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1.
  • Alim, Abdul, 1983-, et al. (författare)
  • Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells
  • 2021
  • Ingår i: Cellular & Molecular Immunology. - : Springer Nature. - 1672-7681 .- 2042-0226. ; 18:10, s. 2383-2392
  • Tidskriftsartikel (refereegranskat)abstract
    • Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system. However, it is not clear the mechanism by which mast cells communicate with peripheral nerves. We previously found that mast cells located within healing tendons can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling. To evaluate this hypothesis, we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type (NMDAR1, NMDAR2A, and NMDAR2B) and the metabotropic type (mGluR2 and mGluR7) at both the mRNA and protein levels. The binding of glutamate to glutamate receptors on the mast cell surface was confirmed. Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2. Glutamate also induced the upregulation of transcription factors, including Egr2, Egr3 and, in particular, FosB. The extensive induction of FosB was confirmed by immunofluorescence assessment. Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate, supporting the supposition of a functional glutamate-glutamate receptor axis in mast cells. Finally, we provide in vivo evidence supporting a functional glutamate-glutamate receptor axis in the mast cells of injured tendons. Together, these findings establish glutamate as an effector of mast cell function, thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.
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2.
  • Alim, Md Abdul, et al. (författare)
  • Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture
  • 2017
  • Ingår i: Cell and Tissue Research. - Berlin Heidelberg : Springer Science and Business Media LLC. - 0302-766X .- 1432-0878. ; 370:3, s. 451-460
  • Tidskriftsartikel (refereegranskat)abstract
    • The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.
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4.
  • Andersson, Therese, et al. (författare)
  • Achilles tendon healing in rats is improved by intermittent mechanical loading during the inflammatory phase
  • 2012
  • Ingår i: Journal of Orthopaedic Research. - : Wiley Online Library. - 0736-0266 .- 1554-527X. ; 30:2, s. 274-279
  • Tidskriftsartikel (refereegranskat)abstract
    • Tendons adapt to changes in mechanical loading, and numerous animal studiesshow that immobilization of a healing tendon is detrimental to the healingprocess. The present study addresses whether the effects of a few episodes ofmechanical loading are different during different phases of healing. Fifty femalerats underwent Achilles tendon transection, and their hind limbs were unloadedby tail suspension on the day after surgery. One group of 10 rats was taken downfrom suspension to walk on a treadmill for 30 minutes per day, on days 2-5 aftertransection. They were euthanized on day 8. Another group underwent similartreadmill running on days 8-11 and was euthanized on day 14. Completelyunloaded groups were euthanized on day 8 and 14. Tendon specimens were thenevaluated mechanically. The results showed that just 4 loading episodesincreased the strength of the healing tendon. This was evident irrespective of thetime-point when loading was applied (early or late). The positive effect on earlyhealing was unexpected, considering that the mechanical stimulation was appliedduring the inflammatory phase, when the calluses were small and fragile. Ahistological study of additional groups with early loading also showed someincreased bleeding in the loaded calluses. Our results indicate that a smallamount of early loading may improve the outcome of tendon healing. This couldbe of interest to clinical practice.
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5.
  • Andersson, Therese, et al. (författare)
  • Growth hormone does not stimulate early healing in rat tendons
  • 2012
  • Ingår i: International Journal of Sports Medicine. - Stuttgart : Georg Thieme Verlag KG. - 0172-4622 .- 1439-3964. ; 33:3, s. 240-243
  • Tidskriftsartikel (refereegranskat)abstract
    • Growth Hormone stimulates bone growth and fracture repair. It acts mainly by increasing the systemic levels of IGF-1. Local treatment with IGF-1 appears to stimulate tendon healing. We therefore hypothesized that systemic treatment with Growth Hormone would also stimulate tendon healing. Rat Achilles tendons were transected and left to heal. 4 groups were studied. Intramuscular injections of botulinum toxin A (Botox) were used to reduce loading in 2 groups. The animals were randomized to twice daily injections of Growth Hormone (n=2×10) or saline (n=2×10), and killed after 10 days. Healing was assessed by mechanical testing. Muscle paralysis induced by Botox reduced the strength of the healing tendon by two thirds. Growth Hormone increased femoral and tibial length in the unloaded, and femoral and tibial weight in the loaded group. Body weight and muscle weight were increased in both. In contrast, there was no increase in the strength of the healing tendons, regardless of mechanical loading status. An increase in peak force of the loaded healing tendons by more than 5% could be excluded with 95% confidence. In spite of its stimulatory effects on other tissues, Growth Hormone did not appear to stimulate tendon or tendon repair.
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6.
  • Andersson, Therese, et al. (författare)
  • Low-level mechanical stimulation is sufficient to improve tendon healing in rats
  • 2012
  • Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 113:9, s. 1398-1402
  • Tidskriftsartikel (refereegranskat)abstract
    • Treatment of tendon injuries often involves immobilization. However, immobilization might not prevent mild involuntary isometric muscle contraction. The effect of weak forces on tendon healing is therefore of clinical interest. Studies of tendon healing with various methods for load reduction in rat Achilles tendon models show a consistent reduction in tendon strength by at least half, compared with voluntary cage activity. Unloading was not complete in any of these models, and the healing tendon was therefore still exposed to mild mechanical stimulation. By reducing the forces acting on the tendon even further, we now studied the effects of this mild stimulation. Rat Achilles tendons were transected and allowed to heal spontaneously under four different loading conditions: 1) normal cage activity; 2) calf muscle paralysis induced by botulinum toxin A (Botox); 3) tail suspension; 4) Botox and tail suspension, combined, to eliminate even mild stimulation. Healing was evaluated by mechanical testing after 8 days. Botox alone and suspension alone both reduced tendon callus size (transverse area), thereby impairing its strength compared with normal cage activity. The combination of Botox and suspension did not further reduce tendon callus size but drastically impaired the material properties of the tendon callus compared with each treatment alone. The peak force was only a fifth of that in the normal cage activity group. The results indicate that also the mild loading that occurs with either Botox or suspension alone stimulates tendon healing. This stimulation appears to affect mainly tissue quality, whereas stronger stimulation also increases callus size.
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7.
  • Andersson, Therese, et al. (författare)
  • Tissue memory in healing tendons : short loading episodes stimulate healing
  • 2009
  • Ingår i: JOURNAL OF APPLIED PHYSIOLOGY. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 107:2, s. 417-421
  • Tidskriftsartikel (refereegranskat)abstract
    • Intact tendons adapt slowly to changes in mechanical loading, whereas in healing tendons the effect of mechanical loading or its absence is dramatic. The longevity of the response to a single loading episode is, however, unknown. We hypothesized that the tissue has a "memory" of loading episodes and that therefore short loadings are sufficient to elicit improved healing. The Achilles tendon of 70 female rats was transected and unloaded by tail suspension for 12 days (suspension started on day 2 after surgery). Each day, the rats were let down from suspension for short daily training episodes according to different regimes: 15 min of cage activity or treadmill running for 15, 30, 60, or 2 x 15 min. Rats with transected Achilles tendons and full-time cage activity served as controls. The results demonstrated that full-time cage activity increased the peak force over three times compared with unloading. Short daily loading episodes (treadmill running) increased the peak force about half as much as full-time activity. Prolongation of treadmill running above 15 min or dividing the daily training in two separate episodes had minimal further effect. This mechanical stimulation increased the cross-sectional area but had no effect on the mechanical properties of the repair tissue. The findings indicate that once the tissue had received information from a certain loading type and level, this is "memorized" and leads to a response lasting many hours. This suggests that patients might be allowed early short loading episodes following, e. g., an Achilles tendon rupture for a better outcome.
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8.
  • Bajuri, M. N., et al. (författare)
  • A hyperelastic fibre-reinforced continuum model of healing tendons with distributed collagen fibre orientations
  • 2016
  • Ingår i: Biomechanics and Modeling in Mechanobiology. - : SPRINGER HEIDELBERG. - 1617-7959 .- 1617-7940. ; 15:6, s. 1457-1466
  • Tidskriftsartikel (refereegranskat)abstract
    • The healing process of ruptured tendons is problematic due to scar tissue formation and deteriorated material properties, and in some cases, it may take nearly a year to complete. Mechanical loading has been shown to positively influence tendon healing; however, the mechanisms remain unclear. Computational mechanobiology methods employed extensively to model bone healing have achieved high fidelity. This study aimed to investigate whether an established hyperelastic fibre-reinforced continuum model introduced by Gasser, Ogden and Holzapfel (GOH) can be used to capture the mechanical behaviour of the Achilles tendon under loading during discrete timepoints of the healing process and to assess the models sensitivity to its microstructural parameters. Curve fitting of the GOH model against experimental tensile testing data of rat Achilles tendons at four timepoints during the tendon repair was used and achieved excellent fits (0.9903 amp;lt; R-2 amp;lt; 0.9986). A parametric sensitivity study using a three-level central composite design, which is a fractional factorial design method, showed that the collagen-fibre-related parameters in the GOH model-kappa, k(1) and k(2)-had almost equal influence on the fitting. This study demonstrates that the GOH hyperelastic fibre-reinforced model is capable of describing the mechanical behaviour of healing tendons and that further experiments should focus on establishing the structural and material parameters of collagen fibres in the healing tissue.
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9.
