| 1. |
- Fjaertoft, Gustav, et al.
(författare)
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Neutrophil CD64 (FcgammaRI) expression is a specific marker of bacterial infection : A study on the kinetics and the impact of major surgery
- 2007
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Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 39:6-7, s. 525-535
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil CD64 expression is a diagnostic marker for the early detection of bacterial infections. The aim was to investigate the kinetics of neutrophil CD64 expression during bacterial infection and the possible impact of surgical trauma. Blood samples were collected daily during 3 d after admission for analysis by flow cytometry of the surface expressions on neutrophils and monocytes of CD64, CD16, CD32, CD11b/CD18 and CD35, and analysis of serum CRP and blood WBC. Serum concentrations of IFNgamma, G-CSF, IL-6 and IL-8 were also analysed in adults. Eight children and 19 adult patients with bacterial infections, 12 patients admitted for hip-arthroplasty because of coxarthrosis and 30 healthy adults were studied. Neutrophil CD64 was increased all 3 d after start of treatment (p<0.0001) in children and adults with bacterial infections. The postoperative increase after surgery was less than the increase seen during bacterial infections (p<0.0001). CRP, G-CSF, IL-6 and IL-8 were raised both in bacterial infections and after surgery. Our results indicate that the expression of CD64 on neutrophils is a specific sign of bacterial infections. Neutrophil expression of CD64, therefore, seems to be a promising tool for the early detection of bacterial infections even during surgery.
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| 2. |
- Marsell, Richard, et al.
(författare)
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GSK-3 inhibition by an orally active small molecule increases bone mass in rats
- 2012
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:3, s. 619-627
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Tidskriftsartikel (refereegranskat)abstract
- Glycogen synthase kinase 3β (GSK-3β) actions are central in the canonical Wnt pathway, important in many biological processes and a potential drug target for treating several diseases. It is appreciated that a balanced Wnt canonical signaling is crucial for the maintenance of normal bone mass. In this study we investigated the effects of a potent orally active GSK-3 inhibitor, AZD2858, on bone mass in rats. Treatment (1μM) of human osteoblast cells with AZD2858 in vitro increased β-catenin levels after a short period of time. In rats, oral AZD2858 treatment caused a dose-dependent increase in trabecular bone mass compared to control after a two-week treatment with a maximum effect at a dose of 20mg/kg once daily (total BMC: 172% of control; p<0.001). A small but significant effect was also seen at cortical sites (total BMC: 111% of control; p<0.001). Biomechanical testing demonstrated an increase in both vertebral compression strength at a dose of 20mg/kg once daily (Load at failure: 370% of control, p<0.001) and diaphyseal strength of femora subjected to a three point bending test (Load at failure: 115% of control; p<0.01). Furthermore, histomorphometry showed a dramatic increase in bone formation indices, and serum markers of both bone formation (Osteocalcin, 146% of control; p<0.001) and resorption (CTX, 189% of control; p<0.001) were elevated. Our conclusion is that a GSK-3 inhibitor drug may prove effective as an anabolic strategy in the treatment of diseases characterized by low bone mass, since AZD2858 has extensive bone building effects at predominantly trabecular sites.
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| 5. |
- Silfverswärd, Carl-Johan, et al.
(författare)
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Bone formation in interleukin-4 and interleukin-13 depleted mice.
