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  • 101.
    Englezou, Pavlos C.
    et al.
    University of Manchester.
    Degli Esposti, Mauro
    University of Manchester.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Reid, Adam J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Mitochondrial involvement in sensory neuronal cell death and survival2012In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 221, no 4, p. 357-367Article in journal (Refereed)
    Abstract [en]

    Peripheral nerve injuries (PNI) are continuing to be an ever-growing socio-economic burden affecting mainly the young working population and the current clinical treatments to PNI provide a poor clinical outcome involving significant loss of sensation. Thus, our understanding of the underlying factors responsible for the extensive loss of the sensory cutaneous subpopulation in the dorsal root ganglia (DRG) that occurs following injury needs to be improved. The current investigations focus in identifying visual cues of mitochondria-related apoptotic events in the various subpopulations of sensory cutaneous neurons. Sensory neuronal subpopulations were identified using FastBlue retrograde labelling following axotomy. Specialised fluorogenic probes, MitoTracker Red and MitoTracker Orange, were employed to visualise the dynamic changes of the mitochondrial population of neurons. The results reveal a fragmented mitochondrial network in sural neurons following apoptosis, whereas a fused elongated mitochondrial population is present in sensory proprioceptive muscle neurons following tibial axotomy. We also demonstrate the neuroprotective properties of NAC and ALCAR therapy in vitro. The dynamic mitochondrial network breaks down following oxidative exposure to hydrogen peroxide (H2O2), but reinitiates fusion after NAC and ALCAR therapy. In conclusion, this study provides both qualitative and quantitative evidence of the susceptibility of sensory cutaneous sub-population in apoptosis and of the neuroprotective effects of NAC and ALCAR treatment on H2O2-challenged neurons.

  • 102.
    Erba, P
    et al.
    University of Manchester, University Hospital of Basel.
    Mantovani, Cristina
    University of Manchester.
    Kalbermatten, Daniel F
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pierer, G
    University Hospital of Basel.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits2010In: Journal of plastic, reconstructive & aesthetic surgery : JPRAS, ISSN 1878-0539, Vol. 63, no 12, p. e811-e817Article in journal (Refereed)
    Abstract [en]

    Adipose tissue-derived stem cells (ADSCs) have shown potential for the treatment of nerve injuries. Most previous efforts have aimed at stimulating regeneration by using neural-differentiation protocols, but the potential of undifferentiated ADSCs to enhance axonal growth as well as their ability to transdifferentiate in situ have been poorly investigated. In this study, using a rat sciatic nerve model we show that ADSCs, transplanted in an artificial nerve conduit, stimulate axonal outgrowth from the proximal nerve stump and evoke greater Schwann cell (SC) proliferation/intrusion in the distal stump. To track the fate of the transplanted cells, we used green fluorescent protein (GFP)-labelling and polymerase chain reaction (PCR) for the detection of the sex determining region Y (SRY) gene in the donor male cells. Both methods indicated a lack of significant quantities of viable cells 14 days after transplantation. These results suggest that any regenerative effect of transplanted ADSCs is more likely to be mediated by an initial boost of released growth factors and/or by an indirect effect on endogenous SCs activity. Future studies need to address long-term cell survival in tissue-engineered nerve conduits to improve the neuroregenerative potential of ADSCs.

  • 103.
    Erba, Paolo
    et al.
    University Hospitals of Basel and Lausanne.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Neural differentiation and therapeutic potential of adipose tissue derived stem cells2010In: Current stem cell research & therapy, ISSN 1574-888X, Vol. 5, no 2, p. 153-160Article, review/survey (Refereed)
    Abstract [en]

    Neural tissue has historically been regarded as having poor regenerative capacity but recent advances in the growing fields of tissue engineering and regenerative medicine have opened new hopes for the treatment of nerve injuries and neurodegenerative disorders. Adipose tissue has been shown to contain a large quantity of adult stem cells (ASC). These cells can be easily harvested with low associated morbidity and because of their potential to differentiate into multiple cell types, their use has been suggested for a wide variety of therapeutic applications. In this review we examine the evidence indicating that ASC can stimulate nerve regeneration by both undergoing neural differentiation and through the release of a range of growth factors. We also discuss some of the issues that need to be addressed before ASC can be developed as an effective cellular therapy for the treatment of neural tissue disorders.

  • 104.
    Eriksson, Anders
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Forensic Medicine.
    Intermediate-sized (skeletin) filaments of heart Purkinje fibres: an investigation into their morphology, composition and function1979Doctoral thesis, comprehensive summary (Other academic)
  • 105.
    Eriksson, Anders
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Kadi, Fawzi
    Malm, Christer
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Skeletal muscle morphology in power-lifters with and without anabolic steroids.2005In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 124, no 2, p. 167-175Article in journal (Refereed)
    Abstract [en]

    The morphological appearance of the vastus lateralis (VL) muscle from high-level power-lifters on long-term anabolic steroid supplementation (PAS) and power-lifters never taking anabolic steroids (P) was compared. The effects of long- and short-term supplementation were compared. Enzyme-immunohistochemical investigations were performed to assess muscle fiber type composition, fiber area, number of myonuclei per fiber, internal myonuclei, myonuclear domains and proportion of satellite cells. The PAS group had larger type I, IIA, IIAB and IIC fiber areas (p<0.05). The number of myonuclei/fiber and the proportion of central nuclei were significantly higher in the PAS group (p<0.05). Similar results were seen in the trapezius muscle (T) but additionally, in T the proportion of fibers expressing developmental myosin isoforms was higher in the PAS group compared to the P group. Further, in VL, the PAS group had significantly larger nuclear domains in fibers containing > or = 5 myonuclei. The results of AS on VL morphology in this study were similar to previously reported short-term effects of AS on VL. The initial effects from AS appear to be maintained for several years.

  • 106.
    Eriksson, Anders
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Lindström, Mona
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Carlsson, Lena
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Hypertrophic muscle fibers with fissures in power-lifters; fiber splitting or defect regeneration?2006In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 126, no 4, p. 409-417Article in journal (Refereed)
    Abstract [en]

    Power-lifters have hypertrophic muscle fibers with fissures seen in cross-sections, called as fiber splitting.Whether this phenomenon is due to real splitting or defective regeneration has not been settled. To elucidate this matter,we have examined biopsies from the trapezius and vastus lateralis of power lifters (P group) and power lifters self-administrating anabolic steroids (PAS group). For this purpose, immunohistochemical staining of serial cross -sections was used. The PAS group had significantly more fibers with fissures than the P group in the vastus lateralis (1.2%+/-0.95% vs 0.35+/-0.34, P < 0.05) but not in the trapezius muscle (1.7% in both groups). Serial sections revealed that the fibers with fissures changed their profile profoundly over short distances. Some such fibers had a mature staining profile, whereas other fibers indicated recent degeneration and/or regeneration. Activation of satellite cells and formation of aberrant segments were also evident. We conclude that the so-called split fibers are due to defect regeneration. Some fibers with fissures are the results of old events of segmental muscle fiber damage, whereas the others reflect an ongoing process. The normal regenerative process is most likely disturbed in power-lifters by their continuous training with repeated high mechanical stress on the muscles.

  • 107. Faroni, Alessandro
    et al.
    Mobasseri, S. Atefeh
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Reid, Adam J.
    Peripheral nerve regeneration: experimental strategies and future perspectives2015In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 82-83, p. 160-167Article, review/survey (Refereed)
    Abstract [en]

    Peripheral nerve injuries represent a substantial clinical problem with insufficient or unsatisfactory treatment options. This review summarises all the events occurring after nerve damage at the level of the cell body, the site of injury and the target organ. Various experimental strategies to improve neuronal survival, axonal regeneration and target reinnervation are described including pharmacological approaches and cell-based therapies. Given the complexity of nerve regeneration, further studies are needed to address the biology of nerve injury, to improve the interaction with implantable scaffolds, and to implement cell-based therapies in nerve tissue engineering. 

  • 108. Fischer, M Dominik
    et al.
    Budak, Murat T
    Bakay, Marina
    Gorospe, J Rafael
    Kjellgren, Daniel
    Pedrosa-Domellöf, F
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Hoffman, Eric P
    Khurana, Tejvir S
    Definition of the unique human extraocular muscle allotype by expression profiling.2005In: Physiol Genomics, ISSN 1531-2267, Vol. 22, no 3, p. 283-91Article in journal (Refereed)
    Abstract [en]

    The extraocular muscles (EOMs) are a unique group of specialized muscles that are anatomically and physiologically distinct from other skeletal muscles. Perhaps the most striking characteristic of the EOMs is their differential sensitivity to disease. EOMs are spared in Duchenne's muscular dystrophy (DMD) despite widespread involvement of other skeletal muscles. Conversely, they are early and prominent targets in myasthenia gravis and mitochondrial myopathies. It is unclear how EOMs achieve such specialization or a differential response to diseases; however, this has been attributed to a unique, group-specific pattern of gene expression or "allotype." To begin to address these issues as well as define the human EOM allotype, we analyzed the human EOM transcriptome using oligonucleotide-based expression profiling. Three hundred thirty-eight genes were found to be differentially expressed in EOM compared with quadriceps femoris limb muscle, using a twofold cutoff. Functional characterization revealed expression patterns corresponding to known metabolic and structural properties of EOMs such as expression of EOM-specific myosin heavy chain (MYH13) and high neural, vascular, and mitochondrial content, suggesting that the profiling was sensitive and specific. Genes related to myogenesis, stem cells, and apoptosis were detected at high levels in normal human EOMs, suggesting that efficient and continuous regeneration and/or myogenesis may be a mechanism by which the EOMs remain clinically and pathologically spared in diseases such as DMD. Taken together, this study provides insight into how human EOMs achieve their unique structural, metabolic, and pathophysiological properties.