  • Bernhardsson, Magnus, 1989-, et al. (författare)
  • Depletion of cytotoxic (CD8+) T cells impairs implant fixation in rat cancellous bone
  • 2019
  • Ingår i: Journal of Orthopaedic Research. - : John Wiley & Sons. - 0736-0266 .- 1554-527X. ; 37:4, s. 805-811
  • Tidskriftsartikel (refereegranskat)abstract
    • As cytotoxic (CD8(+)) T cells seem to impair shaft fracture healing, we hypothesized that depletion of CD8(+) cells would instead improve healing of cancellous bone. Additionally, we also tested if CD8-depletion would influence the healing of ruptured Achilles tendons. Rats received a single injection of either anti-CD8 antibodies or saline and put through surgery 24 h later. Three different surgical interventions were performed as follows: (1) a drill hole in the proximal tibia with microCT (BV/TV) to assess bone formation; (2) a screw in the proximal tibia with mechanical evaluation (pull-out force) to assess fracture healing; (3) Achilles tendon transection with mechanical evaluation (force-at-failure) to assess tendon healing. Furthermore, CD8-depletion was confirmed with flow cytometry on peripheral blood. Flow cytometric analysis confirmed depletion of CD8(+) cells (p amp;lt; 0.001). Contrary to our hypothesis, depletion of CD8(+) cells reduced the implant pull-out force by 19% (p amp;lt; 0.05) and stiffness by 34% (p amp;lt; 0.01), although the bone formation in the drill holes was the same as in the controls. Tendon healing was unaffected by CD8-depletion. Our results suggest that CD8(+) cells have an important part in cancellous bone healing.
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10.
  • Björnsson Hallgren, Hanna Cecilia, 1976-, et al. (författare)
  • Elevated plasma levels of TIMP-1 in patients with rotator cuff tear
  • 2012
  • Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 1745-3682. ; 83:5, s. 523-528
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose:Extracellular matrix remodelling is altered in rotator cuff tears,16partly due to altered expression of matrix metalloproteinases (MMPs) and their inhibitors. It is unclear if this altered expression can be traced as changes in plasma protein levels.The purposes were to measure the plasma level of MMPs and their tissue inhibitors (TIMPs) inpatients with rotator cuff tears and to relate changes in the pattern of MMP and TIMP levels with the extent of the rotator cuff tear.Methods: Blood samples were collected from 17 patients, median 61 (range 39-77) years, with sonographically verified rotator cuff tears (partial- or full-thickness). These were compared with 16 gender and age matched control persons with sonographically intact rotator cuffs. Plasma levels of MMPs and TIMPs were measured simultaneously using Luminex technology and ELISA.Results: The plasma level of TIMP-1 was elevated in patients with rotator cuff tears, especially in those with full-thickness tears. The levels of TIMP-1, TIMP-3 and MMP-9 were higher in patients with full-thickness tears compared to those with partial-thickness tears, but only TIMP-1 was different from controls.Interpretation: The observed elevation of TIMP-1 in plasma might reflect local pathological processes in or around the rotator cuff, or a genetic predisposition in these patients. That levels of TIMP-1 and certain MMP´s was found to differ between partial and full thickness tears may reflect the extent of the lesion or different aetiology and pathomechanisms.
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11.
  • Broström, Anna, et al. (författare)
  • Mellan åkern och havet
  • 2008
  • Ingår i: Inne och ute i Malmö : studier av urbana förändringsprocesser. - 1654-6881. - 9789197723329 ; 2, s. 121-137
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)
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12.
  • Dietrich, Franciele, et al. (författare)
  • Dexamethasone Enhances Achilles Tendon Healing in an Animal Injury Model, and the Effects Are Dependent on Dose, Administration Time, and Mechanical Loading Stimulation
  • 2022
  • Ingår i: American Journal of Sports Medicine. - : Sage Publications Inc. - 0363-5465 .- 1552-3365. ; 50:5, s. 1306-1316
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Corticosteroid treatments such as dexamethasone are commonly used to treat tendinopathy but with mixed outcomes. Although this treatment can cause tendon rupture, it can also stimulate the tendon to heal. However, the mechanisms behind corticosteroid treatment during tendon healing are yet to be understood. Purpose: To comprehend when and how dexamethasone treatment can ameliorate injured tendons by using a rat model of Achilles tendon healing. Study Design: Controlled laboratory study. Methods: An overall 320 rats were used for a sequence of 6 experiments. We investigated whether the drug effect was time-, dose-, and load-dependent. Additionally, morphological data and drug administration routes were examined. Healing tendons were tested mechanically or used for histological examination 12 days after transection. Blood was collected for flow cytometry analysis in 1 experiment. Results: We found that the circadian rhythm and drug injection timing influenced the treatment outcome. Dexamethasone treatment at the right time point (days 7-11) and dose (0.1 mg/kg) significantly improved the material properties of the healing tendon, while the adverse effects were reduced. Local dexamethasone treatment did not lead to increased peak stress, but it triggered systemic granulocytosis and lymphopenia. Mechanical loading (full or moderate) is essential for the positive effects of dexamethasone, as complete unloading leads to the absence of improvements. Conclusion: We conclude that dexamethasone treatment to improve Achilles tendon healing is dose- and time-dependent, and positive effects are perceived even in a partly unloaded condition.
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13.
  • Dietrich, Franciele, et al. (författare)
  • Effect of storage and preconditioning of healing rat Achilles tendon on structural and mechanical properties
  • 2021
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Tendon tissue storage and preconditioning are often used in biomechanical experiments and whether this generates alterations in tissue properties is essential to know. The effect of storage and preconditioning on dense connective tissues, like tendons, is fairly understood. However, healing tendons are unlike and contain a loose connective tissue. Therefore, we investigated if storage of healing tendons in the fridge or freezer changed the mechanical properties compared to fresh tendons, using a pull-to-failure or a creep test. Tissue morphology and cell viability were also evaluated. Additionally, two preconditioning levels were tested. Rats underwent Achilles tendon transection and were euthanized 12 days postoperatively. Statistical analyzes were done with one-way ANOVA or Student’s t-test. Tissue force and stress were unaltered by storage and preconditioning compared to fresh samples, while high preconditioning increased the stiffness and modulus (p ≤ 0.007). Furthermore, both storage conditions did not modify the viscoelastic properties of the healing tendon, but altered transverse area, gap length, and water content. Cell viability was reduced after freezing. In conclusion, preconditioning on healing tissues can introduce mechanical data bias when having extensive tissue strength diversity. Storage can be used before biomechanical testing if structural properties are measured on the day of testing.
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14.
  • Dietrich, Franciele, et al. (författare)
  • Response to mechanical loading in rat Achilles tendon healing is influenced by the microbiome
  • 2020
  • Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 15:3
  • Tidskriftsartikel (refereegranskat)abstract
    • We have previously shown that changes in the microbiome influence how the healing tendon responds to different treatments. The aim of this study was to investigate if changes in the microbiome influence the response to mechanical loading during tendon healing. 90 Sprague-Dawley rats were used. Specific Opportunist and Pathogen Free (SOPF) rats were co-housed with Specific Pathogen Free (SPF) rats, carrying Staphylococcus aureus and other opportunistic microbes. After 6 weeks of co-housing, the SOPF rats were contaminated which was confirmed by Staphylococcus aureus growth. Clean SOPF rats were used as controls. The rats were randomized to full loading or partial unloading by Botox injections in their calf muscles followed by complete Achilles tendon transection. Eight days later, the healing tendons were tested mechanically. The results were analysed by a 2-way ANOVA with interaction between loading and contamination on peak force as the primary outcome and there was an interaction for both peak force (p = 0.049) and stiffness (p = 0.033). Furthermore, partial unloading had a profound effect on most outcome variables. In conclusion, the response to mechanical loading during tendon healing is influenced by changes in the microbiome. Studies aiming for clinical relevance should therefore consider the microbiome of laboratory animals.
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15.
  • Dietrich-Zagonel, Franciele, et al. (författare)
  • Stimulation of Tendon Healing With Delayed Dexamethasone Treatment Is Modified by the Microbiome
  • 2018
  • Ingår i: American Journal of Sports Medicine. - : Sage Publications. - 0363-5465 .- 1552-3365. ; 46:13, s. 3281-3287
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:The immune system reflects the microbiome (microbiota). Modulation of the immune system during early tendon remodeling by dexamethasone treatment can improve rat Achilles tendon healing. The authors tested whether changes in the microbiota could influence the effect of dexamethasone treatment.Hypothesis:A change in microbiome would influence the response to dexamethasone on regenerate remodeling, specifically tendon material properties (peak stress).Study Design:Controlled laboratory study.Methods:Specific opportunist and pathogen-free female rats were housed separately (n = 41) or together with specific pathogen-free rats carrying opportunistic microbes such as Staphylococcus aureus (n = 41). After 6 weeks, all co-housed rats appeared healthy but now carried S aureus. Changes in the gut bacterial flora were tested by API and RapID biochemical tests. All rats (clean and contaminated) underwent Achilles tendon transection under aseptic conditions. Flow cytometry was performed 8 days postoperatively on tendon tissue. Sixty rats received subcutaneous dexamethasone or saline injections on days 5 through 9 after transection. The tendons were tested mechanically on day 12. The predetermined primary outcome was the interaction between contamination and dexamethasone regarding peak stress, tested by 2-way analysis of variance.Results:Dexamethasone increased peak stress in all groups but more in contaminated rats (105%) than in clean rats (53%) (interaction, P = .018). A similar interaction was found for an estimate of elastic modulus (P = .021). Furthermore, dexamethasone treatment reduced transverse area but had small effects on peak force and stiffness. In rats treated with saline only, contamination reduced peak stress by 16% (P = .04) and elastic modulus by 35% (P = .004). Contamination led to changes in the gut bacterial flora and higher levels of T cells (CD3+CD4+) in the healing tendon (P < .05).Conclusion:Changes in the microbiome influence tendon healing and enhance the positive effects of dexamethasone treatment during the early remodeling phase of tendon healing.Clinical Relevance:The positive effect of dexamethasone on early tendon remodeling in rats is strikingly strong. If similar effects could be shown in humans, immune modulation by a few days of systemic corticosteroids, or more specific compounds, could open new approaches to rehabilitation after tendon injury.