- 2008
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Ingår i: Acta orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 79:3, s. 410-20
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Cytokines play an important role in the complex process of bone formation. We have previously found an altered skeletal phenotype with reduction of cortical bone mass in mice depleted of the 2 cytokines interleukin-4 (IL-4) and interleukin-13 (IL 13). The present study was performed to investigate a potential role of IL-4 and IL-13 in fracture healing and bone induction by demineralized xenogenic bone matrix (DXBM). METHODS: Callus formation in IL-4-(/)-IL-13-(/)- (IL-4/13 knockout) and wild-type (WT) male mice was compared using a standardized fracture model. The capacity of IL-4(-/-)IL-13(-/-) and WT male and female mice to form heterotopic bone was compared using intramuscular implants of DXBM. Bone formation and mechanical properties were evaluated by pQCT, ash weight, 3-point bending, radiology, and immunohistology. RESULTS: In the fracture investigation substantial amounts of new bone formation by 5 weeks were found, but no differences in radiographical healing, callus volume, BMD, BMC, or mechanical properties were detected between IL-4(-/-)IL-13(-/-) and WT mice. In the DXBM investigation radiographic analysis confirmed mineralization of implants in both groups, but no difference in the amount of mineral deposition (net bone formation) between IL-4(-/-)IL-13(-/-) and WT mice was found. Immunohistology showed inhibition of autonomic nerves in the capsule of the IL-4(-/-)IL-13(-/-) group along with a lack of vascularization within the implants. INTERPRETATION: Depletion of IL-4 and IL-13 does not cause any major alteration in fracture healing or heterotopic bone formation in mice. The pattern of autonomous nerve expression and expression of markers of neovascularization is, however, altered to some extent by the absence of IL-4 and IL-13.
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| 7. |
- Sisask, Gregor, 1951-
(författare)
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Bone Development and the Nervous System
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Innervation of bone influence bone modeling, growth and remodeling. Pro-inflammatory cytokines released after tissue trauma are recognized as neurotrophic factors as well as factors influencing bone formation. The Wnt signaling pathway, essential for cell migration during embryogenesis is found to influence bone formation during fracture healing. Alterations in growth and bone formation are seen in denervating disorders and in manipulated Wnt signaling. The aim of the present thesis was to study; sensory and autonomic innervation in the developing skeleton in rats and mice, a possible influence on bone formation in IL-4 and IL-13 depleted mice, and fracture healing in altered Wnt signaling by glycogen synthase-3β inhibition in rats.Bone innervation with sensory and autonomic nerves in modeling and growth follows a predictable and reproducible pattern both in the rat and in the mouse with sensory nerves occurring prior to autonomic nerves in areas with high chondrogenic and osteogenic activity. The time lag in occurrence between sensory and autonomic nerves indicates the importance of developmental timing between different nerve qualities in skeletal ontogeny. These findings give substantial morphologic support for important regulatory effects by the nervous system on bone development.Depletion of the anti-inflammatory cytokines IL-4 and IL-13 production in mice resulted in an inhibited autonomic innervation and lack of implant capillary ingrowth, studied by DXBM implants. In fracture healing no differences between IL-4/13 knockout mice and wild type mice were found concerning fracture callus parameters, biomechanical properties or histology except that sensory and autonomic nerves were found in the bone marrow in knockout mice but not in wild type mice.An altered canonical Wnt signaling was achieved by the GSK-3β inhibitor AR28. The increase in cytoplasmic β-catenin, due to inhibited degradation, resulted in a remarkable anabolic effect both on the fractured bone and on fracture healing. The histological analysis showed that the fractures healed without the usual formation of fibro-cartilage callus. This finding suggests that inhibition of GSK-3β inhibits the differentiation of chondrocytes and instead promotes the differentiation of mesenchymal progenitor cells into osteogenic cells.
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| 8. |
- Sisask, Gregor, 1951-, et al.
(författare)
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Ontogeny of sensory and autonomic nerves in the developing mouse skeleton
- 2013
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Ingår i: Autonomic Neuroscience. - : Elsevier BV. - 1566-0702 .- 1872-7484. ; 177:2, s. 237-243
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bone innervation is implicated in bone modeling and remodeling. This study investigates skeletal nerve development in embryonic and newborn mice, focusing on sensory and autonomic nerves and their temporal occurrence. Materials and methods: The ontogeny of innervation and angiogenesis in the hindlimb skeleton of mice was studied from embryonic day (E) 15 to postnatal day (P) 20. Neuronal tissue was immunohistochemically labeled for detection of growth associated protein 43 (GAP-43), protein gene product 9.5 (PGP 9.5), calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), and neuropeptide Y (NPY). Vascular endothelium was labeled for platelet endothelium cell adhesion molecule-1 (PECAM-1). Morphology was evaluated with hematoxylin and eosin staining. Results: GAP-43, PGP 9.5, CGRP, and PECAM-1 were all present at E 15, adjacent to areas with high osteogenic and chondrogenic activity. In the primary ossification centers, GAP-43 was found at E 15, PGP 9.5 at E 17, CGRP at E 19, and NPY at P4. The same time lag in appearance was observed in the secondary ossification centers. The covering capillary network was initially dense, but became mature and sparse from P 12 onwards. Conclusion: A functional nerve supply co-localized with a rich capillary network is seen early in the developing mouse skeleton, especially in areas with high osteogenic activity. Sensory innervation occurs prior to partus, while autonomic innervation (revealed by the presence of NPY and TH) is established post partum. The findings indicate a time-related development of nerves with different qualities, according to skeletal development.