  • 109.
    Fischer, M Dominik
    et al.
    University of Pennsylvania School of Medicine.
    Gorospe, J Rafael
    George Washington University, Washington.
    Felder, Edward
    University of Pennsylvania School of Medicine, Philadelphia.
    Bogdanovich, Sasha
    University of Pennsylvania School of Medicine.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ahima, Rexford S
    University of Pennsylvania School of Medicine, Philadelphia.
    Rubinstein, Neal A
    University of Pennsylvania School of Medicine, Philadelphia.
    Hoffman, Eric P
    George Washington University, Washington.
    Khurana, Tejvir S
    University of Pennsylvania School of Medicine.
    Expression profiling reveals metabolic and structural components of extraocular muscles2002In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 9, no 2, p. 71-84Article in journal (Refereed)
    Abstract [en]

    The extraocular muscles (EOM) are anatomically and physiologically distinct from other skeletal muscles. EOM are preferentially affected in mitochondrial myopathies, but spared in Duchenne's muscular dystrophy. The anatomical and pathophysiological properties of EOM have been attributed to their unique molecular makeup: an allotype. We used expression profiling to define molecular features of the EOM allotype. We found 346 differentially expressed genes in rat EOM compared with tibialis anterior, based on a twofold difference cutoff. Genes required for efficient, fatigue-resistant, oxidative metabolism were increased in EOM, whereas genes for glycogen metabolism were decreased. EOM also showed increased expression of genes related to structural components of EOM such as vessels, nerves, mitochondria, and neuromuscular junctions. Additionally, genes related to specialized functional roles of EOM such as the embryonic and EOM-specific myosin heavy chains and genes for muscle growth, development, and/or regeneration were increased. The EOM expression profile was validated using biochemical, structural, and molecular methods. Characterization of the EOM expression profile begins to define gene transcription patterns associated with the unique anatomical, metabolic, and pathophysiological properties of EOM.

  • 110.
    Fong, Gloria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    Vancouver Coastal Health and Research Institute.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Human tenocytes are stimulated to proliferate by acetylcholine through an EGFR signalling pathway2013In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 351, no 3, p. 465-475Article in journal (Refereed)
    Abstract [en]

    Studies of human patellar and Achilles tendons have shown that primary tendon fibroblasts (tenocytes) not only have the capacity to produce acetylcholine (ACh) but also express muscarinic ACh receptors (mAChRs) through which ACh can exert its effects. In patients with tendinopathy (chronic tendon pain) with tendinosis, the tendon tissue is characterised by hypercellularity and angiogenesis, both of which might be influenced by ACh. In this study, we have tested the hypothesis that ACh increases the proliferation rate of tenocytes through mAChR stimulation and have examined whether this mechanism operates via the extracellular activation of the epidermal growth factor receptor (EGFR), as shown in other fibroblastic cells. By use of primary human tendon cell cultures, we identified cells expressing vimentin, tenomodulin and scleraxis and found that these cells also contained enzymes related to ACh synthesis and release (choline acetyltransferase and vesicular acetylcholine transporter). The cells furthermore expressed mAChRs of several subtypes. Exogenously administered ACh stimulated proliferation and increased the viability of tenocytes in vitro. When the cells were exposed to atropine (an mAChR antagonist) or the EGFR inhibitor AG1478, the proliferative effect of ACh decreased. Western blot revealed increased phosphorylation, after ACh stimulation, for both EGFR and the extracellular-signal-regulated kinases 1 and 2. Given that tenocytes have been shown to produce ACh and express mAChRs, this study provides evidence of a possible autocrine loop that might contribute to the hypercellularity seen in tendinosis tendon tissue.

  • 111.
    Fong, Gloria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Centre for Hip Health and Mobility, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Scott, Alex
    Centre for Hip Health and Mobility, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    The Effects of Substance P and Acetylcholine on Human Tenocyte Proliferation Converge Mechanistically via TGF-β12017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e0174101Article in journal (Refereed)
    Abstract [en]

    Previous in vitro studies on human tendon cells (tenocytes) have demonstrated that the exogenous administration of substance P (SP) and acetylcholine (ACh) independently result in tenocyte proliferation, which is a prominent feature of tendinosis. Interestingly, the possible link between SP and ACh has not yet been explored in human tenocytes. Recent studies in other cell types demonstrate that both SP and ACh independently upregulate TGF-β1 expression via their respective receptors, the neurokinin 1 receptor (NK-1R) and muscarinic ACh receptors (mAChRs). Furthermore, TGF-β1 has been shown to downregulate NK-1R expression in human keratocytes. The aim of this study was to examine if TGF-β1 is the intermediary player involved in mediating the proliferative pathway shared by SP and ACh in human tenocytes. The results showed that exogenous administration of SP and ACh both caused significant upregulation of TGF-β1 at the mRNA and protein levels. Exposing cells to TGF-β1 resulted in increased cell viability of tenocytes, which was blocked in the presence of the TGFβRI/II kinase inhibitor. In addition, the proliferative effects of SP and ACh on tenocytes were reduced by the TGFβRI/II kinase inhibitor; this supports the hypothesis that the proliferative effects of these signal substances are mediated via the TGF-β axis. Furthermore, exogenous TGF-β1 downregulated NK-1R and mAChRs expression at both the mRNA and protein levels, and these effects were negated by simultaneous exposure to the TGFβRI/II kinase inhibitor, suggesting a negative feedback loop. In conclusion, the results indicate that TGF-β1 is the intermediary player through which the proliferative actions of both SP and ACh converge mechanistically.

  • 112.
    Fong, Gloria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Hart, David A.
    Vancouver Coastal Hlth & Res Inst, Ctr Hip Hlth & Mobil, Vancouver, BC, Canada.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    McCormack, Bob
    Vancouver Coastal Hlth & Res Inst, Ctr Hip Hlth & Mobil, Vancouver, BC, Canada.
    Scott, Alex
    Univ British Columbia, Dept Phys Therapy, Vancouver, BC V5Z 1M9, Canada.
    Substance P enhances collagen remodeling and MMP-3 expression by human tenocytes2013In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 31, no 1, p. 91-98Article in journal (Refereed)
    Abstract [en]

    The loss of collagen organization is considered a hallmark histopathologic feature of tendinosis. At the cellular level, tenocytes have been shown to produce signal substances that were once thought to be restricted to neurons. One of the main neuropeptides implicated in tendinosis, substance P (SP), is known to influence collagen organization, particularly after injury. The aim of this study was to examine the influence of SP on collagen remodeling by primary human tendon cells cultured in vitro in three-dimensional collagen lattices. We found that SP stimulation led to an increased rate of collagen remodeling mediated via the neurokinin-1 receptor (NK-1 R), the preferred cell receptor for SP. Gene expression analysis showed that SP stimulation resulted in significant increases in MMP3, COL3A1 and ACTA2 mRNA levels in the collagen lattices. Furthermore, cyclic tensile loading of tendon cell cultures along with the administration of exogenous SP had an additive effect on MMP3 expression. Immunoblotting confirmed that SP increased MMP3 protein levels via the NK-1 R. This study indicates that SP, mediated via NK-1 R, increases collagen remodeling and leads to increased MMP3 mRNA and protein expression that is further enhanced by cyclic mechanical loading.

  • 113.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Differentiation of heart Purkinje fibres: an immuno- and enzyme histochemical and ultrastructural study1982Doctoral thesis, comprehensive summary (Other academic)
  • 114.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    New data favouring that neurotrophins are of importance in arthritis2009In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 11, no 4, p. 122-Article in journal (Other academic)
    Abstract [en]

    Neurotrophins are important in inflammation. In an article in Arthritis Research & Therapy, Barthel and collaborators give new information on the existence of neurotrophin production in the synovial tissue of arthritic joints. These findings, together with other recent findings, stress that neurotrophins should be considered important factors in arthritis. This is reinforced by the facts that they are also produced by articular chondrocytes and that receptors for these are present in the synovial tissue and on chondrocytes. The importance of neurotrophins in joints should be further studied, including examinations on the efficacy of interfering with their effects in arthritis.

  • 115.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of ChAT mRNA and a very marked alpha 7nAChR immunoreaction in the synovial lining layer of the knee joint2012In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 91, no 21-22, p. 1043-1047Article in journal (Refereed)
    Abstract [en]

    Aims: The aim was to examine if there is evidence of acetylcholine (ACh) production within the synovial lining layer and to examine the pattern of alpha 7nAChR expression in the layer. This layer is of relevance clinically as it becomes thickened in response to both rheumatoid arthritis (RA) and osteoarthritis (OA) and as it has been shown to produce proteases that are involved in the cartilage destruction. Main methods: Synovial tissue specimens from the knee joint of patients with RA and OA undergoing prosthetic surgery were examined. In situ hybridization and immunohistochemistry were used for the evaluation of ChAT reaction patterns. Immunohistochemistry was utilized for demonstration of activity of alpha 7nAChR. Key findings: There were ChAT mRNA reactions in the synovial lining layer of both patient categories. On the other hand, no ChAT immunoreactions were detected in the layer. There was a very marked alpha 7nAChR immunoreaction. Significance: There is a potential for ACh production within the synovial lining layer as there are ChAT mRNA reactions. However, the level of ACh production is apparently very low. It is thus possible that there is a down-regulation of ACh production but an apparent upregulation in expression level of alpha 7nAChR. Based on the knowledge that the non-neuronal cholinergic system can have anti-inflammatory effects, the low level of ACh production in the synovial lining layer can be a drawback for the arthritic joints. (C) 2012 Elsevier Inc. All rights reserved.