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16.
  • Eliasson, Pernilla, et al. (författare)
  • Hypoxia Expands Primitive Hematopoietic Progenitor Cells from Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability
  • 2006
  • Ingår i: Journal of Stem Cells. - : Nova Science Publishers, Inc.. - 1556-8539. ; 1:4, s. 247-257
  • Tidskriftsartikel (refereegranskat)abstract
    • Self-renewal is a prerequisite for the maintenance of hematopoietic stem cells (HSCs) in the bone marrow throughout adult life. Cytokines are mainly providing pro-survival signals of HSC, whereas low oxygen levels (hypoxia) were recently shown to influence self-renewal. In contrast, the effects on other progenitor cell types is not clear. In the present work, we have analyzed whether hypoxia has any effects on mouse multipotent progenitors. When bone marrow-derived Lin-Sca1+c-kit+ (LSK) cells were kept in hypoxic cultures (1% O2 ) for 4 days together with cytokines, the numbers of colony forming high-proliferative progenitors (HPP-CFC) and precursors for cobble-stone forming cells (CAFC) were increased compared to normoxic conditions. A similar effect was seen with pre-CFCmulti from unfractionated bone marrow, whereas more committed progenitors (CFU-GM) were expanded better in normoxia compared to hypoxia. The observed increase in numbers of primitive colony-forming progenitor cells was associated with maintenance of the c-kit/Sca-1 phenotype and a preferential expansion of immature  blast-like appearing cells. The results suggest that a major function of hypoxia is to regulate differentiation by increased self-renewal. Furthermore, in cultures of limited cytokine supply, survival of the stem cell-like cell line FDCP-mix was increased during hypoxia. Thus, hypoxia allows for better survival and self-renewal of multipotent progenitors and HSCs from adult bone marrow. Such culture conditions may have beneficial clinical implications for ex vivo purposes and may improve the yields of stem cells and early progenitors.
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17.
  • Eliasson, Pernilla, et al. (författare)
  • Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture
  • 2010
  • Ingår i: Experimental Hematology. - : Elsevier. - 0301-472X .- 1873-2399. ; 38:4, s. 301-310
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. Recent evidence suggests that hematopoietic stem cells (HSCs) in the bone marrow (BM) are located in areas where the environment is hypoxic. Although previous studies have demonstrated positive effects by hypoxia, its role in HSC maintenance has not been fully elucidated, neither has the molecular mechanisms been delineated. Here, we have investigated the consequence of in vitro incubation of HSCs in hypoxia prior to transplantation and analyzed the role of hypoxia-inducible factor (HIF)-1 alpha. Materials and Methods. HSC and progenitor populations isolated from mouse BM were cultured in 20% or 1% O-2, and analyzed for effects on cell cycle, expression of cyclin-dependent kinase inhibitors genes, and reconstituting ability to lethally irradiated mice. The involvement of HIF-1 alpha was studied using methods of protein stabilization and gene silencing. Results. When long-term FLT3(-)CD34(-)Lin(-)Sca-1(+)c-Kit(+) (LSK) cells were cultured in hypoxia, cell numbers were significantly reduced in comparison to normoxia. This was due to a decrease in proliferation and more cells accumulating in G(0). Moreover, the proportion of HSCs with long-term engraftment potential was increased. Whereas expression of the cyclin-dependent kinase inhibitor genes p21(cip1), p27(Kip1), and p57(Kip2) increased in LSK cells by hypoxia, only p21(cip1) was upregulated in FLT3(-)CD34(-)LSK cells. We could demonstrate that expression of p27(KiP1) and p57(Kip2) was dependent of HIF-1 alpha. Surprisingly, overexpression of constitutively active HIF-1 alpha or treatment with the HIF stabilizer agent FG-4497 led to a reduction in HSC reconstituting ability. Conclusions. Our results imply that hypoxia, in part via HIF-1 alpha, maintains HSCs by decreasing proliferation and favoring quiescence.
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18.
  • Eliasson, Pernilla, 1979-, et al. (författare)
  • Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation ability
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • A balanced regulation of the ability of hematopoietic stem cells (HSCs) to undergo self-renewal and give rise to new blood cells is crucial for blood homeostasis. Recent studies utilizing genetically modified mice have demonstrated that reactive oxygen species (ROS) damage cellular functions and decrease the lifespan of long-term (LT) HSCs. These LT-HSCs are predominately located in a low-oxygen, or hypoxic, niche, essential for maintaining stem cell capacities. Here, we show that hypoxic culturing rescues HSCs from oxidative stress-induced cell death. Hypoxia inducible factor (HIF)-1 and its target gene pyruvate dehydrogenase kinase 1 (PDK1) were both crucial for survival and long term repopulating ability of HSCs, but less important for hypoxic resistance towards oxidative stress. Moreover, hypoxia increased the expression of Foxo3a, a transcription factor important in adaption to stress stimuli. In conclusion, hypoxia protects LT-HSCs from oxidative stress, possibly by multiple mechanisms, where Foxo3a is likely to play a central role.
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19.
  • Eliasson, Pernilla, et al. (författare)
  • Influence of a single loading episode on gene expression in healing rat Achilles tendons
  • 2012
  • Ingår i: Journal of applied physiology. - : AMER PHYSIOLOGICAL SOC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA. - 8750-7587 .- 1522-1601. ; 112:2, s. 279-288
  • Tidskriftsartikel (refereegranskat)abstract
    • Mechanical loading stimulates tendon healing via mechanisms that are largely unknown. Genes will be differently regulated in loaded healing tendons, compared to unloaded, just because of the fact that healing processes have been changed. In order to avoid such secondary effects and study the effect of loading per se, we therefore studied the gene expression response shortly after a single loading episode in otherwise unloaded healing tendons. The Achilles tendon was transected in 30 tail suspended rats. The animals were let down from the suspension to load their tendons on a treadmill for 30 min once, 5 days after tendon transection. Gene expression was studied by Affymetrix microarray before, and 3, 12, 24 and 48 h after loading. The strongest response in gene expression was seen 3 hours after loading, when 150 genes were up- or down-regulated (fold change≥ 2, p≤0.05). 12 hours after loading, only 3 genes were up-regulated, while 38 were down-regulated. Less than 7 genes were regulated after 24 and 48 hours. Genes involved in the inflammatory response were strongly regulated at 3 and 12 hours after loading; this included up-regulation of iNOS, PGE synthase, and IL-1β. Also genes involved in wound healing/coagulation, angiogenesis and production of reactive oxygen species were strongly regulated by loading. Microarray results were confirmed for 14 selected genes in a repeat experiment (N=30 rats) using real-time PCR. It was also confirmed that a single loading episode on day 5 increased the strength of the healing tendon on day 12. The fact that there were hardly any regulated genes 24 h after loading suggests that optimal stimulation of healing requires a mechanical loading stimulus every day.
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20.
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21.
  • Eliasson, Pernilla, 1979- (författare)
  • Live and Let Die : Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The hematopoietic stem cell (HSC) is characterized by its ability to self-renew and produce all mature blood cells throughout the life of an organism. This is tightly regulated to maintain a balance between survival, proliferation, and differentiation. The HSCs are located in specialized niches in the bone marrow thought to be low in oxygen, which is suggested to be involved in the regulation of HSC maintenance, proliferation, and migration. However, the importance of hypoxia in the stem cell niche and the molecular mechanisms involved remain fairly undefined. Another important regulator of human HSCs maintenance is the tyrosine kinase receptor FLT3, which triggers survival of HSCs and progenitor cells. Mutations in FLT3 cause constitutively active signaling. This leads to uncontrolled survival and proliferation, which can result in development of acute myeloid leukemia (AML). One of the purposes with this thesis is to investigate how survival, proliferation and self-renewal in normal HSCs are affected by hypoxia. To study this, we used both in vitro and in vivo models with isolated Lineage-Sca-1+Kit+ (LSK) and CD34-Flt3-LSK cells from mouse bone marrow. We found that hypoxia maintained an immature phenotype. In addition, hypoxia decreased proliferation and induced cell cycle arrest, which is the signature of HSCs with long term multipotential capacity. A dormant state of HSCs is suggested to be critical for protecting and preventing depletion of the stem cell pool. Furthermore, we observed that hypoxia rescues HSCs from oxidative stress-induced cell death, implicating that hypoxia is important in the bone marrow niche to limit reactive oxidative species (ROS) production and give life-long protection of HSCs. Another focus in this thesis is to investigate downstream pathways involved in tyrosine kinase inhibitor-induced cell death of primary AML cells and cell lines expressing mutated FLT3. Our results demonstrate an important role of the PI3K/AKT pathway to mediate survival signals from FLT3. We found FoxO3a and its target gene Bim to be key players of apoptosis in cells carrying oncogenic FLT3 after treatment with tyrosine kinase inhibitors. In conclusion, this thesis highlights hypoxic-mediated regulation of normal HSCs maintenance and critical effectors of apoptosis in leukemic cells expressing mutated FLT3.
