| 1. |
- Anesater, Erik, et al.
(författare)
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A Rigid Disc for Protection of Exposed Blood Vessels During Negative Pressure Wound Therapy
- 2013
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Ingår i: Surgical Innovation. - : SAGE Publications. - 1553-3506 .- 1553-3514. ; 20:1, s. 74-80
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Tidskriftsartikel (refereegranskat)abstract
- Background. There are increasing reports of serious complications and deaths associated with negative pressure wound therapy (NPWT). Bleeding may occur when NPWT is applied to a wound with exposed blood vessels. Inserting a rigid disc in the wound may protect these structures. The authors examined the effects of rigid discs on wound bed tissue pressure and blood flow through a large blood vessel in the wound bed during NPWT. Methods. Wounds were created over the femoral artery in the groin of 8 pigs. Rigid discs were inserted. Wound bed pressures and arterial blood flow were measured during NPWT. Results. Pressure transduction to the wound bed was similar for control wounds and wounds with discs. Blood flow through the femoral artery decreased in control wounds. When a disc was inserted, the blood flow was restored. Conclusions. NPWT causes hypoperfusion in the wound bed tissue, presumably as a result of mechanical deformation. The insertion of a rigid barrier alleviates this effect and restores blood flow.
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| 2. |
- Anesäter, Erik, et al.
(författare)
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The influence on wound contraction and fluid evacuation of a rigid disc inserted to protect exposed organs during negative pressure wound therapy.
- 2011
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Ingår i: International Wound Journal. - 1742-481X. ; 8, s. 393-399
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Tidskriftsartikel (refereegranskat)abstract
- The use of a rigid disc as a barrier between the wound bed and the wound filler during negative pressure wound therapy (NPWT) has been suggested to prevent damage to exposed organs. However, it is important to determine that the effects of NPWT, such as wound contraction and fluid removal, are maintained during treatment despite the use of a barrier. This study was performed to examine the effect of NPWT on wound contraction and fluid evacuation in the presence of a rigid disc. Peripheral wounds were created on the backs of eight pigs. The wounds were filled with foam, and rigid discs of different designs were inserted between the wound bed and the foam. Wound contraction and fluid evacuation were measured after application of continuous NPWT at -80 mmHg. Wound contraction was similar in the presence and the absence of a rigid disc (84 ± 4% and 83 ± 3%, respectively, compared with baseline). Furthermore, the rigid disc did not affect wound fluid removal compared with ordinary NPWT (e.g. after 120 seconds, 71 ± 4 ml was removed in the presence and 73 ± 3 ml was removed in the absence of a disc). This study shows that a rigid barrier may be placed under the wound filler to protect exposed structures during NPWT without affecting wound contraction and fluid removal, which are two crucial features of NPWT.
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| 3. |
- Anesäter, Erik, et al.
(författare)
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The use of a rigid disc to protect exposed structures in wounds treated with negative pressure wound therapy: Effects on wound bed pressure and microvascular blood flow.
- 2012
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Ingår i: Wound Repair and Regeneration. - 1524-475X. ; 20:4, s. 611-616
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Tidskriftsartikel (refereegranskat)abstract
- There are increasing reports of deaths and serious complications associated with the use of negative pressure wound therapy (NPWT). Bleeding may occur in patients when NPWT is applied to a wound with exposed blood vessels or vascular grafts, possibly due to mechanical deformation and hypoperfusion of the vessel walls. Recent evidence suggests that using a rigid barrier disc to protect underlying tissue can prevent this mechanical deformation. The aim of this study was to examine the effect of rigid discs on the tissue exposed to negative pressure with regard to tissue pressure and microvascular blood flow. Peripheral wounds were created on the backs of eight pigs. The pressure and microvascular blood flow in the wound bed were measured when NPWT was applied. The wound was filled with foam, and rigid discs of different designs were inserted between the wound bed and the foam. The discs were created with or without channels (to accommodate exposed sensitive structures such as blood vessels and nerves), perforations, or a porous dressing that covered the underside of the discs (to facilitate pressure transduction and fluid evacuation). When comparing the results for pressure transduction to the wound bed, no significant differences were found using different discs covered with dressing, whereas pressure transduction was lower with bare discs. Microvascular blood flow in the wound bed decreased by 49 ± 7% when NPWT was applied to control wounds. The reduction in blood flow was less in the presence of a protective disc (e.g., -6 ± 5% for a dressing-covered, perforated disc, p = 0.006). In conclusion, NPWT causes hypoperfusion of superficial tissue in the wound bed. The insertion of a rigid barrier counteracts this effect. The placement of a rigid disc over exposed blood vessels or nerves may protect these structures from rupture and damage.