  • 116.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Recent studies using an overuse animal model show that signal substances are highly involved in muscle derangement and muscle inflammation2013In: Proceedings of the International Congress on Sports Science Research and Technology Support / [ed] Jan Cabri, Pedro Pezarat Correia, João Barreiros, SciTePress, 2013, Vol. 1, p. 64-70p. 64-70Conference paper (Other academic)
    Abstract [en]

    Muscle overuse is a frequent condition accompanying sports-related activities. There is a lack of knowledge concerning the importance of signal substances in situations when overuse leads to markedly affected muscle structure and muscle inflammation. Recent observations on signal substance systems for the muscle tissue in situations with muscle overuse, noted via the use of a rabbit model, are therefore here focused on. The signal substance systems are the tachykinin system, the TNF-alpha system and the glutamate system. The studies have shown that all three systems are involved in the myositis/muscle derangement processes that occur. A central finding is the notion that signal substances in all three systems become locally produced in the muscle tissue and that there is a marked presence of receptors for these in the inflammatory/affected muscle tissue. The relevance of the findings in relation to what is known for the systems and possibilities in treatment regimens are discussed. Th e findings suggest that signal substances, more than what has been previously considered, should be taken into consideration as factors of relevance in situations when overuse leads to structural derangement and muscle inflammation.

  • 117.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The Cholinergic System Can Be of Unexpected Importance in Osteoarthritis2012In: Priciples of Osteoarthritis, Its definition, character, derivation and modality-related recognition / [ed] Rotschild BM, InTech, 2012, p. 461-472Chapter in book (Refereed)
    Abstract [en]

    The main belief is that joints such as the knee and ankle joints are not innervated by nerves with a cholinergic function. That includes  the assumption that these joints are not innervated by the vagus nerve (van Maanen et al., 2009a, see also Grimsholm et al., 2008). Accordingly, there is actually no morphologic proof of a cholinergic innervation of the knee joint, nor of the ankle joint. Despite this fact, it is shown that electrical and pharmacological stimulation of the vagus nerve has a diminishing effect on carragenan-induced paw inflammation in rats (Borovikova et al., 2000a) and that interference with the effects of the vagus nerve leads to effects on the knee joint arthritis as seen experimentally (van Maanen et al., 2009b). There are also other findings which  show the potential effects that interference with vagal effects has on joint inflammation. These will be discussed below. It is actually strange that interference with cholinergic effects, as via manpulations of the vagus nerve, has effects in knee joint inflamed synovium without presence of a vagal nerve innervation. One possibility is that the effects are indirect, via an occurrence of vagal effects on other sites such as the spleen (Huston et  al., 2006, see also van Maanen et al., 2009a). However, another possibility is that there is  a non-neuronal production of acetylcholine (ACh) within the synovial tissue itself. This has actually been shown to be the case (Grimsholm et al., 2008) (see  further in paragraph 3).

  • 118.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Further proof of the existence of a non-neuronal cholinergic system in the human Achilles tendon: Presence of the AChR alpha 7 receptor in tendon cells and cells in the peritendinous tissue2015In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 29, no 1, p. 195-200Article in journal (Refereed)
    Abstract [en]

    Human tendon cells have the capacity for acetylcholine (ACh) production. It is not known if the tendon cells also have the potential for ACh breakdown, nor if they show expression of the nicotinic acetylcholine receptor AChR alpha 7 (alpha 7nAChR). Therefore, tendon tissue specimens from patients with midportion Achilles tendinopathy/tendinosis and from normal midportion Achilles tendons were examined. Reaction for the degradative enzyme acetylcholinesterase (AChE) was found in some tenocytes in only a few tendinopathy tendons, and was never found in those of control tendons. Tenocytes displayed more regularly alpha 7nAChR immunoreactivity. However, there was a marked heterogeneity in the degree of this reaction within and between the specimens. alpha 7nAChR immunoreactivity was especially pronounced for tenocytes showing an oval/widened appearance. There was a tendency that the magnitude of alpha 7nAChR immunoreactivity was higher in tendinopathy tendons as compared to control tendons. A stronger alpha 7nAChR immunoreactivity than seen for tenocytes was observed for the cells in the peritendinous tissue. It is likely that the alpha 7nAChR may be an important part of an auto-and paracrine loop of non-neuronal ACh that is released from the tendon cells. The effects may be related to proliferative and blood vessel regulatory functions as well as features related to collagen deposition. ACh can furthermore be of importance in leading to anti-inflammatory effects in the peritendinous tissue, a tissue nowadays considered to be of great relevance for the tendinopathy process. Overall, the findings show that tendon tissue, a tissue known to be devoid of cholinergic innervation, is a tissue in which there is a marked non-neuronal cholinergic system.

  • 119.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bjur, Dennis
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Norrgård, Örjan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Dalén, Tore
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novel information on the non-neuronal cholinergic system in orthopedics provides new possible treatment strategies for inflammatory and degenerative diseases2009In: Orthopedic Reviews, ISSN 2035-8237, Vol. 1, no 1, p. 39-46Article in journal (Refereed)
    Abstract [en]

    Anti-cholinergic agents are used in thetreatment of several pathological conditions.Therapy regimens aimed at up-regulatingcholinergic functions, such as treatment withacetylcholinesterase inhibitors, are also currentlyprescribed. It is now known that not onlyis there a neuronal cholinergic system but alsoa non-neuronal cholinergic system in variousparts of the body. Therefore, interference withthe effects of acetylcholine (ACh) broughtabout by the local production and release ofACh should also be considered. Locally producedACh may have proliferative, angiogenic,wound-healing, and immunomodulatory functions.Interestingly, cholinergic stimulationmay lead to anti-inflammatory effects. Withinthis review, new findings for the locomotorsystem of a more widespread non-neuronalcholinergic system than previously expectedwill be discussed in relation to possible newtreatment strategies. The conditions discussedare painful and degenerative tendon disease(tendinopathy/tendinosis), rheumatoid arthritis,and osteoarthritis.

  • 120.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bjur, Dennis
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Den kroniskt smärtande senan - histopatologi.2007In: Idrottsskador - frontlinjen inom behandling och rehablitering, p. 267-274Article in journal (Refereed)
    Abstract [en]

    I denna artikel belyses de morfologiska förändringar man ser i Achilles- och patellarsena vid tendinos. Fokus riktas inte minst på nya fynd avseende utseenden för sencellerna (tenocyterna). Vidare ges en kortfattad beskrivning av vad man idag känner till avseende nervrelaterade aspekter för dessa senor hos människa. Det är sannolikt att kunskap om dessa är viktig för att man rätt ska förstå de smärtsymptom som föreligger vid tendinos och även de effekter som nyare tids behandlingar har vid dessa kroniska smärttillstånd.

  • 121.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bjur, Dennis
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Förändringar i kroniskt smärtande sena.2006In: Svensk Idrottsforskning: Organ för Centrum för Idrottsforskning, ISSN 1103-4629, Vol. 25, no 3, p. 8-10Article in journal (Refereed)
    Abstract [en]

    Vad känner man till om de förändringar som sker i en kroniskt smärtande sena?

    Hur ser sencellerna ut och hur påverkas nerverna vid tendinos? I denna sammanställning kommer de förändringar man ser i Akilles- och patellarsena vid tendinos att belysas. Fokus riktas inte minst på nya fynd avseende utseenden för sencellerna (tenocyterna). Vidare ges en kortfattad beskrivning av vad man idag känner till avseende nervrelaterade aspekter för dessa senor hos människa. Det är sannolikt att kunskap om dessa är viktig för att man rätt ska förstå de smärtsymptom som föreligger vid tendinos och även de effekter som nyare tids behandlingar har vid dessa kroniska smärttillstånd.

  • 122.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Vascular NK-1 receptor occurrence in normal and chronic painful Achilles and patellar tendons: studies on chemically unfixed as well as fixed specimens.2005In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 126, no 3, p. 173-181Article in journal (Refereed)
    Abstract [en]

    It is not known as to whether the Achilles and patellar tendons contain neurokinin-1 (NK-1) receptors. This is a drawback when considering the fact that pain symptoms are frequent in these and as recent studies show that the pain symptoms might be cured via interference with blood vessel function. In the present study, the human Achilles and patellar tendons were examined concerning immunohistochemical expression of the NK-1 receptor. Chemically unfixed and fixed specimens, TRITC and PAP stainings and a battery of NK-1 receptor antibodies, including antibodies against the C-terminus and the N-terminal region, were utilized. NK-1 receptor immunoreaction could be detected in inner parts of the walls of large blood vessels and in the walls of small blood vessels. To some extent, NK-1 immunoreaction was also detectable in small nerve fascicles and in tenocytes. It was found to be of utmost importance to apply both chemically unfixed and fixed specimens. The use of chemically unfixed tissue was found advantageous in order to depict the immunoreactions in the blood vessel walls. The observations represent new findings and are of relevance as substance P (SP) is known to be of importance where neurogenic angiogenesis contributes to diseases and as SP on the whole has profound effects concerning blood vessel regulation.

