| 1. |
- Nygren, Jens Martin, 1976-, et al.
(författare)
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Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation
- 2004
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 10:5, s. 494-501
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have suggested that bone marrow cells might possess a much broader differentiation potential than previously appreciated. In most cases, the reported efficiency of such plasticity has been rather low and, at least in some instances, is a consequence of cell fusion. After myocardial infarction, however, bone marrow cells have been suggested to extensively regenerate cardiomyocytes through transdifferentiation. Although bone marrow-derived cells are already being used in clinical trials, the exact identity, longevity and fate of these cells in infarcted myocardium have yet to be investigated in detail. Here we use various approaches to induce acute myocardial injury and deliver transgenically marked bone marrow cells to the injured myocardium. We show that unfractionated bone marrow cells and a purified population of hematopoietic stem and progenitor cells efficiently engraft within the infarcted myocardium. Engraftment was transient, however, and hematopoietic in nature. In contrast, bone marrow-derived cardiomyocytes were observed outside the infarcted myocardium at a low frequency and were derived exclusively through cell fusion.
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| 2. |
- Varga, Tibor V, et al.
(författare)
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Acute and Long-Term Changes in Blood-Borne Biomarkers in Response to Dynamic Standing in Nonambulant Children With Cerebral Palsy
- 2024
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Ingår i: Pediatric Exercise Science. - Champaign, IL : Human Kinetics. - 0899-8493 .- 1543-2920. ; 36:1, s. 15-22
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate acute and long-term changes in hormonal and inflammatory biomarkers in nonambulant children with cerebral palsy in response to dynamic standing exercise.Methods: Fourteen children with severe cerebral palsy were recruited. Anthropometrics and body composition measures were obtained. Physical activity levels before the study were assessed using hip-worn accelerometry. All children underwent a 30-minute dynamic standing exercise using the Innowalk standing aid. Respiratory data during exercise were collected using indirect calorimetry. Blood samples were collected before and after exercise. Blood samples were also obtained after two 16-week exercise protocols, in a resting state. Hormonal and inflammatory metabolites were measured from blood serum/plasma, and acute and long-term changes in biomarker levels were assessed using Wilcoxon signed-rank tests.Results: Of the 14 children at baseline, all had slightly/moderately/severely elevated C-reactive protein and cortisol levels. C-reactive protein levels were decreased following a 30-minute bout of dynamic standing (before exercise: 53 mg/L [interquartile range: 40-201]; after exercise: 39 mg/L [interquartile range: 20-107]; P = .04).Conclusions: We show that several hormonal and inflammatory biomarkers are dysregulated in children with cerebral palsy. Our preliminary results from a small, but deep-phenotyped prospective cohort indicate acute and long-term alterations of several biomarkers in response to exercise. ©2023 The Authors.
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| 3. |
- Walsh, Stuart, et al.
(författare)
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Myogenic reprogramming of bone marrow derived cells in a W⁴¹Dmd(mdx) deficient mouse model
- 2011
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Ingår i: PLOS ONE. - San Francisco : Public Library of Science. - 1932-6203. ; 6:11, s. e27500-
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Tidskriftsartikel (refereegranskat)abstract
- Lack of expression of dystrophin leads to degeneration of muscle fibers and infiltration of connective and adipose tissue. Cell transplantation therapy has been proposed as a treatment for intractable muscle degenerative disorders. Several reports have demonstrated the ability of bone-marrow derived cells (BMDC) to contribute to non-haematopoietic tissues including epithelium, heart, liver, skeletal muscle and brain following transplantation by means of fusion and reprogramming. A key issue is the extent to which fusion and reprogramming can occur in vivo, particularly under conditions of myogenic deterioration.To investigate the therapeutic potential of bone marrow transplantation in monogenetic myopathy, green fluorescent protein-positive (GFP+) bone marrow cells were transplanted into non-irradiated c-kit receptor-deficient (W⁴¹) mdx mice. This model allows BMDC reconstitution in the absence of irradiation induced myeloablation. We provide the first report of BMDC fusion in a W⁴¹Dmd(mdx) deficient mouse model.In the absence of irradiation induced injury, few GFP+ cardiomyocytes and muscle fibres were detected 24 weeks post BMT. It was expected that the frequency of fusion in the hearts of W⁴¹Dmd(mdx) mice would be similar to frequencies observed in infarcted mice. Although, it is clear from this study that individual cardiomyocytes with monogenetic deficiencies can be rescued by fusion, it is as clear that in the absence of irradiation, the formation of stable and reprogrammed fusion hybrids occurs, with the current techniques, at very low levels in non-irradiated recipients.