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| 4. |
- Pasupuleti, Mukesh, et al.
(författare)
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Antimicrobial activity of human prion protein is mediated by its N-terminal region
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:10, s. e7358-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cellular prion-related protein (PrP(c)) is a cell-surface protein that is ubiquitously expressed in the human body. The multifunctionality of PrP(c), and presence of an exposed cationic and heparin-binding N-terminus, a feature characterizing many antimicrobial peptides, made us hypothesize that PrP(c) could exert antimicrobial activity. METHODOLOGY AND PRINCIPAL FINDINGS: Intact recombinant PrP exerted antibacterial and antifungal effects at normal and low pH. Studies employing recombinant PrP and N- and C-terminally truncated variants, as well as overlapping peptide 20mers, demonstrated that the antimicrobial activity is mediated by the unstructured N-terminal part of the protein. Synthetic peptides of the N-terminus of PrP killed the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, and the Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungus Candida parapsilosis. Fluorescence studies of peptide-treated bacteria, paired with analysis of peptide effects on liposomes, showed that the peptides exerted membrane-breaking effects similar to those seen after treatment with the "classical" human antimicrobial peptide LL-37. In contrast to LL-37, however, no marked helix induction was detected for the PrP-derived peptides in presence of negatively charged (bacteria-mimicking) liposomes. PrP furthermore showed an inducible expression during wounding of human skin ex vivo and in vivo, as well as stimulation of keratinocytes with TGF-alpha in vitro. CONCLUSIONS: The demonstration of an antimicrobial activity of PrP, localisation of its activity to the N-terminal and heparin-binding region, combined with results showing an increased expression of PrP during wounding, indicate that PrPs could have a previously undisclosed role in host defense.
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| 5. |
- Roupé, Karl Markus, et al.
(författare)
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Transcription Factor Binding Site Analysis Identifies FOXO Transcription Factors as Regulators of the Cutaneous Wound Healing Process.
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- The search for significantly overrepresented and co-occurring transcription factor binding sites in the promoter regions of the most differentially expressed genes in microarray data sets could be a powerful approach for finding key regulators of complex biological processes. To test this concept, two previously published independent data sets on wounded human epidermis were re-analyzed. The presence of co-occurring transcription factor binding sites for FOXO1, FOXO3 and FOXO4 in the majority of the promoter regions of the most significantly differentially expressed genes between non-wounded and wounded epidermis implied an important role for FOXO transcription factors during wound healing. Expression levels of FOXO transcription factors during wound healing in vivo in both human and mouse skin were analyzed and a decrease for all FOXOs in human wounded skin was observed, with FOXO3 having the highest expression level in non wounded skin. Impaired re-epithelialization was found in cultures of primary human keratinocytes expressing a constitutively active variant of FOXO3. Conversely knockdown of FOXO3 in keratinocytes had the opposite effect and in an in vivo mouse model with FOXO3 knockout mice we detected significantly accelerated wound healing. This article illustrates that the proposed approach is a viable method for identifying important regulators of complex biological processes using in vivo samples. FOXO3 has not previously been implicated as an important regulator of wound healing and its exact function in this process calls for further investigation.