  • 123.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Grimsholm, Ola
    University of Gothenburg.
    Dalén, Tore
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Measurements in the Blood of BDNF for RA Patients and in Response to Anti-TNF Treatment Help Us to Clarify the Magnitude of Centrally Related Pain and to Explain the Relief of This Pain upon Treatment2011In: International Journal of Inflammation, ISSN 2042-0099, E-ISSN 2042-0099, Vol. 2011, p. 650685-Article, review/survey (Refereed)
    Abstract [en]

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin with functions related to neuronal survival/proliferation processes and inflammation. BDNF is also an important central pain mediator. The levels of BDNF have been found to be high for RA patients with severe disease and to become lowered in response to anti-TNF treatment. New information says that the levels of BDNF in the blood parallel the BDNF concentrations in the brain and that BDNF can pass the blood-brain barrier. Furthermore, most of the circulating BDNF is produced in the brain. Habitual and regular exercise, in contrast to temporary exercise, does also lead to a lowering of BDNF blood levels. Both anti-TNF treatment and habitual and regular exercise do have pain-relieving effects. It might be that the pain-relieving effect of anti-TNF treatment is related to an affection of central neuronal regions, hereby influencing BDNF production. Measurements of BDNF in the blood help us to clarify the magnitude of centrally related pain for RA patients and help us to explain the relief of this pain in response to anti-TNF treatment.

  • 124.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Renström, Lina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Purdam, Craig
    Gaida, James E.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. School of Primary Health Care, Monash University, Frankston, Australia.
    TNF-Alpha in the Locomotor System beyond Joints: High Degree of Involvement in Myositis in a Rabbit Model.2012In: International Journal of Rheumatology, ISSN 1687-9260, E-ISSN 1687-9279, Vol. 2012, p. 637452-Article in journal (Refereed)
    Abstract [en]

    The importance of TNF-alpha in arthritis is well documented. It may be that TNF-alpha is also markedly involved in muscle inflammation (myositis). An animal model where this can be investigated is needed. A newly developed rabbit myositis model involving pronounced muscle overuse and local injections of substances having proinflammatory effects was therefore used in the present study. The aim was to investigate the patterns of TNF-alpha expression in the developing myositis and to evaluate the usefulness of this myositis model for further TNF-alpha research. Human rheumatoid arthritis (RA) synovial tissue was examined as a reference. TNF-alpha immunoexpression and TNF-alpha mRNA, visualized via in situ hybridization, were detected in cells in the inflammatory infiltrates of the affected muscle (soleus muscle). Coexistence of TNF-alpha and CD68 immunoreactions was noted, suggesting that the TNF-alpha reactive cells are macrophages. Expression of TNF-alpha mRNA was also noted in muscle fibers and blood vessel walls in areas with inflammation. These findings demonstrate that TNF-alpha is highly involved in the myositis process. The model can be used in further studies evaluating the importance of TNF-alpha in developing myositis.

  • 125.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    In mid-portion Achilles tendinosis the plantaris tendon shows the same tendinosis-like morphological features and expression of the non-neuronal cholinergic system as the Achilles tendon itself2013In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 94, no 4, p. A3-A3Article in journal (Other academic)
  • 126.
    Fridén, Jan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. the Department of Physiology III, Karolinska Institutet, Stockholm, Sweden.
    Exercise-induced muscle soreness: a qualitative and quantitative study of human muscle morphology and function1983Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Exercise-induced muscle soreness is characterized by stiffness, tenderness and pain during active movements and weakness of the affected musculature the days after unusually or particularly heavy work. The most pronounced subjective symptoms do not arise immediately but rather between a couple of hours to some days after the exercise (a delayed-onset of muscle soreness), the intensity of pain is greatest about 48 hours after the work. A particular association exists between muscle soreness and eccentric contractions. Despite the fact that muscle soreness is a well known phenomenon in the sphere of sports as well as working life, the pathophysiological mechanisms underlying this are still not understood.

    In the present study a detailed analysis of human muscle fibre population structure after high tension work (eccentric exercise) that gave rise to muscle soreness, was carried out. The objective was to elucidate how fibres of different types are influenced by repeated muscle contractions reaching extreme tension levels using qualitative and quantitative light and electron microscopic techniques. It was hoped that such morphological analysis would provide a basis for discussion of possible causes for muscle soreness. The muscle function after the work was measured by isokinetic methods.

    To improve the basis for the ultrastructural analysis the fibre populations in untrained and en­durance trained human m. vastus lateralis of age-matched individuals were classified into different fibre type groups according to their ultrastructure. The selective glycogen depletion from Type 1 fibres seen after long term submaximal work, visualized electron microscopically with PA-TSC-SP staining, substantiated the usefulness of the appearance of the M-band to differentiate between fibre types. Stereological data showed that neither volume density of mitochondria nor of lipid droplets provide sufficient criteria to differentiate between fibre types.

    After an eccentric exercise regimen sore muscles (m. soleus or m. vastus lateralis) showed disturb­ances of the cross striated band pattern. Fibres with disorganized myofibrillar material made up 1/3, 1/2 and 1/10 of the analysed material, 1 hour, 3 and 6 days after exercise, respectively. The myofibril­lar lesions were preferably localized in the Z-band. This showed streaming, broadening and sometimes total disruption. The Type 2 fibres were most affected.

    The reduction of strength was greatest with the most rapid contractions. Strength remained de­creased the period when the structural damage was most pronounced. Eight weeks of eccentric muscle training reduced all the above negative effects.

    The results indicate that the Z-disc constitute the weak link in the myofibrillar contractile chain at high muscle tensions. It is suggested that the myofibrillar lesions are a direct result of mechanical tearing. Rupture of myofibrils is thought to result in formation of protein components and a con- sequental release of protein bound ions that via osmosis result in oedema and soreness. Training, using eccentric contractions over a long period of time leads to adaptations at the fibre level by a reorgani­zation of the contractile apparatus as well as an optimization of nervous coordination.

  • 127. Fridén, Jan
    et al.
    Pontén, Eva
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Department of Orthopaedics, Uppsala University, Uppsala, Sweden.
    Lieber, Richard L
    Effect of muscle tension during tendon transfer on sarcomerogenesis in a rabbit model2000In: Journal of Hand Surgery-American Volume, ISSN 0363-5023, E-ISSN 1531-6564, Vol. 25, no 1, p. 138-143Article in journal (Refereed)
    Abstract [en]

    Sarcomere number change was investigated in an animal model of tendon transfer. In 9 adult New Zealand white rabbits, the flexor digitorum longus muscle was cut distally and transferred and woven into the tibialis anterior tendon. Ankles were then immobilized for 3 weeks in 75 degrees flexion. Transferred flexor digitorum longus muscles were harvested and complete architectural analysis was performed. Sarcomere lengths were measured using laser diffraction. Serial sarcomere number in transferred flexor digitorum longus fibers was a strong function of the sarcomere length at the time of transfer. A highly significant negative correlation between these 2 parameters was approximated by a linear relationship. Based on this finding, we conclude that serial sarcomere number is significantly affected by the degree of stretch during the transfer itself. This could easily compromise the purpose of surgical tendon transfer by reducing the procedure to little more than a tenodesis.

  • 128.
    Gaida, J
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. School of Primary Health Care, Monash University, Melbourne, Australia.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Cook, J
    School of Primary Health Care, Monash University, Melbourne, Australia.
    Decreased tumour necrosis factor alpha (tnf-a) in serum of patients with achilles tendinopathy: further evidence against the role of inflammation in the chronic stage2014In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 48, no 7, p. 597-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Altered expression of several cytokines and growth factors has been shown in biopsies of tendinopathy tissue. Biopsy studies are however challenged by capacity to obtain i) healthy tissue for comparison, ii) multiple samples to monitor cytokine dynamics, and iii) tissue from recent onset tendinopathy. An alternative is to study cytokines in blood samples. Whether cytokines in blood samples reflect tissue levels and the degree of tendinopathy is unknown.

    OBJECTIVE: To measure serum concentration of six cytokines and growth factors suggested to have a role in tendon response to load among individuals with chronic Achilles tendinopathy and controls.

    DESIGN: In this cross-sectional study, serum cytokine concentrations were measured from fasting blood samples on the BioPlex-200.

    SETTING: Sports Medicine Unit, Umeå University.

    PARTICIPANTS: Participants were recreationally active individuals. Achilles tendinopathy (n=22) was diagnosed on clinical criteria and confirmed with ultrasound examination. The control group (n=10) had no history of tendon pain and had normal ultrasound findings.

    INDEPENDENT VARIABLES: Serum concentration of tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), basic fibroblast growth factor (bFGF), platelet derived growth factor BB (PDGF-BB), interferon gamma (IFN-γ), and vascular-derived endothelial growth factor (VEGF) were the independent variables.

    MAIN OUTCOME MEASUREMENTS: A diagnosis of Achilles tendinopathy (yes/no) was defined as the key outcome variable prior to data collection.

    RESULTS: TNF-α concentration was lower in the tendinopathy group than the control group (P=.018); there were no other group differences.

    CONCLUSIONS: The observations indicate a lowering of the TNF-α concentration in the chronic phase of Achilles tendinopathy. As TNF-α levels are elevated in chronic inflammatory conditions, this reinforces that chronic Achilles tendinopathy is not an inflammatory disorder. Collecting a blood sample to study disease biomarkers leaves the tendon intact and therefore this design can be used to study cytokine dynamics with multiple sampling during disease progression and recovery.