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| 4. |
- Ashfaq, Awais, 1990-, et al.
(författare)
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Readmission prediction using deep learning on electronic health records
- 2019
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Ingår i: Journal of Biomedical Informatics. - Maryland Heights, MO : Elsevier BV. - 1532-0464 .- 1532-0480. ; 97
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Tidskriftsartikel (refereegranskat)abstract
- Unscheduled 30-day readmissions are a hallmark of Congestive Heart Failure (CHF) patients that pose significant health risks and escalate care cost. In order to reduce readmissions and curb the cost of care, it is important to initiate targeted intervention programs for patients at risk of readmission. This requires identifying high-risk patients at the time of discharge from hospital. Here, using real data from over 7500 CHF patients hospitalized between 2012 and 2016 in Sweden, we built and tested a deep learning framework to predict 30-day unscheduled readmission. We present a cost-sensitive formulation of Long Short-Term Memory (LSTM) neural network using expert features and contextual embedding of clinical concepts. This study targets key elements of an Electronic Health Record (EHR) driven prediction model in a single framework: using both expert and machine derived features, incorporating sequential patterns and addressing the class imbalance problem. We evaluate the contribution of each element towards prediction performance (ROC-AUC, F1-measure) and cost-savings. We show that the model with all key elements achieves higher discrimination ability (AUC: 0.77; F1: 0.51; Cost: 22% of maximum possible savings) outperforming the reduced models in at least two evaluation metrics. Additionally, we present a simple financial analysis to estimate annual savings if targeted interventions are offered to high risk patients. © 2019 The Authors
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| 5. |
- Kielland, Anders, et al.
(författare)
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In vivo imaging of reactive oxygen and nitrogen species in inflammation using the luminescent probe L-012
- 2009
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Ingår i: Free Radical Biology & Medicine. - Philadelphia, PA : Elsevier. - 0891-5849 .- 1873-4596. ; 47:6, s. 760-766
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Tidskriftsartikel (refereegranskat)abstract
- Production of reactive oxygen and nitrogen species (ROS/RNS) is an important part of the inflammatory response, but prolonged elevated levels of ROS/RNS as under chronic inflammation can contribute to the development of disease. Monitoring ROS/RNS in living animals is challenging due to the rapid turnover of ROS/RNS and the limited sensitivity and specificity of ROS/RNS probes. We have explored the use of the chemiluminescent probe L-012 for noninvasive imaging of ROS/RNS production during inflammation in living mice. Various inflammatory conditions were induced, and L-012-dependent luminescence was recorded with an ultrasensitive CCD camera. Strong luminescent signals were observed from different regions of the body corresponding to inflammation. The signal was reduced by administration of the SOD mimetic tempol, the NADPH oxidase inhibitor apocynin, and the inhibitor of nitric oxide synthesis L-NAME, signifying the requirement for the presence of ROS/RNS. Additionally, the L-012 signal was abolished in mice with a mutation in the Ncf1 gene, encoding a protein in the NADPH oxidase complex 2, which generates ROS/RNS during inflammation. In conclusion, L-012 is well distributed in the mouse body and mediates a strong ROS/RNS-dependent luminescent signal in vivo and is useful for monitoring the development and regulation of inflammation in living organisms. © 2009 Elsevier Inc. All rights reserved.