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| 6. |
- Roupé, Markus
(författare)
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Epidermal Reactions to Injury with Implications for Innate Immunity
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract The epidermis is one of our primary interfaces towards the external milieu. Following injury, the physical barrier function of the skin is destroyed and the epidermis is left vulnerable to microbial invasion. Inducible innate immune response mechanisms exist to keep the wound site free from infection, thus allowing the wound to heal and the epidermis to re-establish its barrier function. The main focus of the present thesis has been to investigate the regulatory mechanisms of some of these responses. In paper I we present an injury-induced mechanism for increasing the production of antimicrobial peptides (AMPs) in the skin mediated by the epidermal growth factor receptor (EGFR) transactivation process. In paper II we further highlight the importance of this mechanism by demonstrating that it is responsible for the bulk of the expression of the AMPs known to be induced in epidermis during the proliferative phase of wound healing. In addition we show that the EGFR-mediated increase in interleukin-8 (IL-8) production represents the primary source of chemotactic activity towards neutrophils generated in injured human epidermis. Thus a novel molecular link between cutaneous injury and neutrophil accumulation is provided. In paper III we disclose a possible role of the prion protein as an AMP in host defense, based on its antimicrobial properties and EGFR-dependent induction in response to injury. In paper IV we furthermore report an increased expression of several protease inhibitors during wound healing and a change in gene expression in the epidermal tissue representing a shift in the apoptotic balance. The shift indicates a reduced sensitivity to the extrinsic pathway of apoptosis and concomitantly, an apparently increased sensitivity to the intrinsic pathway of apoptosis. Taken together we hypothesize that this represents an epidermal response to cope with the external detrimental effects of inflammation while safeguarding itself against the increased risk of malignant transformation accompanying the increased proliferation. Finally we identify a highly significant overrepresentation of transcription factor binding sites for forkhead box O1 (FOXO1), FOXO4 and STAT5A, in the most differentially expressed genes in injured skin. This indicates, for the first time, that these transcription factors might play a major role in the wound healing process.
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| 7. |
- Roupé, Markus, et al.
(författare)
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Gene expression demonstrates increased resilience toward harmful inflammatory stimuli in the proliferating epidermis of human skin wounds
- 2010
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Ingår i: Experimental Dermatology. - : Wiley. - 0906-6705 .- 1600-0625. ; 19:8, s. 329-332
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Tidskriftsartikel (refereegranskat)abstract
- We examined the epidermal gene expression during the proliferative phase of wound healing. Matrix metalloproteases were the group of proteases most prominently up-regulated in skin wounds, whereas serine protease inhibitors were the most strongly up-regulated protease inhibitors. Furthermore, we found down-regulation of genes involved in the extrinsic pathway of apoptosis. This together with the up-regulation of inhibitors of leukocyte serine proteases likely represents a protective step to ensure survival of keratinocytes in the inflammatory wound environment. The down-regulation of proapoptotic genes in the extrinsic pathway of apoptosis was not accompanied by a down-regulation of receptors indicating that the keratinocytes in skin wounds did not become less responsive to external stimuli. Examining the transcription factor binding sites in the promoters of the most differentially expressed genes between normal skin and skin wounds a significant overrepresentation of binding sites were found for STAT-5, SRY and members of the FOXO-family of transcription factors.
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| 8. |
- Roupé, Markus, et al.
(författare)
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Injury Is a Major Inducer of Epidermal Innate Immune Responses during Wound Healing.
- 2010
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 130, s. 1167-1177
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Tidskriftsartikel (refereegranskat)abstract
- We examined the importance of injury for the epidermal innate immune response in human skin wounds. We found that injury, independent of infiltrating inflammatory cells, generated prominent chemotactic activity toward neutrophils in injured skin because of IL-8 production. Furthermore, injury was a major inducer of the expression of antimicrobial (poly)peptides (AMPs) in skin wounds. In human skin, these injury-induced innate immune responses were mediated by activation of the epidermal growth factor receptor (EGFR). Consequently, inhibition of the EGFR blocked both the chemotactic activity generated in injured skin and the expression of the majority of the AMPs. The importance of injury was confirmed in mouse experiments in vivo, in which injury independent of infection was a potent inducer of AMPs in skin wounds. To our knowledge, these data thereby provide a previously unreported molecular link between injury and neutrophil accumulation and identify the molecular background for the vast expression of IL-8 and AMPs in wounded epidermis. Conceptually, these data show that the growth factor response elicited by injury is important for the recruitment of neutrophils in skin wounds.Journal of Investigative Dermatology advance online publication, 3 September 2009; doi:10.1038/jid.2009.284.