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22.
  • Eliasson, Pernilla, et al. (författare)
  • Mechanical load and BMP signaling during tendon repair : A role for follistatin?
  • 2008
  • Ingår i: Clinical Orthopaedics and Related Research. - : Ovid Technologies (Wolters Kluwer Health). - 0009-921X .- 1528-1132. ; 466:7, s. 1592-1597
  • Tidskriftsartikel (refereegranskat)abstract
    • Healing of the rat Achilles tendon is sensitive to mechanical loading, and the callus strength is reduced by 3/4 after 14 days, if loading is prevented. Exogenous GDFs stimulate tendon healing. This response is influenced by loading: without loading, cartilage and bone formation is initiated. This implies BMP signaling is crucial during tendon healing and influenced by mechanical loading. We therefore asked if mechanical loading influences the gene expression of the BMP signaling system in intact and healing tendons, and how the BMP signaling system changes during healing. The genes were four BMPs (OP-1/BMP-7, GDF-5/CDMP-1/BMP-14, GDF-6/CDMP2/BMP-13, and GDF-7/CDMP-3/BMP-12), two receptors (BMPR1b and BMPR2), and the antagonists follistatin and noggin. The Achilles tendon was transected in rats and left to heal. Half of the rats had one Achilles tendon unloaded by injection of Botox in the calf muscles. Ten tendons were analyzed before transection and for each of four time points. All genes except noggin were expressed at all points, but followed different patterns during healing. Loading strongly decreased the expression of follistatin, which could lead to increased signaling. The BMP system appears involved in tendon maintenance and healing, and may respond to mechanical loading.
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23.
  • Eliasson, Pernilla, et al. (författare)
  • Myostatin in tendon maintenance and repair
  • 2009
  • Ingår i: Growth Factors. - : Informa UK Limited. - 0897-7194 .- 1029-2292. ; 27:4, s. 247-254
  • Tidskriftsartikel (refereegranskat)abstract
    • Myostatin, a negative regulator of muscle growth, has recently been found to be expressed in tendons. Myostatin-deficient mice have weak and brittle tendons, which suggest that myostatin could be important for tendon maintenance. Follistatin expression in the callus tissue after tendon transection is influenced by loading. We found that follistatin antagonises myostatin, but not GDF-5 or OP-1 in vitro. To study if myostatin might play a physiological role in soft tissue, we transected 64 rat Achilles tendons and studied the gene expression for myostatin and its receptors at four different time-points during healing. Intact tendons were also studied. All samples were studied with or without mechanical loading. Unloading was achieved with botulinum toxin injections in the calf muscles. The expression of the myostatin gene was more than 40 times higher in intact tendons than in the callus tissue during tendon healing. The expression of myostatin was also influenced by loading status in both intact and healing tendons. Thereafter, we measured the mechanical properties of healing tendons after local myostatin administration. This treatment increased the volume and the contraction of the callus after 8 days, but did not improve its strength. Our results indicate that myostatin plays a positive role in tendon maintenance and that exogenous protein administration stimulates proliferation and growth of early repair tissue. However, no effect on further development towards connective tissue formation was found.
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24.
  • Eliasson, Pernilla, et al. (författare)
  • Primary gene response to mechanical loading in healing rat Achilles tendons
  • 2013
  • Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 114:11, s. 1519-1526
  • Tidskriftsartikel (refereegranskat)abstract
    • Loading can stimulate tendon healing. In healing rat Achilles tendons, we have found more than 150 genes upregulated or downregulated 3 h after one loading episode. We hypothesized that these changes were preceded by a smaller number of regulatory genes and thus performed a microarray 15 min after a short loading episode, to capture the primary response to loading. We transected the Achilles tendon of 54 rats and allowed them to heal. The hind limbs were unloaded by tail-suspension during the entire experiment, except during the loading episode. The healing tendon tissue was analyzed by mechanical testing, microarray, and quantitative real-time polymerase chain reaction (qRT-PCR). Mechanical testing showed that 5 min of loading each day for 4 days created stronger tissue. The microarray analysis after one loading episode identified 15 regulated genes. Ten genes were analyzed in a repeat experiment with new rats using qRT-PCR. This confirmed the increased expression of four genes: early growth response 2 (Egr2), c-Fos, FosB, and regulation of G protein signaling 1 (Rgs1). The other genes were unaltered. We also analyzed the expression of early growth response 1 (Egr1), which is often coregulated with c-Fos or Egr2, and found that this was also increased after loading. Egr1, Egr2, c-Fos, and FosB are transcription factors that can be triggered by numerous stimuli. However, Egr1 and Egr2 are necessary for normal tendon development, and can induce ectopic expression of tendon markers. The five regulated genes appear to constitute a general activation machinery. The further development of gene regulation might depend on the tissue context.
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25.
  • Eliasson, Pernilla, et al. (författare)
  • Rat Achilles tendon healing : mechanical loading and gene expression
  • 2009
  • Ingår i: JOURNAL OF APPLIED PHYSIOLOGY. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 107:2, s. 399-407
  • Tidskriftsartikel (refereegranskat)abstract
    • Injured tendons require mechanical tension for optimal healing, but it is unclear which genes are upregulated and responsible for this effect. We unloaded one Achilles tendon in rats by Botox injections in the calf muscles. The tendon was then transected and left to heal. We studied mechanical properties of the tendon calluses, as well as mRNA expression, and compared them with loaded controls. Tendon calluses were studied 3, 8, 14, and 21 days after transection. Intact tendons were studied similarly for comparison. Altogether 110 rats were used. The genes were chosen for proteins marking inflammation, growth, extracellular matrix, and tendon specificity. In intact tendons, procollagen III and tenascin-C were more expressed in loaded than unloaded tendons, but none of the other genes was affected. In healing tendons, loading status had small effects on the selected genes. However, TNF-alpha transforming growth factor-beta 1, and procollagens I and III were less expressed in loaded callus tissue at day 3. At day 8 procollagens I and III, lysyl oxidase, and scleraxis had a lower expression in loaded calluses. However, by days 14 and 21, procollagen I, cartilage oligomeric matrix protein, tenascin-C, tenomodulin, and scleraxis were all more expressed in loaded calluses. In healing tendons, the transverse area was larger in loaded samples, but material properties were unaffected, or even impaired. Thus mechanical loading is important for growth of the callus but not its mechanical quality. The main effect of loading during healing might thereby be sought among growth stimulators. In the late phase of healing, tendon-specific genes (scleraxis and tenomodulin) were upregulated with loading, and the healing tissue might to some extent represent a regenerate rather than a scar.
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26.
  • Eliasson, Pernilla (författare)
  • Response to mechanical loading in healing tendons
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Ruptured tendons heal faster if they are exposed to mechanical loading. Loading creates deformation of the extracellular matrix and cells, which give rise to intracellular signalling, increased gene expression and protein synthesis. The effects of loading have been extensively studied in vitro, and in intact tendons in vivo. However, the response to loading in healing tendons is less known.The general aim of this thesis was to understand more about the response to mechanical loading during tendon healing. The specific aims were to find out how short daily loading episodes could influence tendon healing, and to understand more about genes involved in tendon healing.The studies were performed using rat models. Unloading of healing tendons resulted in a weaker callus tissue. This could be reversed to some extent by short daily loading episodes. Loading induced more matrix production, making the tendons thicker and stronger, but there was no improvement in the material properties of the matrix. Lengthening is one potential adversity with early loading, during tendon healing in patients. This was also seen with continuous loading in the rat models. However, short loading episodes did not result in any lengthening, not even when loading was applied during the inflammatory phase of healing. It also appeared as loading once daily was enough to make healing tendons stronger, while loading twice daily with 8 hours interval did not give any additional effect. The strongest gene expression response to one loading episode was seen after 3 hours. The gene expression changes persisted 12 hours after the loading episode but had disappeared by 24 hours. Loading appeared to regulate genes involved in inflammation, wound healing and coagulation, angiogenesis, and production of reactive oxygen species. Inflammation-associated genes were regulated both by continuous loading and by one short loading episode. Inflammation is an important part of the healing response, but too much can be harmful. Loading might therefore have a role in fine-tuning the inflammatory response during healing.In conclusion, these studies show that short daily loading episodes during early tendon healing could potentially be beneficial for rehabilitation. Loading might have a role in regulating the inflammatory response during healing.
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27.