  • 129.
    Gaida, James E.
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. University of Canberra Research Institute for Sport and Exercise (UCRISE); Discipline of Physiotherapy, University of Canberra.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Institute of Sport Exercise and Health, University College Hospital London.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Cook, Jill L.
    A pilot study on biomarkers for tendinopathy: lower levels of serum TNF-alpha and other cytokines in females but not males with Achilles tendinopathy2016In: BMC Sports Science Medicine and Rehabilitation, ISSN 2052-1847, Vol. 8, article id 5Article in journal (Refereed)
    Abstract [en]

    Background: Achilles tendinopathy is a painful musculoskeletal condition that is common among athletes, and which limits training capacity and competitive performance. The lack of biomarkers for tendinopathy limits research into risk factors and also the evaluation of new treatments. Cytokines and growth factors involved in regulating the response of tendon cells to mechanical load have potential as biomarkers for tendinopathy. Methods: This case-control study compared serum concentration of cytokines and growth factors (TNF-alpha, IL-1 beta, bFGF, PDFG-BB, IFN-gamma, VEGF) between individuals with chronic Achilles tendinopathy and controls. These were measured in fasting serum from 22 individuals with chronic Achilles tendinopathy and 10 healthy controls. Results were analysed in relation to gender and physical activity pattern. Results: TNF-alpha concentration was lower in the entire tendinopathy group compared with the entire control group; none of the other cytokines were significantly different. TNF-alpha levels were nevertheless highly correlated with the other cytokines measured, in most of the subgroups. Analysed by gender, TNF-alpha and PDGF-BB concentrations were lower in the female tendinopathy group but not the male tendinopathy group. A trend was seen for lower IL-1 beta in the female tendinopathy group. Physical activity was correlated with TNF-alpha, PDGF-BB and IL-1 beta to varying extents for control subgroups, but not for the female tendinopathy group. No correlations were seen with BMI or duration of symptoms. Conclusions: This pilot study indicates a lower level of TNF-alpha and PDGF-BB, and to some extent IL-1 beta among females, but not males, in the chronic phase of Achilles tendinopathy. It is suggested that future studies on tendinopathy biomarkers analyse male and female data separately. The lack of correlation between cytokine level and physical activity in the female tendinopathy group warrants further study.

  • 130.
    Gaida, James Edmund
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. University of Canberra, Canberra, ACT, Australia ; University of Canberra Research Institute for Sport and Exercise (UCRISE), Canberra, ACT, Australia.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. Institute of Sport Exercise and Health, University College Hospital London, London, UK.
    Scott, A.
    Mousavizadeh, R.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Apolipoprotein A1 distribution pattern in the human Achilles tendon2018In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 28, no 5, p. 1506-1513Article in journal (Refereed)
    Abstract [en]

    Metabolic factors such as cholesterol appear to play an important role in the development of Achilles tendinopathy. There is, however, no morphologic proof explaining the link between high cholesterol and tendinopathy. As apolipoprotein A1 (Apo-A1) is essential for reverse cholesterol transport, it may be related to cholesterol overload in tendon. Nothing is known about Apo-A1 expression in tendon tissue. We examined the distribution of Apo-A1 protein in biopsies from normal and tendinopathy-affected human Achilles tendons, and APOA1 mRNA production from cultured human hamstring tenocytes. Specific immunoreactions for Apo-A1 were detected. The tenocytes showed specific Apo-A1 immunoreactions. These reactions were usually distinct in the tendinopathy specimens. While the tendinopathy specimens often showed granular/small deposit reactions, the slender tenocytes of control specimens did not show this pattern. The magnitude of Apo-A1 immunoreactivity was especially marked in the tendinopathy specimens, as there is a high number of tenocytes. Reactions were also seen in the walls of blood vessels located within the tendon tissue proper of both the normal and tendinopathy tendons and within the peritendinous/fatty tissue of the tendinopathy tendons. The reactions were predominantly in the form of deposit reactions within the smooth muscle layer of the vessel walls. Cultured hamstring tenocytes produced APOA1 mRNA. We demonstrated the presence of Apo-A1 in human tendon tissue. This suggests there may be a link between Achilles tendinopathy and cholesterol metabolism. We hypothesize that Apo-A1 may be important for tenocyte and blood vessel function within tendons.

  • 131.
    Gaida, James Edmund
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bagge, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Purdam, Craig
    Cook, Jill
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Evidence of the TNF-α system in the human Achilles tendon: expression of TNF-α and TNF receptor at both protein and mRNA levels in the tenocytes2012In: Cells Tissues Organs, ISSN 1422-6405, E-ISSN 1422-6421, Vol. 196, no 4, p. 339-352Article in journal (Refereed)
    Abstract [en]

    Understanding adaption to load is essential for prevention and treatment of tendinopathy/tendinosis. Cytokine release in response to load is one mechanism involved in mechanotransduction. The cytokine tumor necrosis factor alpha (TNF-α) is implicated in tendinosis and can induce apoptotic effects via tumor necrosis factor receptor 1 (TNFR1). The complete absence of information concerning the TNF-α system in Achilles tendon is a limitation as mid-portion Achilles tendinosis is very frequent. Purpose: To examine expression patterns of TNF-α and its two receptors (TNFR1 and TNFR2) in human Achilles tendinosis and control tissue and to biochemically confirm the presence of TNF-α in tendinosis tissue. Methods: TNF-α and TNFR1 mRNA were detected via in situ hybridization. TNF-α, TNFR1, and TNFR2 were demonstrated immunohistochemically. Apoptosis markers were utilized. ELISA was used to detect TNF-α. Results: TNF-α and TNFR1 mRNA was detected in tenocytes of both tendinosis and control tendons. Tenocytes from both groups displayed specific immunoreactions for TNF-α, TNFR1, and TNFR2. The widened/rounded tenocytes of tendinosis samples exhibited the most intense immunoreactions. Apoptosis was detected in only a subpopulation of the tenocytes in tendinosis tissue. TNF-α was measurable in tendinosis tissue. Inflammatory cells were not seen. Conclusion: This is the first evidence of the existence of the TNF-α system in the human Achilles tendon. Findings are confirmed at mRNA and protein levels as well as biochemically. The TNF-α system was in principle confined to the tenocytes. The connection between tenocyte morphology and the expression pattern of TNF-α, TNFR1, and TNFR2 suggests that the TNF-α system may be involved in tenocyte activation in Achilles tendinosis.

  • 132. Georgiou, M.
    et al.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bunting, S. C.
    Golding, J. P.
    Loughlin, A. J.
    Phillips, J. B.
    A nerve repair conduit containing differentiated adipose-derived stem cells within engineered neural tissue can support and guide neuronal growth in vitro and in vivo2012In: Journal of tissue engineering and regenerative medicine, ISSN 1932-6254, Vol. 6, no Suppl. 1, p. 259-Article in journal (Other academic)
  • 133. Georgiou, Melanie
    et al.
    Golding, Jon P.
    Loughlin, Alison J.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Phillips, James B.
    Engineered neural tissue with aligned, differentiated adipose-derived stem cells promotes peripheral nerve regeneration across a critical sized defect in rat sciatic nerve2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 37, p. 242-251Article in journal (Refereed)
    Abstract [en]

    Adipose-derived stem cells were isolated from rats and differentiated to a Schwann cell-like phenotype in vitro. The differentiated cells (dADSCs) underwent self-alignment in a tethered type-1 collagen gel, followed by stabilisation to generate engineered neural tissue (EngNT-dADSC). The pro-regenerative phenotype of dADSCs was enhanced by this process, and the columns of aligned dADSCs in the aligned collagen matrix supported and guided neurite extension in vitro. EngNT-dADSC sheets were rolled to form peripheral nerve repair constructs that were implanted within NeuraWrap conduits to bridge a 15 mm gap in rat sciatic nerve. After 8 weeks regeneration was assessed using immunofluorescence imaging and transmission electron microscopy and compared to empty conduit and nerve graft controls. The proportion of axons detected in the distal stump was 3.5 fold greater in constructs containing EngNT-dADSC than empty tube controls. Our novel combination of technologies that can organise autologous therapeutic cells-within an artificial tissue construct provides a promising new cellular biomaterial for peripheral nerve repair. 

  • 134.
    Granberg, I
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Lindell, Björn
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Eriksson, Per-Olof
    Umeå University, Faculty of Medicine, Department of Odontology, Clinical Oral Physiology.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Capillary supply in relation to myosin heavy chain fibre composition of human intrinsic tongue muscles2010In: Cells Tissues Organs, ISSN 1422-6405, E-ISSN 1422-6421, Vol. 192, no 5, p. 303-313Article in journal (Refereed)
    Abstract [en]

    The capillary supply and myosin heavy chain (MyHC) composition of three different intrinsic tongue muscles was analysed in the anterior and posterior regions of the human tongue with biochemical and immunohistochemical techniques. Mean capillary density for the whole tongue was 796 ± 82 cap/mm², without regional differences. The overall number of capillaries around each fibre (CAF) was higher in the posterior than in the anterior region (2.5 vs. 2.1, p = 0.009). However, correcting for regional differences in fibre size, CAF per fibre area was higher in the anterior region (4.3 vs. 3.0, p < 0.001). Muscle fibres containing fast MyHCs predominated in the anterior region (78.7%), consisting of MyHCIIa (58.5%), MyHCIIx (1.0%), MyHCIIa+MyHCIIx (11.3%) and MyHCI+MyHCIIa (7.9%). Fibres containing slow MyHC predominated in the posterior region (65.2%), consisting of MyHCI (45.5%) and MyHCI+MyHCIIa (19.7%). A minor fibre population (<2%) contained unusual MyHC isoforms, namely MyHC foetal, MyHC slow-tonic, MyHC α-cardiac or MyHC embryonic. The microvascularization of the human tongue was twice as high as in human limb muscles. Regional similarities in capillary supply, but differences in fibre phenotype composition, suggest that human tongue muscle fibres are fatigue resistant independently of MyHC content. High frequency of hybrid fibres, that is fibres co-expressing two or more MyHC isoforms, indicates a wider spectrum of fibre contractile properties than in limb muscles. In conclusion, human intrinsic tongue muscles showed internal specialization in distribution of MyHC isoforms and capillary supply, but not in the expression of unusual MyHCs.