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| 6. |
- Khmaladze, Ia, et al.
(författare)
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Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice
- 2014
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Washington, DC : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:35, s. E3669-E3678
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by gammadelta T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fcgamma receptor III, mast cells, and histamine) and adaptive immune players (alphabeta T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-alpha secretion and stimulation of local gammadelta T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.
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| 7. |
- Shen, Weixing, et al.
(författare)
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Protective effects of Wang-Bi tablet on bone destruction in collagen-induced arthritis by regulating osteoclast-osteoblast functions.
- 2019
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Ingår i: Journal of Ethnopharmacology. - : Elsevier BV. - 0378-8741 .- 1872-7573. ; 238
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Tidskriftsartikel (refereegranskat)abstract
- ETHNOPHARMACOLOGICAL RELEVANCE: Wang-bi tablet (WB) consists of 17 traditional Chinese medicines and has been used for treating rheumatoid arthritis (RA) in China for many years, however, its pharmacologic mechanism is not clear.AIM OF STUDY: The aim of this study was to investigate the therapeutic effect of WB on collagen-induced mouse arthritis and explored the underlying mechanism.MATERIALS AND METHODS: DBA/1 mice were used to establish a type II collagen-induced arthritis (CIA) model. From the day of arthritis onset, mice were treated daily by gavage with either total glucosides of paeony (TGP, 0.37 g/kg/d) or WB at a lower (1.11 g/kg/d, WBL) or higher dose of (3.33 g/kg/d, WBH) for 8 weeks. The severity of arthritis, levels of cytokines and the activation of signaling pathways were determined.RESULTS: Our results revealed that WB treatment effectively alleviated inflammatory symptoms and prevented bone erosions and joint destructions. It obviously decreased the serum concentration of pro-inflammatory cytokines TNF-α, IL-6 and IL-17α, while increased the concentration of anti-inflammatory cytokine IL-10. Interestingly, the proportion of splenic Treg cells were increased significantly. In vitro experiments showed that WB inhibited the differentiation of osteoclasts. Consistently, the mRNA levels of tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CtsK), and the activation of NF-κB and JAK-STAT3 signaling pathways in the paws of CIA mice were inhibited by WB treatment. On the other hand, up-regulation of osteogenic genes Runx2, Osterix mRNA, and activation of Wnt/β-catenin signaling pathway along with a decreased receptor activator of nuclear factor κB ligand (RANKL) expression were found in WB treated mice.CONCLUSION: Our results suggest that the therapeutic effect of Wang-bi tablet could be attributed to its inhibitory activity on NF-κB and STAT3 signaling pathway-mediated osteoclast differentiation, and its enhancement on Wnt/β-catenin signaling pathway-mediated osteoblast functions.
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| 8. |
- Tong, D. M., et al.