  • Eliasson, Pernilla, 1982-, et al. (författare)
  • Simvastatin and atorvastatin reduce the mechanical properties of tendon constructs in vitro and introduce catabolic changes in the gene expression pattern
  • 2017
  • Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Treatment with lipid-lowering drugs, statins, is common all over the world. Lately, the occurrence of spontaneous tendon ruptures or tendinosis have suggested a negative influence of statins upon tendon tissue. But how statins might influence tendons is not clear. In the present study, we investigated the effect of statin treatment on mechanical strength, cell proliferation, collagen content and gene expression pattern in a tendon-like tissue made from human tenocytes in vitro. Human tendon fibroblasts were grown in a 3D tissue culture model (tendon constructs), and treated with either simvastatin or atorvastatin, low or high dose, respectively, for up to seven days. After seven days of treatment, mechanical testing of the constructs was performed. Collagen content and cell proliferation were also determined. mRNA levels of several target genes were measured after one or seven days. The maximum force and stiffness were reduced by both statins after 7 days (pamp;lt;0.05), while the cross sectional area was unaffected. Further, the collagen content was reduced by atorvastatin (p = 0.01) and the cell proliferation rate was decreased by both types of statins (pamp;lt;0.05). Statin treatment also introduced increased mRNA levels of MMP-1, MMP-3, MMP-13, TIMP-1 and decreased levels of collagen type 1 and 3. In conclusion, statin treatment appears to have a negative effect on tendon matrix quality as seen by a reduced strength of the tendon constructs. Further, activated catabolic changes in the gene expression pattern and a reduced collagen content indicated a disturbed balance in matrix production of tendon due to statin administration.
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28.
  • Eliasson, Pernilla T., et al. (författare)
  • Statin treatment increases the clinical risk of tendinopathy through matrix metalloproteinase release - a cohort study design combined with an experimental study
  • 2019
  • Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent experimental evidence indicates potential adverse effects of statin treatment on tendons but previous clinical studies are few and inconclusive. The aims of our study were, first, to determine whether statin use in a cohort design is associated with tendinopathy disorders, and second, to experimentally understand the pathogenesis of statin induced tendinopathy. We studied association between statin use and different tendon injuries in two population-based Swedish cohorts by time-dependent Cox regression analysis. Additionally, we tested simvastatin in a 3D cell culture model with human tenocytes. Compared with never-users, current users of statins had a higher incidence of trigger finger with adjusted hazard ratios (aHRs) of 1.50 for men (95% confidence interval [CI] 1.21-1.85) and 1.21 (1.02-1.43) for women. We also found a higher incidence of shoulder tendinopathy in both men (aHR 1.43; 1.24-1.65) and women (aHR 1.41; 0.97-2.05). Former users did not confer a higher risk of tendinopathies. In vitro experiments revealed an increased release of matrix metalloproteinase (MMP)-1 and MMP-13 and a weaker, disrupted matrix after simvastatin exposure. Current statin use seems to increase the risk of trigger finger and shoulder tendinopathy, possibly through increased MMP release, and subsequently, a weakened tendon matrix which will be more prone to injuries.
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29.
  • Eliasson, Pernilla T., et al. (författare)
  • The Ruptured Achilles Tendon Elongates for 6 Months After Surgical Repair Regardless of Early or Late Weightbearing in Combination With Ankle Mobilization: A Randomized Clinical Trial
  • 2018
  • Ingår i: American Journal of Sports Medicine. - : SAGE PUBLICATIONS INC. - 0363-5465 .- 1552-3365. ; 46:10, s. 2492-2502
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Treatment strategies for Achilles tendon rupture vary considerably, and clinical outcome may depend on the magnitude of tendon elongation after surgical repair. The aim of this project was to examine whether tendon elongation, mechanical properties, and functional outcomes during rehabilitation of surgically repaired acute Achilles tendon ruptures were influenced by different rehabilitation regimens during the early postsurgical period. Hypothesis: Restricted early weightbearing that permits only limited motion about the ankle in the early phase of tendon healing limits tendon elongation and improves functional outcome. Study Design:Randomized controlled trial; Level of evidence, 1. Methods: 75 consecutive patients with an acute Achilles tendon rupture were included. They underwent surgical repair, and tantalum beads were placed in the distal and proximal parts of the tendon; thereafter, the patients were randomized into 3 groups. The first group was completely restricted from weightbearing until week 7. The second group was completely restricted from weightbearing until week 7 but performed ankle joint mobilization exercises. The first and second groups were allowed full weightbearing after week 8. The third group was allowed partial weightbearing from day 1 and full weightbearing from week 5. All patients received the same instructions in home exercise guidelines starting from week 9. Results: The rehabilitation regimen in the initial 8 weeks did not significantly influence any of the measured outcomes including tendon elongation. Achilles tendon elongation and tendon compliance continued for up to 6 months after surgery, and muscle strength, muscle endurance, and patient-reported functional scores did not reach normal values at 12 months. Conclusion: Differences in rehabilitation loading pattern in the initial 8 weeks after the repair of an Achilles tendon rupture did not measurably alter the outcome. The time to recover full function after an Achilles tendon rupture is at least 12 months.
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30.
  • Eliasson, Pernilla, et al. (författare)
  • The Hematopoietic Stem Cell Niche: Low in Oxygen but a Nice Place to be
  • 2010
  • Ingår i: Journal of Cellular Physiology. - : Wiley. - 0021-9541 .- 1097-4652. ; 222:1, s. 17-22
  • Forskningsöversikt (refereegranskat)abstract
    • The enormous regenerative capacity of the blood system to sustain functionally mature cells are generated from highly proliferative, short-lived progenitors, which in turn arise from a rare population of pluripotent and self-renewing hematopoietic stem cells (HSC). In the bone marrow, these stem cells are kept in a low proliferative, relatively quiescent state in close proximity to stromal cells and osteoblasts, forming specialized niches. The interaction in particular to bone is crucial to prevent exhaustion of HSCs from uncontrolled cell-cycle entry and to excessive proliferation. In addition, the niche and its components protect stem cells from stress, such as accumulation of reactive oxygen species and DNA damage. One of the key issues is to identify conditions to increase the number of HSCs, either in vivo or during ex vivo growth cultures. This task has been very difficult to resolve and most attempts have been unsuccessful. However, the mechanistic insights to HSC self-renewal and preservation are gradually increasing and there is now hope that future research will enable scientists and clinicians to modulate the process. In this review, we will focus on the molecular mechanisms of self-renewal and HSC maintenance in the light of novel findings that HSCs reside at the lowest end of an oxygen gradient. Hypoxia appears to regulate hematopoiesis in the bone marrow by maintaining important HSC functions, such as cell cycle control, survival, metabolism, and protection against oxidative stress. To improve the therapeutic expansion of HSCs we need to learn more about the molecular mechanisms of hypoxia-mediated regulation.
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31.
  • Eliasson, Pernilla, et al. (författare)
  • Unloaded rat Achilles tendons continue to grow, but lose viscoelasticity
  • 2007
  • Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 103:2, s. 459-463
  • Tidskriftsartikel (refereegranskat)abstract
    • Tendons can function as springs and thereby preserve energy during cyclic loading. They might also have damping properties, which, hypothetically, could reduce risk of microinjuries due to fatigue at sites of local stress concentration within the tendon. At mechanical testing, damping will appear as hysteresis. How is damping influenced by training or disuse? Does training decrease hysteresis, thereby making the tendon a better spring, or increase hysteresis and thus improve damping? Seventy-eight female 10-wk-old Sprague-Dawley rats were randomized to three groups. Two groups had botulinum toxin injected into the calf muscles to unload the left Achilles tendon through muscle paralysis. One of these groups was given doxycycline, as a systemic matrix metalloproteinase inhibitor. The third group served as loaded controls. The Achilles tendons were harvested after 1 or 6 wk for biomechanical testing. An increase with time was seen in tendon dry weight, wet weight, water content, transverse area, length, stiffness, force at failure, and energy uptake in all three groups (P < 0.001 for each parameter). Disuse had no effect on these parameters. Creep was decreased with time in all groups. The only significant effect of disuse was on hysteresis (P = 0.004) and creep (P = 0.007), which both decreased with disuse compared with control, and on modulus, which was increased (P = 0.008). Normalized glycosaminoglycan content was unaffected by time and disuse. No effect of doxycycline was observed. The results suggest that in growing animals, the tendons continue to grow regardless of mechanical loading history, whereas maintenance of damping properties requires mechanical stimulation.
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32.
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33.
  • Halvarsson, Camilla, 1985-, et al. (författare)
  • Putative Role of Nuclear Factor-Kappa B But Not Hypoxia-Inducible Factor-1α in Hypoxia-Dependent Regulation of Oxidative Stress in Hematopoietic Stem and Progenitor Cells
  • 2019
  • Ingår i: Antioxidants and Redox Signaling. - : Mary Ann Liebert. - 1523-0864 .- 1557-7716. ; 31:3, s. 211-226
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: Adaptation to low oxygen of hematopoietic stem cells (HSCs) in the bone marrow has been demonstrated to depend on the activation of hypoxia-inducible factor (HIF)-1α as well as the limited production of reactive oxygen species (ROS). In this study, we aimed at determining whether HIF-1α is involved in protecting HSCs from ROS.Results: Oxidative stress was induced by DL-buthionine-(S,R)-sulfoximine (BSO)-treatment, which increases the mitochondrial ROS level. Hypoxia rescued Lineage-Sca-1+c-kit+ (LSK) cells from BSO-induced apoptosis, whereas cells succumbed to apoptosis in normoxia. Apoptosis in normoxia was inhibited with the antioxidant N-acetyl-L-cysteine or by overexpression of anti-apoptotic BCL-2. Moreover, stabilized expression of oxygen-insensitive HIFs could not protect LSK cells from oxidative stress-induced apoptosis at normoxia, neither could short hairpin RNA to Hif-1α inhibit the protective effects by hypoxia in LSK cells. Likewise, BSO treatment of LSK cells from Hif-1α knockout mice did not suppress the effects seen in hypoxia. Microarray analysis identified the nuclear factor-kappa B (NF-κB) pathway as a pathway induced by hypoxia. By using NF-κB lentiviral construct and DNA-binding assay, we found increased NF-κB activity in cells cultured in hypoxia compared with normoxia. Using an inhibitor against NF-κB activation, we could confirm the involvement of NF-κB signaling as BSO-mediated cell death was significantly increased in hypoxia after adding the inhibitor.Innovation: HIF-1α is not involved in protecting HSCs and progenitors to elevated levels of ROS on glutathione depletion during hypoxic conditions.Conclusion: The study proposes a putative role of NF-κB signaling as a hypoxia-induced regulator in early hematopoietic cells.