  • 135.
    Grimsholm, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Reumatologi.
    Dalén, Tore
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics. Ortopedi.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    BDNF in RA: Downregulated in plasma following anti-TNF treatment but no correlation with inflammatory parameters.2008In: Clinical Rheumatology, ISSN 0770-3198, Vol. 27, no 10, p. 1289-1297Article in journal (Refereed)
    Abstract [en]

    The involvement of brain-derived neurotrophic factor (BDNF) in rheumatoid arthritis (RA) is largely unknown. The distribution of BDNF and its associated receptors, TrkB and p75, in the synovial tissue of patients with RA was examined and contrasted with that in patients with osteoarthritis (OA). Additionally, levels of BDNF in both synovial tissue and synovial fluid were measured. Furthermore, the effects of anti-tumour necrosis factor (anti-TNF; infliximab) treatment on BDNF levels in the plasma of RA patients were analysed. Cells in the synovium showed immunoreactivity for BDNF and BDNF-, p75- and TrkB-receptor immunoreactions were seen in nerve fibres of nerve fascicles and in association with sensory corpuscles. The levels of BDNF in synovial tissue were not correlated with the number of inflammatory cells observed microscopically or with levels of TNFα. Nor did the BDNF levels in synovial fluid correlate with erythrocyte sedimentation rate (ESR) or white blood cell counts. Anti-TNF treatment lead to a decrease in plasma levels of BDNF 14 weeks after the initiation of anti-TNF therapy, i.e., 8 weeks after the last infusion. Higher levels of BDNF were observed in RA patients at baseline compared with those for healthy individuals. However, the levels of BDNF in plasma of patients treated with anti-TNF did not correlate with the changes in ESR or a disease activity score. The clinical significance of this study is that anti-TNF treatment influences plasma levels of BDNF although there was no evidence that BDNF levels correlate with inflammatory parameters in either infliximab-treated or non-infliximab-treated patients with RA. Instead it is likely that sources other than inflammatory cells, including nerve structures, are important sources of BDNF and that the effects of anti-TNF treatment on BDNF levels may be related to effects on circulating and various local cells and/or BDNF-containing neurons.

  • 136.
    Grimsholm, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Dalén, Tore
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Unexpected finding of a marked non-neuronal cholinergic system in human knee joint synovial tissue.2008In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 442, no 2, p. 128-33Article in journal (Refereed)
    Abstract [en]

    The cholinergic anti-inflammatory pathway is a newly discovered pathway. Another recent concept is the existence of a non-neuronal cholinergic system that has, so far, been defined for human tendons, intestine, airways and urinary bladder. The existence of such a system in joint synovial tissue is yet to be described. We therefore aimed to investigate the expression of choline acetyltransferase (ChAT) at both the protein and mRNA level using immunohistochemistry and in situ hybridisation, in human knee synovial tissue from rheumatoid arthritis (RA) and osteoarthritis (OA) patients. The biopsy samples were collected from patients undergoing knee prosthetic surgery. Our results show that both ChAT protein and mRNA is expressed in fibroblast-like and mononuclear-like cells, and to some extent in blood vessel walls in the synovial tissue. The mononuclear-like cells showing ChAT expression were scattered throughout the synovial tissue or located in association with lymphoid aggregates. Thus, we present the first evidence of the existence of a marked non-neuronal cholinergic system in human synovial tissue. The existence of this system could lead to the development of alternative medications to those currently in use. The system might function as a cholinergic anti-inflammatory pathway in synovial tissue. Our observations show that synovial tissue of patients with marked RA or OA, a tissue in which cholinergic innervation is not proven to exist, is supplied with acetylcholine via production in non-neuronal cells within the tissue.

  • 137.
    Grimsholm, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Levels of gastrin-releasing peptide and substance P in synovial fluid and serum correlate with levels of cytokines in rheumatoid arthritis.2005In: Arthritis research & therapy, ISSN 1478-6362, Vol. 7, no 3, p. R416-426Article in journal (Refereed)
    Abstract [en]

    It is well known that cytokines are highly involved in the disease process of rheumatoid arthritis (RA). Recently, targeting of neuropeptides has been suggested to have potential therapeutic effects in RA. The aim of this study was to investigate possible interrelations between five neuropeptides (bombesin/gastrin-releasing peptide (BN/GRP), substance P (SP), vasoactive intestinal peptide, calcitonin-gene-related peptide, and neuropeptide Y) and the three cytokines tumour necrosis factor (TNF)-alpha, IL-6, and monocyte chemoattractant protein-1 in synovial fluid of patients with RA. We also investigated possible interrelations between these neuropeptides and soluble TNF receptor 1 in serum from RA patients. Synovial fluid and sera were collected and assayed with ELISA or RIA. The most interesting findings were correlations between BN/GRP and SP and the cytokines. Thus, in synovial fluid, the concentrations of BN/GRP and SP grouped together with IL-6, and SP also grouped together with TNF-alpha and monocyte chemoattractant protein-1. BN/GRP and SP concentrations in synovial fluid also grouped together with the erythrocyte sedimentation rate. In the sera, BN/GRP concentrations and soluble TNF receptor 1 concentrations were correlated. These results are of interest because blocking of SP effects has long been discussed in relation to RA treatment and because BN/GRP is known to have trophic and growth-promoting effects and to play a role in inflammation and wound healing. Furthermore, the observations strengthen a suggestion that combination treatment with agents interfering with neuropeptides and cytokines would be efficacious in the treatment of RA. In conclusion, BN/GRP and SP are involved together with cytokines in the neuroimmunomodulation that occurs in the arthritic joint.

  • 138.
    Grimsholm, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Rantapää-Dahlqvist, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Dalén, Tore
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Observations favouring the occurrence of local production and marked effects of bombesin/gastrin-releasing peptide in the synovial tissue of the human knee joint: comparisons with substance P and the NK-1 receptor.2008In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 42, no 2, p. 133-145Article in journal (Refereed)
    Abstract [en]

    We have previously shown that levels of the neuropeptides substance P (SP) and bombesin/gastrin-releasing peptide (BN/GRP) in blood and synovial fluid correlate with levels of pro-inflammatory cytokines in patients with rheumatoid arthritis (RA). It is well-established that SP is present in nerve endings in the synovium whilst the source of BN/GRP in human joints is completely unknown. Nor is it known whether GRP-receptors (GRP-R) are present in human synovial tissue. This study aimed to investigate the expression pattern of SP, BN/GRP and their receptors (NK-1R and GRP-R) in synovial tissue. Synovial tissue specimens from patients with RA or osteoarthritis (OA) were processed for immunohistochemistry, in situ hybridisation and ELISA. The results show the presence of BN/GRP, but not SP, in cells in the synovial tissue at both the protein and mRNA level. We did not find immunoreactive BN/GRP in nerve structures. NK-1R and GRP-R were also expressed at both protein and mRNA levels in cells associated with blood vessels and cells in the interstitial tissue. ELISA analyses revealed both SP and BN/GRP to be present in synovial tissue extracts and that synovial levels of SP were higher in RA patients than those with OA. Our results indicate that BN/GRP is produced by non-neuronal cells in the synovial tissue. Furthermore, both BN/GRP and SP may exert their effects on the synovial tissue through the respective receptors. These results suggest that BN/GRP and SP may modulate inflammation and vascular events, and possibly healing processes in the synovium. Finally, nerves should not be considered as the source of BN/GRP in synovial tissue although this peptide is presumably intimately involved functionally in synovial tissue, a previously unrecognised fact.

  • 139.
    Gustafsson, Hans
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Salivary gland neoplasms: studies on the cytoskeleton, the secretory apparatus and the nuclear DNA content1986Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The heterogeneity of salivary gland neoplasms have made classification and prognostication of these tumours sometimes difficult, and the in­troduction of techniques, such as enzyme and carbohydrate histochemis­try and electron microscopy have only to a certain extent increased our knowledge in these respects. In the present study immunohistochemical methods have been used to identify intermediate filament proteins (IFP) in normal fetal and adult parotid glands, as well as in salivary neo­plasms. The intermediate filaments (IF) make up the cytoskeleton in eucaryotic cells. Epithelial tissue contains IF composed of different cytokeratins (CK 1-19) whilst mesenchymal tissue generally contains IF composed of vimentin, and the IFP pattern is very stable even during cell transformation. It would thus be possible to further clarify the histogenesis of salivary neoplasms by identifying IFP, in addition the IFP pattern would probably be useful in tumour typing. Furthermore, ultrastructural cytochemical studies, microspectorphotometry on nuclear DNA as well as enzyme secretory studies of certain tumour types were carried out, in order to further characterize the biology of salivary neoplasms.