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| 9. |
- Runstrom, Anna, et al.
(författare)
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IgM single antigen bead HLA-assay is affected by imlifidase through the cleavage of IgG but not IgM
- 2021
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Ingår i: Transplant Immunology. - : Elsevier. - 0966-3274 .- 1878-5492. ; 68
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The aim of this study was to investigate if human IgM is a cleavable substrate for imlifidase and to explain an observed effect in anti-HLA IgM single antigen bead (SAB) assays in sensitized patients. Methods: Serum samples collected pre-and 24 h post-imlifidase administration from sensitized patients enrolled in a phase II trial were investigated for anti-HLA IgG and IgM using SAB assays, with and without in vitro IgG depletion using a CaptureSelectTM affinity matrix. In addition, pre-dose samples and purified human IgM samples were treated with imlifidase in vitro and evaluated by SDS-PAGE, Western blot (PE-conjugated anti-human IgM) and SAB (IgG, IgM) assays. Results: By comparing the mean fluorescence intensity (MFI) of HLA-beads, pre-and post-imlifidase administration, three IgM-related patterns were observed; IgM-specific HLA-SABs with an increased MFI post-imlifidase, IgM-specific HLA-SABs with a decreased MFI post-imlifidase, and IgM-specific HLA-SABs with a marginal MFI difference between the pre-and post-imlifidase administration. These IgM signal patterns were observed despite neither purified IgM nor serum IgM could be cleaved by imlifidase. After removing IgG, the effects observed on anti-HLA IgM was largely eliminated with the biggest differences seen in patients with very high anti-HLA IgG in pre-dose samples. Conclusion: We demonstrate that imlifidase does not cleave human IgM, including HLA-specific IgM antibodies from highly sensitized subjects. Observed decreases of SAB-HLA IgM signals after imlifidase treatment may result from the cleavage of IgG-IgM complexes which are bound to SAB-HLA. Serum analysis of patients with high levels of anti-HLA IgG will result in a more accurate SAB-HLA IgM reading after IgG depletion.
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| 10. |
- Secundino, Ismael, et al.
(författare)
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Host and pathogen hyaluronan signal through human siglec-9 to suppress neutrophil activation.
- 2016
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Ingår i: Journal of Molecular Medicine. - : Springer Science and Business Media LLC. - 1432-1440 .- 0946-2716. ; 94, s. 219-219
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Tidskriftsartikel (refereegranskat)abstract
- Inhibitory CD33-related Siglec receptors regulate immune cell activation upon engaging ubiquitous sialic acids (Sias) on host cell surface glycans. Through molecular mimicry, Sia-expressing pathogen group B Streptococcus binds inhibitory human Siglec-9 (hSiglec-9) to blunt neutrophil activation and promote bacterial survival. We unexpectedly discovered that hSiglec-9 also specifically binds high molecular weight hyaluronan (HMW-HA), another ubiquitous host glycan, through a region of its terminal Ig-like V-set domain distinct from the Sia-binding site. HMW-HA recognition by hSiglec-9 limited neutrophil extracellular trap (NET) formation, oxidative burst, and apoptosis, defining HMW-HA as a regulator of neutrophil activation. However, the pathogen group A Streptococcus (GAS) expresses a HMW-HA capsule that engages hSiglec-9, blocking NET formation and oxidative burst, thereby promoting bacterial survival. Thus, a single inhibitory lectin receptor detects two distinct glycan "self-associated molecular patterns" to maintain neutrophil homeostasis, and two leading human bacterial pathogens have independently evolved molecular mimicry to exploit this immunoregulatory mechanism.
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