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34.
  • Halvarsson, Camilla, et al. (författare)
  • Pyruvate dehydrogenase kinase 1 is essential for transplantable mouse bone marrow hematopoietic stem cell and progenitor function
  • 2017
  • Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Accumulating evidence suggests that hypoxic areas in the bone marrow are crucial for maintenance of hematopoietic stem cells (HSCs) by supporting a quiescent state of cell cycle and regulating the transplantation capacity of long-term (LT)-HSCs. In addition, HSCs seem to express a metabolic profile of energy production away from mitochondrial oxidative phosphorylation in favor of glycolysis. At oxygen deprivation, hypoxia inducible factor 1 alpha (HIF-1 alpha) is known to induce glycolytic enzymes as well as suppressing mitochondrial energy production by inducing pyruvate dehydrogenase kinase 1 (Pdk1) in most cell types. It has not been established whether PDK1 is essential for HSC function and mediates hypoxia-adapting functions in HSCs. While the Pdk gene family contains four members (Pdk1-4), it was recently shown that Pdk2 and Pdk4 have an important role in regulating LT-HSCs. Principle findings Here we demonstrate that PDK1 activity is crucial for transplantable HSC function. Whereas Pdkl, Pdk2, and Pdk3 transcripts were expressed at higher levels in different subtypes of HSCs compared to differentiated cells, we could not detect any major differences in expression between LT-HSCs and more short-term HSCs and multipotent progenitors. When studying HIF-1 alpha-mediated regulation of Pdk activity in vitro, Pdk1 was the most robust target regulated by hypoxia, whereas Pdk2, Pdk3, and Pdk4 were not affected. Contrary, genetic ablation in a cre-inducible Hif-1 alpha knockout mouse did not support a link between HIF-1 alpha and Pdk1. Silencing of Pdk1 by shRNA lentiviral gene transfer partially impaired progenitor colony formation in vitro and had a strong negative effect on both long-term and short-term engraftment in mice. Conclusions Our study demonstrates that PDK1 has broad effects in hematopoiesis and is a critical factor for engraftment of both HSCs and multipotent progenitors upon transplantation to recipient mice. While Pdk1 was a robust hypoxia-inducible gene mediated by HIF-1 alpha in vitro, we could not find evidence of any in vivo links between Pdk1 and HIF-1 alpha.
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35.
  • Hammerman, Malin, et al. (författare)
  • Different gene response to mechanical loading during early and late phases of rat Achilles tendon healing
  • 2017
  • Ingår i: Journal of applied physiology. - : AMER PHYSIOLOGICAL SOC. - 8750-7587 .- 1522-1601. ; 123:4, s. 800-815
  • Tidskriftsartikel (refereegranskat)abstract
    • Mechanical loading stimulates tendon healing both when applied in the inflammatory phase and in the early remodeling phase of the process, although not necessarily via the same mechanisms. We investigated the gene response to mechanical loading in these two phases of tendon healing. The right Achilles tendon in rats was transected, and the hindlimbs were unloaded by tail suspension. The rats were exposed to 5 min of treadmill running 3 or 14 days after tendon transection. Thereafter, they were resuspended for 15 min or 3 h until euthanasia. The controls were suspended continuously. Gene analysis was first performed by microarray analysis followed by quantitative RTPCR on selected genes, focusing on inflammation. Fifteen minutes after loading, the most important genes seemed to be the transcription factors EGR1 and C-FOS, regardless of healing phase. These transcription factors might promote tendon cell proliferation and differentiation, stimulate collagen production, and regulate inflammation. Three hours after loading on day 3, inflammation was strongly affected. Seven inflammation-related genes were upregulated according to PCR: CCL20, CCL7, IL-6, NFIL3, PTX3, SOCS1, and TLR2. These genes can be connected to macrophages, T cells, and recruitment of leukocytes. According to Ingenuity Pathway Analysis, the recruitment of leukocytes was increased by loading on day 3, which also was confirmed by histology. This inflammation-related gene response was not seen on day 14. Our results suggest that the immediate gene response after mechanical loading is similar in the early and late phases of healing but the late gene response is different. NEW amp; NOTEWORTHY This study investigates the direct effect of mechanical loading on gene expression during different healing phases in tendon healing. One isolated episode of mechanical loading was studied in otherwise unloaded healing tendons. This enabled us to study a time sequence, i.e., which genes were the first ones to be regulated after the loading episode.
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36.
  • Hammerman, Malin, et al. (författare)
  • Different mechanisms activated by mild versus strong loading in rat Achilles tendon healing
  • 2018
  • Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 13:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Mechanical loading stimulates Achilles tendon healing. However, various degrees of loading appear to have different effects on the mechanical properties of the healing tendon, and strong loading might create microdamage in the tissue. This suggests that different mechanisms might be activated depending on the magnitude of loading. The aim of this study was to investigate these mechanisms further. Methods Female rats had their right Achilles tendon cut transversely and divided into three groups: 1) unloading (calf muscle paralysis by Botox injections, combined with joint fixation by a steel-orthosis), 2) mild loading (Botox only), 3) strong loading (free cage activity). Gene expression was analyzed by PCR, 5 days post-injury, and mechanical testing 8 days post-injury. The occurrence of microdamage was analyzed 3, 5, or 14 days post-injury, by measuring leakage of injected fluorescence-labelled albumin in the healing tendon tissue. Results Peak force, peak stress, and elastic modulus of the healing tendons gradually improved with increased loading as well as the expression of extracellular matrix genes. In contrast, only strong loading increased transverse area and affected inflammation genes. Strong loading led to higher fluorescence (as a sign of microdamage) compared to mild loading at 3 and 5 days post-injury, but not at 14 days. Discussion Our results show that strong loading improves both the quality and quantity of the healing tendon, while mild loading only improves the quality. Strong loading also induces microdamage and alters the inflammatory response. This suggests that mild loading exert its effect via mechanotransduction mechanisms, while strong loading exert its effect both via mechanotransduction and the creation of microdamage. Conclusion In conclusion, mild loading is enough to increase the quality of the healing tendon without inducing microdamage and alter the inflammation in the tissue. This supports the general conception that early mobilization of a ruptured tendon in patients is advantageous.
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37.
  • Hammerman, Malin, et al. (författare)
  • Microtrauma stimulates rat Achilles tendon healing via an early gene expression pattern similar to mechanical loading
  • 2014
  • Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 116:1, s. 54-60
  • Tidskriftsartikel (refereegranskat)abstract
    • Mechanical loading increases the strength of healing tendons, but also induces small localized bleedings. Therefore, it is unclear if increased strength after loading is a response to mechanotransduction or microtrauma. We have previously found only five genes to be up-regulated 15 min after a single loading episode, of them four were transcription factors. These genes are followed by hundreds of genes after 3 h, many of them involved in inflammation. We now compared healing in mechanically unloaded tendons with or without added microtrauma induced by needling of the healing tissue. Nineteen rats received Botox into the calf muscle to reduce loading, and the Achilles tendon was transected. Ten rats were randomized to needling days 2-5. Mechanical testing on day 8 showed increased strength by 45% in the needling group. Next, another 24 rats were similarly unloaded, and 16 randomized to needling on day 5 after transection. Nineteen characteristic genes, known to be regulated by loading in this model, were analyzed by qRT-PCR. Four of these genes were regulated 15 min after needling. Three of them (Egr1, c-Fos, Rgs1) were among the five regulated genes after loading in a previous study. Sixteen of the 19 genes were regulated after 3 h, in the same way as after loading. In conclusion, needling increased strength, and there was a striking similarity between the gene expression response to needling and mechanical loading. This suggests that the response to loading in early tendon healing can, at least in part, be a response to microtrauma.
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38.