    The immunohistochemical investigations showed that in normal parotid tissue, the different cell types differed in IFP expression: acinar cells express mainly CK 18 and myoepithelial cells mainly CK 17 and 19, whilst duct cells contained a broad range of CK. Vimentin could in ad­dition to CK be detected in myoepithelial cells and basal cells of ex­cretory ducts. Fetal parotid cells showed a similar CK pattern as mature duct cells. In addition, vimentin could be found in some basal cells of the terminal tubules of the fetal glands. Salivary neoplasms could be divided into three types with regard to their IFP pattern:

    1.  Acinic cell carcinomas showed a CK-pattern similar to normal acinar cells but a co-expression of CK and vimentin was present in some cells.
    2.  Adenoid cystic carcinomas, mixed tumours and basal cell adenomas showed a CK-pattern of normal duct or myoepithelial cells. The peri­pheral cells were also vimentin positive. 3. Mucoepidermoid carcinomas and adenocarcinomas had a similar CK-pattern as duct cells, and no tu­mour cells contained vimentin. This indicates that typing of IFP may be useful for subgrouping of salivary neoplasms.

    By stereological measurements, the cells of acinic cell carcinomas were found to be very similar to normal parotid acinar cells. Furthermore, they contained amylase and after stimulation by norepiphrine a secre­tory response was induced, with a rise in intracellular cAMP as well as a release of amylase. By single cell measurements of nuclear DNA con­tent, no difference was found between acinic cell carcinomas with de­finite metastasis and those without recurrence, both in paraffin sec­tions and cytological smears.

  • 140.
    Hadrevi, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Hellström, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Kieselbach, Thomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Protein differences between human trapezius and vastus lateralis muscles determined with a proteomic approach2011In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 12, no 181, p. 11-Article in journal (Refereed)
    Abstract [en]

    Background: The trapezius muscle is a neck muscle that is susceptible to chronic pain conditions associated with repetitive tasks, commonly referred to as chronic work-related myalgia, hence making the trapezius a muscle of clinical interest. To provide a basis for further investigations of the proteomic traits of the trapezius muscle in disease, two-dimensional difference gel electrophoresis (2D-DIGE) was performed on the healthy trapezius using vastus lateralis as a reference. To obtain as much information as possible from the vast proteomic data set, both one-way ANOVA, with and without false discovery rate (FDR) correlation, and partial least square projection to latent structures with discriminant analysis (PLS-DA) were combined to compare the outcome of the analysis.

    Results: The trapezius and vastus lateralis showed significant differences in metabolic, contractile and regulatory proteins, with different results depending on choice of statistical approach and pre-processing technique. Using the standard method, FDR correlated one-way ANOVA, 42 protein spots differed significantly in abundance between the two muscles. Complementary analysis using immunohistochemistry and western blot confirmed the results from the 2D-DIGE analysis.

    Conclusions: The proteomic approach used in the present study combining 2D-DIGE and multivariate modelling provided a more comprehensive comparison of the protein profiles of the human trapezius and vastus lateralis muscle, than previously possible to obtain with immunohistochemistry or SDS-PAGE alone. Although 2D-DIGE has inherent limitations it is particularly useful to comprehensively screen for important structural and metabolic proteins, and appears to be a promising tool for future studies of patients suffering from chronic work related myalgia or other muscle diseases.

  • 141.
    Hadrévi, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ghafouri, Bijar
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden.
    Larsson, Britt
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University.
    Gerdle, Björn
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University.
    Hellström, Fredrik
    Centre for Musculoskeletal Research, Department of Occupational and Public Health Sciences, Faculty of Health and Occupational Studies , University of Gävle, Umeå, Sweden.
    Multivariate Modeling of Proteins Related to Trapezius Myalgia, a Comparative Study of Female Cleaners with or without Pain2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e73285-Article in journal (Refereed)
    Abstract [en]

    The prevalence of chronic trapezius myalgia is high in women with high exposure to awkward working positions, repetitive movements and movements with high precision demands. The mechanisms behind chronic trapezius myalgia are not fully understood. The purpose of this study was to explore the differences in protein content between healthy and myalgic trapezius muscle using proteomics. Muscle biopsies from 12 female cleaners with work-related trapezius myalgia and 12 pain free female cleaners were obtained from the descending part of the trapezius. Proteins were separated with two-dimensional differential gel electrophoresis (2D-DIGE) and selected proteins were identified with mass spectrometry. In order to discriminate the two groups, quantified proteins were fitted to a multivariate analysis: partial least square discriminate analysis. The model separated 28 unique proteins which were related to glycolysis, the tricaboxylic acid cycle, to the contractile apparatus, the cytoskeleton and to acute response proteins. The results suggest altered metabolism, a higher abundance of proteins related to inflammation in myalgic cleaners compared to healthy, and a possible alteration of the contractile apparatus. This explorative proteomic screening of proteins related to chronic pain in the trapezius muscle provides new important aspects of the pathophysiology behind chronic trapezius myalgia.

  • 142.
    Hadrévi, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ghafouri, Bijar
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden.
    Sjörs, Anna
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden; Institute of Stress Medicine, Carl Skottsbergs gata 22B, SE 41319 Gothenburg, Sweden.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Larsson, Britt
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden.
    Crenshaw, A. G.
    Centre for Musculoskeletal Research, Department of Occupational and Public Health Sciences, Faculty of Health and Occupational Studies , University of Gävle, Umeå, Sweden.
    Gerdle, Björn
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden.
    Hellström, Fredrik
    Centre for Musculoskeletal Research, Department of Occupational and Public Health Sciences, Faculty of Health and Occupational Studies , University of Gävle, Umeå, Sweden.
    Comparative metabolomics of muscle interstitium fluid in human trapezius myalgia: an in vivo microdialysis study2013In: European Journal of Applied Physiology, ISSN 1439-6319, E-ISSN 1439-6327, Vol. 113, no 12, p. 2977-2989Article in journal (Other academic)
    Abstract [en]

    The mechanisms behind trapezius myalgia are unclear. Many hypotheses have been presented suggesting an altered metabolism in the muscle. Here, muscle microdialysate from healthy and myalgic muscle is analysed using metabolomics. Metabolomics analyse a vast number of metabolites, enabling a comprehensive explorative screening of the cellular processes in the muscle.

    Microdialysate samples were obtained from the shoulder muscle of healthy and myalgic subjects that performed a work and stress test. Samples from the baseline period and from the recovery period were analysed using gas chromatography-mass spectrometry (GC-MS) together with multivariate analysis to detect differences in extracellular content of metabolites between groups. Systematic differences in metabolites between groups were identified using multivariate analysis and orthogonal partial least square discriminate analysis (OPLS-DA). A complementary Mann-Whitney U test of group difference in individual metabolites was also performed.

    A large number of metabolites were detected and identified in this screening study. At baseline, no systematic differences between groups were observed according to the OPLS-DA. However, two metabolites, l-leucine and pyroglutamic acid, were significantly more abundant in the myalgic muscle compared to the healthy muscle. In the recovery period, systematic difference in metabolites between the groups was observed according to the OPLS-DA. The groups differed in amino acids, fatty acids and carbohydrates. Myristic acid and putrescine were significantly more abundant and beta-d-glucopyranose was significantly less abundant in the myalgic muscle.

    This study provides important information regarding the metabolite content, thereby presenting new clues regarding the pathophysiology of the myalgic muscle.

  • 143. Hagert, Elisabet
    et al.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Ljung, Björn-Ove
    Differences in the presence of mechanoreceptors and nerve structures between wrist ligaments may imply differential roles in wrist stabilization.2005In: Journal of Orthopaedic Research, ISSN 0736-0266, Vol. 23, no 4, p. 757-63Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to analyze human wrist ligaments with regard to presence of general innervation and mechanoreceptors. The ligaments studied were: dorsal radiocarpal (DRC), dorsal intercarpal (DIC), long radiolunate (LRL), radioscaphocapitate (RSC), ulnocarpal (UC), scapholunate interosseous (SLI) and lunotriquetral interosseous (LTI) ligaments. Specific immunohistochemical markers were used to target neural/perineurial structures. Both Ruffini and Pacini-like mechanoreceptors (sensory corpuscles) as well as nerve fascicles/free nerve fibers were identified. Ruffini corpuscles were primarily identified via their dendritic intracapsular nerve endings, whereas the Pacini-like corpuscles were identified through their thick perineurial capsules with marked p75 immunoreaction. The wrist ligaments were found to vary in innervation, the DIC, DRC and SLI being richly innervated, whereas the LRL being almost without innervation. The difference in innervation between the ligaments might reflect differential function. Ligaments without innervation might act as structures of passive restraint, whereas ligaments with rich innervation are proposed to also provide proprioceptive information. Wrist ligament injuries should, therefore, be regarded as a disturbance not only of the intrinsic carpal kinematics, but also of the coordination and proprioception of the entire wrist joint.