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| 9. |
- Sisask, Gregor, 1951-, et al.
(författare)
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Ontogeny of sensory nerves in the developing skeleton
- 1995
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Ingår i: Anatomical Record. - : Wiley. - 0003-276X .- 1097-0185. ; 243:2, s. 234-240
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies have shown that the neuropeptide calcitonin gene-related peptide (CGRP) have an influence on osteoclastic bone resorption and that CGRP and substance P (SP), both wellknown markers for sensory neurons, behave as growth factors.Materials and Methods: The ontogeny of the sensory nerves in the hindlimb skeleton of the rat was studied from gestational day (GD) 15 to neonatal day (ND) 24 by immunohistochemistry. Neurofilaments and nerve terminals were labelled with protein gene-product 9.5 (PGP 9.5) and synaptophycin (SYN) respectively.Results: PGP 9.5 appeared at GD 15 and SYN at GD 19, both in the perichondrial tissue of the long bones. One week later, at ND 4 nerve fibre, immunoreactive to PGP 9.5 and SYN were observed within the bone organ. Sensory nerves, indicated by CGRP and SP, were first discerned at GD 18-19 in the periosteal tissue of the diaphyseal and metaphseal regions and in the bone organ at ND 4. Approximately at ND 6, vascular as well as non-vascular nerves extended into the metaphyses and at ND 8 into the epiphyses, concomitant with the first signs of mineralization.Conclusions: The study shows that a functional sensory nerve supply of the developing bone organ occurs immediatly prior to partus, apparently parallel with an increasing mineralization. The combined findings may indicate a sensory influence on developmental processes in the skeleton
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| 10. |
- Sisask, Gregor, et al.
(författare)
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Rats treated with AZD2858, a GSK3 inhibitor, heal fractures rapidly without endochondral bone formation
- 2013
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 54:1, s. 126-132
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Tidskriftsartikel (refereegranskat)abstract
- Fracture healing is a complex interplay between endochondral and intramembranous bone formation processes. The canonical Wnt/β-catenin pathway enhances new bone formation and may play a role in fracture healing. Glycogen synthase kinase 3β (GSK3β) is a key regulator of β-catenin degradation. In this study, we investigate the effects of AZD2858, an orally bioactive GSK3 inhibitor, on fracture healing. Femoral fractures were produced in rats after the insertion of a femoral nail. The rats were treated with oral administration of AZD2858 at a dose of 30μmol/kg (20mg/kg) daily for up to 3weeks, while control animals were administered vehicle. At 4days, and at 1, 2 and 3weeks, histological analysis was performed, and at the 2 and 3week time points, we performed peripheral quantitative computed tomography (pQCT), X-rays, and four-point bending tests. Peripheral QCT showed an increase in both mineral density (of 28% at 2weeks and 38% at 3weeks) and mineral content (of 81% at 2weeks and 93% at 3weeks) in the calluses from AZD2858 treated animals as compared to vehicle treated animals. Histological analysis demonstrated that rats treated with GSK3 inhibitor healed their fractures rapidly, but without the pre-formation of cartilage tissue. Furthermore, four-point bending tests of fractured femora from animals treated for 2 and 3weeks showed an increase in strength in treated animals compared to their vehicle-treated controls. In conclusion, AZD2858, a potent GSK3 inhibitor, has a substantial impact on fracture healing. The fractures healed with a bony callus without an obvious endochondral component, suggesting that AZD2858 drives mesenchymal cells into the osteoblastic pathway. This leads to direct bone repair in an unstable fracture milieu.
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