  • Hammerman, Malin, 1984- (författare)
  • Tendon Healing : Mechanical Loading, Microdamage and Gene Expression
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Mechanical loading and the inflammatory response during tendon healing might be important for the healing process. Mechanical loading can improve the healing tendon but the mechanism is not fully understood. The aim of this thesis was to further clarify the effect of mechanical loading on tendon healing and how mechanical loading affects the inflammatory response during the healing process.We used a rat Achilles tendon model to study healing. The rats were exposed to different degrees of loading by unloading methods such as paralysis of the calf muscles with Botox, tail suspension, and an orthosis (a boot). Full loading was achieved by free cage activity or treadmill walking. Microdamage in tendons, unloaded with Botox, was also investigated by needling. The healing tendons were evaluated in a materials testing machine (to analyze the mechanical properties), by gene expression analysis (microarray and PCR), or histology.Our results show that moderate loading (unloading with Botox) improves the mechanical properties of healing tendons compared to minimal loading (unloading with Botox in combination with tail suspension or a boot), especially the material properties. In accordance to these findings, expression of extracellular matrix genes were also increased by moderate compared to minimal loading.Full loading improved all mechanical properties and the expression of extracellular matrix genes was further increased compared to moderate loading. However, structural properties, such as the strength and the size of the healing tendon, were more affected by full loading. Full loading also affected the expression of inflammation-related genes during the early healing phase, 3 and 5 days after tendon injury, and increased the number of immune cells in the healing tendon tissue. Also microdamage of the healing tendon (detected by blood leakage) was increased by full loading compared to moderate loading during the early healing phase.Induced microdamage by repeated needling in the healing tendon tissue increased the structural properties of the healing tendon. The gene expression after needling was similar to the gene expression after full loading.The improvement of mechanical properties by loading in healing tendons was decreased by an anti-inflammatory drug called parecoxib, which decreases the production of prostaglandins by inhibiting COX-2 activity. The effect of parecoxib was reduced when loading was reduced but we could not confirm that the effect of parecoxib was related to the degree of loading. However, parecoxib abolished the stimulatory effect of microdamage.In conclusion, these studies show that moderate loading improves the quality of the healing tendon whereas full loading also increases the quantity of the healing tendon tissue. Full loading creates microdamage and increases inflammation during the early healing phase. The strong effect of full loading on the structural properties might be due to microdamage. Indeed, the anti-inflammatory drug parecoxib seems to impair mechanical stimulation of healing tendons by reducing the response to microdamage.
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39.
  • Herchenhan, Andreas, et al. (författare)
  • Early Growth Response Genes Increases Rapidly After Mechanical Overloading and Unloading in Tendon Constructs
  • 2020
  • Ingår i: Journal of Orthopaedic Research. - : WILEY. - 0736-0266 .- 1554-527X. ; 38:1, s. 173-181
  • Tidskriftsartikel (refereegranskat)abstract
    • Tendon cells exist in a dense extracellular matrix and mechanical loading is important for the strength development of this matrix. We therefore use a three-dimensional (3D) culture system for tendon formation in vitro. The objectives of this study were to elucidate the temporal expression of tendon-related genes during the formation of artificial tendons in vitro and to investigate if early growth response-1 (EGR1), EGR2, FOS, and cyclooxygenase-1 and -2 (PTGS1 and PTGS2) are sensitive to mechanical loading. First, we studied messenger RNA (mRNA) levels of several tendon-related genes during formation of tendon constructs. Second, we studied the mRNA levels of, for example, EGR1 and EGR2 after different degrees of loading; dynamic physiologic-range loading (2.5% strain), dynamic overloading (approximately 10% strain), or tension release. The gene expression for tendon-related genes (i.e., EGR2, MKX, TNMD, COL3A1) increased with time after seeding into this 3D model. EGR1, EGR2, FOS, PTGS1, and PTGS2 did not respond to physiologic-range loading. But overloading (and tension release) lead to elevated levels of EGR1 and EGR2 (p amp;lt;= 0.006). FOS and PTGS2 were increased after overloading (both p amp;lt; 0.007) but not after tension release (p = 0.06 and 0.08). In conclusion, the expression of tendon-related genes increases during the formation of artificial tendons in vitro, including EGR2. Furthermore, the gene expression of EGR1 and EGR2 in human tendon cells appear to be sensitive to overloading and unloading but did not respond to the single episode of physiologic-range loading. These findings could be helpful for the understanding of tendon tensional homeostasis. (c) 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res
  •  
40.
  • Hoeffner, Rikke, et al. (författare)
  • Muscle fascicle and sarcomere adaptation in response to Achilles tendon elongation in an animal model
  • 2023
  • Ingår i: Journal of applied physiology. - : AMER PHYSIOLOGICAL SOC. - 8750-7587 .- 1522-1601. ; 135:2, s. 326-333
  • Tidskriftsartikel (refereegranskat)abstract
    • Permanent loss of muscle function seen after an Achilles tendon rupture may partly be explained by tendon elongation and accompanying shortening of the muscle. Muscle fascicle length shortens, serial sarcomere number is reduced, and the sarcomere length is unchanged after Achilles tendon transection (ATT), and these changes are mitigated with suturing. The method involved in this study was a controlled laboratory study. Two groups of rats underwent ATT on one side with a contralateral control (CTRL): A) ATT with 3 mm removal of the Achilles tendon and no suturing (substantial tendon elongation), and B) ATT with suture repair (minimal tendon elongation). The operated limb was immobilized for 2 wk to reduce load. Four weeks after surgery the rats were euthanized, and hindlimbs were analyzed for tendon length, gastrocnemius medialis (GM) muscle mass, length, fascicle length, sarcomere number and length. No differences were observed between the groups, and in both groups the Achilles tendon length was longer (15.2%, P < 0.001), GM muscle mass was smaller (17.5%, P < 0.001), and muscle length was shorter (8.2%, P < 0.001) on the ATT compared with CTRL side. GM fascicle length was shorter (11.2%, P < 0.001), and sarcomere number was lower (13.8%, P < 0.001) on the ATT side in all regions. Sarcomere length was greater in the proximal (5.8%, P < 0.001) and mid (4.2%, P 1/4 0.003), but not distal region on the ATT side. In this animal model, regardless of suturing, ATT resulted in tendon elongation, loss of muscle mass and length, and reduced serial sarcomere number, which resulted in an "overshoot" lengthening of the sarcomeres.
  •  
41.
  • Khayyeri, Hanifeh, et al. (författare)
  • A Fibre-Reinforced Poroviscoelastic Model Accurately Describes the Biomechanical Behaviour of the Rat Achilles Tendon
  • 2015
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 10:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Computational models of Achilles tendons can help understanding how healthy tendons are affected by repetitive loading and how the different tissue constituents contribute to the tendons biomechanical response. However, available models of Achilles tendon are limited in their description of the hierarchical multi-structural composition of the tissue. This study hypothesised that a poroviscoelastic fibre-reinforced model, previously successful in capturing cartilage biomechanical behaviour, can depict the biomechanical behaviour of the rat Achilles tendon found experimentally. Materials and Methods We developed a new material model of the Achilles tendon, which considers the tendons main constituents namely: water, proteoglycan matrix and collagen fibres. A hyperelastic formulation of the proteoglycan matrix enabled computations of large deformations of the tendon, and collagen fibres were modelled as viscoelastic. Specimen-specific finite element models were created of 9 rat Achilles tendons from an animal experiment and simulations were carried out following a repetitive tensile loading protocol. The material model parameters were calibrated against data from the rats by minimising the root mean squared error (RMS) between experimental force data and model output. Results and Conclusions All specimen models were successfully fitted to experimental data with high accuracy (RMS 0.42-1.02). Additional simulations predicted more compliant and soft tendon behaviour at reduced strain-rates compared to higher strain-rates that produce a stiff and brittle tendon response. Stress-relaxation simulations exhibited strain-dependent stress-relaxation behaviour where larger strains produced slower relaxation rates compared to smaller strain levels. Our simulations showed that the collagen fibres in the Achilles tendon are the main load-bearing component during tensile loading, where the orientation of the collagen fibres plays an important role for the tendons viscoelastic response. In conclusion, this model can capture the repetitive loading and unloading behaviour of intact and healthy Achilles tendons, which is a critical first step towards understanding tendon homeostasis and function as this biomechanical response changes in diseased tendons.
  •  
42.
  • Khayyeri, Hanifeh, et al. (författare)
  • Diminishing effects of mechanical loading over time during rat Achilles tendon healing
  • 2020
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:12 December
  • Tidskriftsartikel (refereegranskat)abstract
    • Mechanical loading affects tendon healing and recovery. However, our understanding about how physical loading affects recovery of viscoelastic functions, collagen production and tissue organisation is limited. The objective of this study was to investigate how different magnitudes of loading affects biomechanical and collagen properties of healing Achilles tendons over time. Achilles tendon from female Sprague Dawley rats were cut transversely and divided into two groups; normal loading (control) and reduced loading by Botox (unloading). The rats were sacrificed at 1, 2- and 4-weeks post-injury and mechanical testing (creep test and load to failure), small angle x-ray scattering (SAXS) and histological analysis were performed. The effect of unloading was primarily seen at the early time points, with inferior mechanical and collagen properties (SAXS), and reduced histological maturation of the tissue in unloaded compared to loaded tendons. However, by 4 weeks no differences remained. SAXS and histology revealed heterogeneous tissue maturation with more mature tissue at the peripheral region compared to the center of the callus. Thus, mechanical loading advances Achilles tendon biomechanical and collagen properties earlier compared to unloaded tendons, and the spatial variation in tissue maturation and collagen organization across the callus suggests important regional (mechano-) biological activities that require more investigation.
  •  
43.
