfold capillaries were investigated by capillary microscopy and photographed in 17 consecutive SSc patients (five with diffuse cutaneous systemic sclerosis (dSSc) and 12 with limited cutaneous systemic sclerosis (lSSc)) and in 17 healthy controls. Investigators having no access to clinical data made drawings from magnified projections of coded photographs and analysed them using a computer program. Capillary density (capillary loops/mm in the distal row) and median capillary loop area were calculated. Presence of functional or organic arterial changes was evaluated by measurement of finger pressure with finger cooling. Plasma concentration of von Willebrand factor (VWF) was analysed using an enzyme linked immunosorbent assay (ELISA).RESULTS: In 16 of 17 SSc patients and 13 of 17 controls the technical quality of the photographs was sufficient for computer analysis. Capillary density was decreased in dSSc (median 6.9 loops/mm) and in lSSc (median 3.8 loops/mm) compared with healthy controls (8.9 loops/mm) and median capillary loop area was increased in dSSc (7.3 x 10(-3) mm2) and in lSSc (8.5 x 10(-3) mm2) compared with healthy controls (5.0 x 10(-3) mm2). An inverse relation was found between capillary density and median capillary loop area in SSc patients. Plasma VWF was increased in patients (median 401 IE/l in dSSc and 409 IE/l in lSSc) compared with controls matched for age and sex (median 276 IE/l). Computer based analysis showed capillary density below the control range and median capillary loop area above the control range in 14 of 16 SSc patients. Measurement of finger pressure with finger cooling showed organic vascular changes in nine of 13 SSc patients.CONCLUSION: Computer based quantitative analysis has low interobserver variability and is a quantitative and sensitive method of assessing capillary abnormalities in SSc.
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| 19. |
- Westergren-Thorsson, G, et al.
(author)
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Altered dermatan sulfate proteoglycan synthesis in fibroblast cultures established from skin of patients with systemic sclerosis
- 1996
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In: Journal of Rheumatology. - 0315-162X. ; 23:8, s. 406-1398
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To study whether changes in the properties of skin from patients with systemic sclerosis (SSc) are the result of altered metabolism of dermatan sulfate proteoglycans.METHODS: Fibroblast cultures were established from skin of healthy controls, and from affected and unaffected skin of patients with SSc. Synthesized proteoglycans were labeled with 3H glucosamine and 35S sulfate. The amount of mRNA of the different dermatan sulfate proteoglycans was determined by hybridization with the corresponding cDNA probes.RESULTS: A 2-fold increase in secretion of total proteoglycans was found in cell cultures from affected and normal appearing skin from patients with SSc. The production of 2 different dermatan sulfate proteoglycans was increased. Aggrecan/versican increased 4-fold and decorin 2-fold in cultures of affected skin from patients with SSc. The mRNA for decorin increased 3-fold, while the mRNA level for versican increased only slightly. Similar but less marked changes were noted in cultures from normal appearing skin. In contrast, the biglycan mRNA level decreased and the product could only be found in very small amounts in SSc cultures.CONCLUSION: This marked alteration of dermatan sulfate proteoglycan metabolism distinguishes not only affected skin but also normal appearing SSc skin from that of controls. The altered proteoglycan production may affect organization of matrix fibers and thereby the fibrotic process observed in patients with SSc.
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| 20. |
- Wollheim, F. A.
(author)
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Nanna Svartz (1890–1986) : Die erste Frau auf einem medizinischen Lehrstuhl in Schweden
- 2017
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In: Zeitschrift für Rheumatologie. - : Springer Science and Business Media LLC. - 0340-1855 .- 1435-1250. ; 76:9, s. 813-819
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Journal article (peer-reviewed)abstract
- Nanna Svartz was a charismatic character who played a significant role in Swedish medicine in the mid-twentieth century. As one of five brothers and sisters, she escaped an early death from tuberculosis. She reached 96 years of age. Her diligence and sense of duty were legendary, along with her ambition to fully prove herself as “the first female professor”. She inherited a certain insecurity from her father that led to her difficulty in taking criticism. Despite extensive academic obligations, she worked as a treating doctor for 55 years and always took her time with her patients, especially if they held important public positions. Nanna was honoured several times in her lifetime. Among others, she was a member of the Leopoldina, the National Academy of Germany, and received many honorary doctorates, for example, from Rockefeller College (USA) and the Åbo University (Turku, Finland). She was an honorary member of over 40 scientific societies. Underneath the new auditorium in the Karolinska Institute, a restaurant and a street in her home town of Västerås bear her name. An annual international Nanna Svartz Lecture is held by the Swedish Society for Rheumatology, and a Nanna Svartz Prize is awarded annually to a deserving young Swedish rheumatologist.
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| 21. |
- Wu, Chuanyan, et al.
(author)
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Elevated circulating follistatin associates with an increased risk of type 2 diabetes
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-10
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Journal article (peer-reviewed)abstract
- The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04-1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09-1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.
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