(författare)
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A Shared Epitope of Collagen Type XI and Type II Is Recognized by Pathogenic Antibodies in Mice and Human with Arthritis
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Collagen XI (CXI) is a heterotrimeric molecule with triple helical structure in which the alpha 3(XI) chain is identical to the alpha 1(II) chain of collagen II (CII), but with extensive posttranslational modifications. CXI molecules are intermingled in the cartilage collagen fibers, which are mainly composed of CII. One of the alpha chains in CXI is shared with CII and contains the immunodominant T cell epitope, but it is unclear whether there are shared B cell epitopes as the antibodies tend to recognize the triple helical structures. Methods: Mice expressing the susceptible immune response gene A(q) were immunized with CII or CXI. Serum antibody responses were measured, monoclonal antibodies were isolated and analyzed for specificity to CII, CXI, and triple helical collagen peptides using bead-based multiplex immunoassays, enzyme-linked immunosorbent assays, and Western blots. Arthritogenicity of the antibodies was investigated by passive transfer experiments. Results: Immunization with CII or CXI leads to a strong T and B cell response, including a cross-reactive response to both collagen types. Immunization with CII leads to severe arthritis in mice, with a response toward CXI at the chronic stage, whereas CXI immunization induces very mild arthritis only. A series of monoclonal antibodies to CXI were isolated and of these, the L10D9 antibody bound to both CXI and CII equally strong, with a specific binding for the D3 epitope region of alpha 3(XI) or alpha 1(II) chain. The L10D9 antibody binds cartilage in vivo and induced severe arthritis. In contrast, the L5F3 antibody only showed weak binding and L7D8 antibody has no binding to cartilage and did not induce arthritis. The arthritogenic L10D9 antibody bound to an epitope shared with CII, the triple helical D3 epitope. Antibody levels to the shared D3 epitope were elevated in the sera from mice with arthritis as well as in rheumatoid arthritis. Conclusion: CXI is immunologically not exposed in healthy cartilage but contains T and B cell epitopes cross-reactive with CII, which could be activated in both mouse and human arthritis and could evoke an arthritogenic response.
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| 9. |
- Kolossov, Eugen, et al.
(författare)
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Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium
- 2006
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Ingår i: Journal of Experimental Medicine. - New York, USA : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 203:10, s. 2315-2327
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Tidskriftsartikel (refereegranskat)abstract
- Cellular cardiomyoplasty is an attractive option for the treatment of severe heart failure. It is, however, still unclear and controversial which is the most promising cell source. Therefore, we investigated and examined the fate and functional impact of bone marrow (BM) cells and embryonic stem cell (ES cell)-derived cardiomyocytes after transplantation into the infarcted mouse heart. This proved particularly challenging for the ES cells, as their enrichment into cardiomyocytes and their long-term engraftment and tumorigenicity are still poorly understood. We generated transgenic ES cells expressing puromycin resistance and enhanced green fluorescent protein cassettes under control of a cardiac-specific promoter. Puromycin selection resulted in a highly purified (>99%) cardiomyocyte population, and the yield of cardiomyocytes increased 6-10-fold because of induction of proliferation on purification. Long-term engraftment (4-5 months) was observed when co-transplanting selected ES cell-derived cardiomyocytes and fibroblasts into the injured heart of syngeneic mice, and no teratoma formation was found (n = 60). Although transplantation of ES cell-derived cardiomyocytes improved heart function, BM cells had no positive effects. Furthermore, no contribution of BM cells to cardiac, endothelial, or smooth muscle neogenesis was detected. Hence, our results demonstrate that ES-based cell therapy is a promising approach for the treatment of impaired myocardial function and provides better results than BM-derived cells.
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| 10. |
- Nygren, Jens Martin, 1976-, et al.
(författare)
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Myeloid and lymphoid contribution to non-haematopoietic lineages through irradiation-induced heterotypic cell fusion
- 2008
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Ingår i: Nature Cell Biology. - London : Nature Publishing Group. - 1465-7392 .- 1476-4679. ; 10:5, s. 584-92
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have suggested that regeneration of non-haematopoietic cell lineages can occur through heterotypic cell fusion with haematopoietic cells of the myeloid lineage. Here we show that lymphocytes also form heterotypic-fusion hybrids with cardiomyocytes, skeletal muscle, hepatocytes and Purkinje neurons. However, through lineage fate-mapping we demonstrate that such in vivo fusion of lymphoid and myeloid blood cells does not occur to an appreciable extent in steady-state adult tissues or during normal development. Rather, fusion of blood cells with different non-haematopoietic cell types is induced by organ-specific injuries or whole-body irradiation, which has been used in previous studies to condition recipients of bone marrow transplants. Our findings demonstrate that blood cells of the lymphoid and myeloid lineages contribute to various non-haematopoietic tissues by forming rare fusion hybrids, but almost exclusively in response to injuries or inflammation.
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