  • Li, Junhong, et al. (författare)
  • Secretome from myoblasts statically loaded at low intensity promotes tenocyte proliferation via the IGF-1 receptor pathway
  • 2023
  • Ingår i: The FASEB Journal. - : John Wiley & Sons. - 0892-6638 .- 1530-6860. ; 37:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Exercise is widely recognized as beneficial for tendon healing. Recently, it has been described that muscle-derived molecules secreted in response to static exercise influence tendon healing. In this study, the optimal static loading intensity for tendon healing and the composition of secretome released by myoblasts in response to different intensities of static strain were investigated. In an in vitro coculture model, myoblasts were mechanically loaded using a Flexcell Tension System. Tenocytes were seeded on transwell inserts that allowed communication between the tenocytes and myoblasts without direct contact. Proliferation and migration assays, together with RNA sequencing, were used to determine potential cellular signaling pathways. The secretome from myoblasts exposed to 2% static loading increased the proliferation and migration of the cocultured tenocytes. RNA-seq analysis revealed that this loading condition upregulated the expression of numerous genes encoding secretory proteins, including insulin-like growth factor-1 (IGF-1). Confirmation of IGF-1 expression and secretion was carried out using qPCR and enzyme-linked immunosorbt assay (ELISA), revealing a statistically significant upregulation in response to 2% static loading in comparison to both control conditions and higher loading intensities of 5% and 10%. Addition of an inhibitor of the IGF-1 receptor (PQ401) to the tenocytes significantly reduced myoblast secretome-induced tenocyte proliferation. In conclusion, IGF-1 may be an important molecule in the statically loaded myoblast secretome, which is responsible for influencing tenocytes during exercise-induced healing.
  •  
44.
  • Lundin, Anna-Carin (författare)
  • Tendinosis in Trigger Finger
  • 2017
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Trigger finger is one of the most common hand conditions, with a prevalence of almost 3%. The aetiology remains unclear even though many causes have been suggested. The prevailing paradigm is that the pathogenesis of trigger finger is ascribed to primary changes in the first fibrous condensation of the tendon sheath (A1-pulley). Several studies have investigated pathology in the pulley, but few have investigated the tendon. The general aim of this thesis was to find out if there is pathology in the trigger finger tendon and to define it.We first looked at trigger finger tendon biopsies in a light microscope, and found that they were histologically different from healthy tendons. They showed signs of micro-ruptures, collagen degradation, increased amounts of ground substance, both hyper- and hypo-cellular areas, round active cell nuclei and absence of inflammatory cells, all similar to tendinosis. The histological picture was further assessed by using a scoring system for Achilles tendinosis. The trigger finger tendons scored high, suggesting a similar histopathology.Next, we performed a quantitative real-time polymerase chain reaction (qPCR) on trigger finger tendons. We assessed the mRNA expression of 10 genes, which have been described to be differently expressed in Achilles tendinosis (collagen 1 and 3, versican, decorin, biglycan, aggrecan, MMP-2, MMP-3, ADAMTS-5, and TIMP-3). The overall expression pattern agreed with previous studies on Achilles tendinosis, suggesting that the cellular function in trigger finger tendons is disturbed in a similar way as in Achilles tendinosis.Recent experimental and observational research has suggested potential side effects of statin treatment on tendons, but firm evidence was lacking. We performed an epidemiological study on two large population-based cohorts. Statin use was found to increase the risk of both trigger finger and tendinosis in the shoulder and Achilles tendons, especially among men. This suggests a similar pathology in trigger finger and tendinosis.We have also studied the time to treatment effect after a single injection of glucocorticoid in trigger finger. Our results suggest that 60-80% of patients can expect resolution of the triggering within 14 days, and half of them within seven days. This result allows correct information to be given to the patient and proper planning of follow-ups.In conclusion, the pathology in trigger finger tendons is similar to tendinosis in other tendons.
  •  
45.
  • Lundin, Anna-Carin, et al. (författare)
  • Trigger finger and tendinosis
  • 2012
  • Ingår i: Journal of Hand Surgery, European Volume. - : Sage Publications. - 1753-1934 .- 2043-6289. ; 37:3, s. 233-236
  • Tidskriftsartikel (refereegranskat)abstract
    • The pathogenesis of trigger finger has generally been ascribed to primary changes in the pulley. Histological examination of the affected tendons has rarely been done. We studied biopsies from tendons of trigger fingers from 29 patients and compared these to biopsies from six intact tendons. We used a modified Movin score, which describes the tendinosis of the Achilles tendon. Trigger finger tendons had a high score (14.2; SD, 2.2) consistent with tendinosis, while the controls were almost normal (2.5; SD, 1.9). This suggests that the tendon is also affected, and that trigger finger is a form of tendinosis.
  •  
46.
  • Lundin, Anna-Carin, et al. (författare)
  • Trigger finger, tendinosis, and intratendinous gene expression
  • 2014
  • Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : Wiley. - 0905-7188 .- 1600-0838. ; 24:2, s. 363-368
  • Tidskriftsartikel (refereegranskat)abstract
    • The pathogenesis of trigger finger has generally been ascribed to primary changes in the first annular ligament. In contrast, we recently found histological changes in the tendons, similar to the findings in Achilles tendinosis or tendinopathy. We therefore hypothesized that trigger finger tendons would show differences in gene expression in comparison to normal tendons in a pattern similar to what is published for Achilles tendinosis. We performed quantitative real-time polymerase chain reaction on biopsies from finger flexor tendons, 13 trigger fingers and 13 apparently healthy control tendons, to assess the expression of 10 genes which have been described to be differently expressed in tendinosis (collagen type 1a1, collagen 3a1, MMP-2, MMP-3, ADAMTS-5, TIMP-3, aggrecan, biglycan, decorin, and versican). In trigger finger tendons, collagen types 1a1 and 3a1, aggrecan and biglycan were all up-regulated, and MMP-3and TIMP-3 were down-regulated. These changes were statistically significant and have been previously described for Achilles tendinosis. The remaining four genes were not significantly altered. The changes in gene expression support the hypothesis that trigger finger is a form of tendinosis. Because trigger finger is a common condition, often treated surgically, it could provide opportunities for clinical research on tendinosis.
  •  
47.
  • Magnusson, S. Peter, et al. (författare)
  • Heterotopic Ossification After an Achilles Tendon Rupture Cannot Be Prevented by Early Functional Rehabilitation: A Cohort Study
  • 2020
  • Ingår i: Clinical Orthopaedics and Related Research. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-921X .- 1528-1132. ; 478:5, s. 1101-1108
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Tendon loading might play a role in the development of heterotopic ossification after Achilles tendon ruptures. Early heavy loading on a healing tendon in animals has been shown to prolong the proinflammatory response, and inflammatory cells are thought to drive heterotopic ossification formation. Taken together, this suggests that early rehabilitation might influence heterotopic ossification development. Questions/purposes The purposes of this study were to investigate (1) whether the presence of heterotopic ossification after Achilles tendon ruptures influences clinical outcome and (2) whether early mobilization or weightbearing prevents the development of heterotopic ossification. Methods This was a retrospective analysis of 69 patients from a previous clinical trial. All patients were treated surgically, but with three different early rehabilitation protocols after surgery: late weightbearing and ankle immobilization, late weightbearing and ankle mobilization, and early weightbearing and ankle mobilization. Plain radiographs taken 2, 6, 12, 26, and 52 weeks postoperatively were analyzed for heterotopic ossification, which was detected in 19% of patients (13 of 69) at 52 weeks. Heterotopic ossification was measured, scored, and correlated to clinical outcomes; heel-raise index (HRI), ankle joint ROM, tendon strain, Achilles tendon rupture score (ATRS), and Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire scores at 26 and 52 weeks postoperatively. Results Heterotopic ossification had no adverse effects on patient-reported outcomes (ATRS or VISA-A), tendon strain, or ROM. In fact, patients with heterotopic ossification tended to have a better HRI at 52 weeks compared with patients without (mean difference 14% [95% CI -0.2 to 27]; p = 0.053). Neither the occurrence (heterotopic ossification/no heterotopic ossification) nor the heterotopic ossification severity (ossification score) differed between the three rehabilitation groups. Seventeen percent of the patients (four of 24) with early functional rehabilitation (early weightbearing and ankle joint mobilization exercise) had heterotopic ossification (score, 2-3) while late weightbearing and immobilization resulted in heterotopic ossification in 13% of the patients (score, 3-4). Conclusions Heterotopic ossification occurs relatively frequently after Achilles tendon ruptures but appears to have no adverse effects on functional outcomes. Furthermore, heterotopic ossification develops during the first 6 weeks after rupture, and weightbearing or ankle-joint mobilization does not prevent this from occurring.
  •  
48.
  •  
49.
  • Nilson, Tomas, 1963-, et al. (författare)
  • Epilog. Det halländska kulturarvet : säcken knyts ihop
  • 2021
  • Ingår i: "Men här var det annorlunda". - Halmstad : Akademin för Lärande, Humaniora och Samhälle, Högskolan i Halmstad. - 9789151982397 ; , s. 305-325
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)
  •  
50.
  • Nilson, Tomas, 1963-, et al. (författare)
  • Prolog. Om undersökningar av Hallands kultur och kulturarv
  • 2021
  • Ingår i: "Men här var det annorlunda". - Halmstad : Akademin för Lärande, Humaniora och Samhälle, Högskolan i Halmstad. - 9789151982397 ; , s. 7-45
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)
  •  
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