  • 144. Hagert, Elisabet
    et al.
    Garcia-Elias, Marc
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Ljung, Björn-Ove
    Immunohistochemical analysis of wrist ligament innervation in relation to their structural composition.2007In: Journal of Hand Surgery-American volume, ISSN 0363-5023, Vol. 32, no 1, p. 30-6Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To analyze ligament innervation and the structural composition of wrist ligaments to investigate the potential differences in sensory and biomechanical functions. METHODS: The ligaments analyzed were the dorsal radiocarpal, dorsal intercarpal, scaphotriquetral, dorsal scapholunate interosseous, scaphotrapeziotrapezoid, radioscaphoid, scaphocapitate, radioscaphocapitate, long radiolunate, short radiolunate, ulnolunate, palmar lunotriquetral interosseous, triquetrocapitate, and triquetrohamate ligaments. The ligaments were harvested from 5 cadaveric, fresh-frozen specimens. By using the immunohistochemical markers p75, Protein Gene Product 9.5, and S-100 protein, the mechanoreceptors and nerve fibers could be identified. RESULTS: The innervation pattern in the ligaments was found to vary distinctly, with a pronounced innervation in the dorsal wrist ligaments (dorsal radiocarpal, dorsal intercarpal, scaphotriquetral, dorsal scapholunate interosseous), an intermediate innervation in the volar triquetral ligaments (palmar lunotriquetral interosseous, triquetrocapitate, triquetrohamate), and only limited/occasional innervation in the remaining volar wrist ligaments. The innervation pattern also was reflected in the structural differences between the ligaments. When present, mechanoreceptors and nerve fibers were consistently found in the loose connective tissue in the outer region (epifascicular region) of the ligament. Hence, ligaments with abundant innervation had a large epifascicular region, as compared with the ligaments with limited innervation, which consisted mostly of densely packed collagen fibers. CONCLUSIONS: The results of our study suggest that wrist ligaments vary with regard to sensory and biomechanical functions. Rather, based on the differences found in structural composition and innervation, wrist ligaments are regarded as either mechanically important ligaments or sensory important ligaments. The mechanically important ligaments are ligaments with densely packed collagen bundles and limited innervation. They are located primarily in the radial, force-bearing column of the wrist. The sensory important ligaments, by contrast, are richly innervated although less dense in connective tissue composition and are related to the triquetrum. The triquetrum and its ligamentous attachments are regarded as key elements in the generation of the proprioceptive information necessary for adequate neuromuscular wrist stabilization.

  • 145. Hagert, Elisabet
    et al.
    Ljung, Björn-Ove
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    General innervation pattern and sensory corpuscles in the scapholunate interosseous ligament.2004In: Cells Tissues Organs, ISSN 1422-6405, Vol. 177, no 1, p. 47-54Article in journal (Refereed)
    Abstract [en]

    The scapholunate interosseous ligament (SLIL) is biomechanically important in maintaining wrist motion and grip strength in the hand, but its possible sensory role in the dynamic muscular stability of the wrist joint has not been examined. The aim of this study was to use immunohistochemical methods to analyze the general innervation and the possible existence of sensory corpuscles in the SLIL. The ligament was excised in its entirety from 9 patients. Antibodies against the low-affinity p75 neurotrophic receptor (p75) were used to reveal sensory corpuscles as well as general innervation. Furthermore, antibodies against the general nerve marker protein gene product 9.5 (PGP 9.5) and the glial marker S-100 were used to additionally depict innervation and corpuscular structures. Blood vessels occurred in areas interspersed throughout the homogeneous collagenous structure. In these vascularized areas, the SLIL was found to be supplied with nerve fascicles and sensory corpuscles of both the Ruffini and lamellated type. p75 immunoreactivity (IR) was detected in association with the nerve fascicles and the corpuscles, particularly in their capsule. S-100 IR was found in the Schwann cells in the central regions of the corpuscle, and PGP 9.5 IR marked the axonal structures in the corpuscles. New information on neurotrophin receptor distribution in ligaments has been obtained here. The presence of nerve fascicles and particularly sensory corpuscles in the SLIL suggests that the ligament has a proprioceptive role in the stability of the wrist. The marked p75 IR further indicates that neurotrophins play a part in a proprioceptive system in the ligament, given the importance of neurotrophins in maintaining sensory function.

  • 146.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Winther, Johanna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Rudolfsson, Stina H
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Karalija, Amar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Egevad, Lars
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm.
    Granfors, Torvald
    Department of Urology, Central Hospital, Västerås, Sweden.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e105063Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: ErbB2 is a member of the epidermal growth factor family of tyrosine kinases that is centrally involved in the pathogenesis of prostate cancer and several studies have reported that a high expression of this protein has prognostic value. In the present study, we have investigated whether tumour ErbB2 immunoreactivity (ErbB2-IR) has clinically useful prognostic value, i.e. that it provides additional prognostic information to that provided by routine clinical tests (Gleason score, tumour stage).

    METHODOLOGY/PRINCIPAL FINDINGS: ErbB2-IR was measured in a well-characterised tissue microarray of tumour and non-malignant samples obtained at diagnosis. Additionally, mRNA levels of ErbB2-IR in the prostate were determined in the rat following manipulation of circulating androgen levels. Tumour ErbB2-IR was significantly associated with the downstream signalling molecule phosphorylated-Akt and with the cell proliferation marker Ki-67. The significant association of tumour ErbB2-IR with the Gleason score at diagnosis was lost when controlled for the association of both parameters with Ki-67. In the rat prostate, mRNA for ErbB2 was inversely associated with circulating androgen levels. There was no association between ErbB2-IR and the androgen receptor (AR)-IR in the tumours, but an interaction between the two parameters was seen with respect to their association with the tumour stage. Tumour ErbB2-IR was confirmed to be a prognostic marker for disease-specific survival, but it did not provide significant additive information to the Gleason score or to Ki-67.

    CONCLUSIONS/SIGNIFICANCE: It is concluded that tumour ErbB2-IR is of limited clinical value as a prognostic marker to aid treatment decisions, but could be of pathophysiological importance in prostate cancer.

  • 147.
    Hansson, M
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kjörell, U
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ingrowth of sympathetic innervation occurs concomitantly with a decrease of ANP in the growing rat cardiac ventricles.2001In: Anatomy and Embryology, ISSN 0340-2061, E-ISSN 1432-0568, Vol. 203, no 1, p. 35-44Article in journal (Refereed)
    Abstract [en]

    The relationship between the immunohistochemical expression of atrial natriuretic peptide and the occurrence of sympathetic nerve fibres, as visualized by staining for tyrosine hydroxylase, in the growing rat heart was evaluated. Rats were investigated at four different stages from birth to 21 days postnatally. The effects of chemical destruction of sympathetic nerve terminals in neonatal rats on the cardiac atrial natriuretic peptide content were furthermore examined by use of radioimmunoassay. There was in principle a reciprocal pattern of immunoreaction for atrial natriuretic peptide and tyrosine hydroxylase positive innervation in the ventricular myocardium, atrial natriuretic peptide reaction becoming less and less pronounced with the ingrowth of innervation positive for tyrosine hydroxylase. Furthermore, in the peripheral Purkinje fibre network, there was a marked atrial natriuretic peptide immunoexpression and scarce or no nerve fibres throughout the examination period. The radioimmunoassay measurements showed that chemical sympathectomy lead to elevated cardiac levels of atrial natriuretic peptide. The study shows that sympathetic innervation grows into the ventricular parts concomitantly with the occurrence of a decline in atrial natriuretic peptide expression during development of the heart. Furthermore, it is shown that a reversion of the in growth of sympathetic innervation by destruction of cardiac sympathetic nerves at an early stage leads to increased levels of atrial natriuretic peptide in the heart. The results give new evidence to the phenomenon that the atrial natriuretic peptide levels in the ventricular myocardium and the peripheral parts of the conduction system are under influence of the presence of sympathetic innervation.

  • 148.
    Hansson, Magnus
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Receptor binding occurrence and plasma levels of natriuretic peptides in response to sympathectomy.2005In: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 67, no 2, p. 90-99Article in journal (Refereed)
  • 149.
    Hansson, Magnus
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Expression of brain natriuretic peptide in the rat heart studies during heart growth and in relation to sympathectomy2004In: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 64, no 1, p. 30-42Article in journal (Refereed)
    Abstract [en]

    Brain natriuretic peptide (BNP) might be of importance during heart development and is described to be increasingly expressed in congestive heart failure and to affect the progress of this condition. However, details in the normal expression of BNP are still unclear in various parts of the adult and growing heart, including the conduction system. In this study, we investigated the expression of BNP in relation to that of atrial natriuretic peptide (ANP) in the growing as well as in the adult rat heart. The effects of chemical sympathectomy in adult rats were also examined. Contrary to previous BNP immunohistochemical studies, the BNP antiserum was preabsorbed with an excess of ANP before staining to abolish the crossreactivity with ANP. There was a pronounced BNP immunoreaction in the auricles, the trabeculated ventricular walls, and the peripheral parts of the conduction system at 0-1 days postnatally. The degree of immunoreaction gradually decreased with increasing age. A similar developmental pattern was seen concerning ANP expression, but the magnitude of the latter clearly exceeded that for BNP. Immunoreaction for BNP was never detected in the atrioventricular (AV) node and AV bundle at any stage. In contrast to the situation for ANP previously observed, no obvious changes in BNP immunoreaction patterns were observed in response to sympathectomy. This is the first study to thoroughly demonstrate the expression of BNP in the various regions of the rat heart during growth and in the normal and sympathectomized adult stage. The observations are related to possible functions of natriuretic peptides in the growing and adult heart.

  • 150.
    Harandi, Vahid M.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    A Muscle Perspective on the Pathophysiology of Amyotrophic Lateral Sclerosis: Differences between extraocular and limb muscles2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder. ALS has been traditionally believed to be primarily a motor neuron disease. However, accumulating data indicate that loss of contact between the axons and the muscle fibres occurs early; long before the death of motor neurons and that muscle fibres may initiate motor neuron degeneration. Thus, the view of ALS is changing focus from motor neurons alone to also include the muscle fibres and the neuromuscular junctions (NMJs). While skeletal muscles are affected in ALS, oculomotor disturbances are not dominant features of this disease and extraocular muscles (EOMs) are far less affected than limb muscles. Why oculomotor neurons and EOMs are capable to be more resistant in the pathogenetic process of ALS is still unknown.

    The overall goal of this thesis is to explore the pathophysiology of ALS from a muscle perspective and in particular study the expression and distribution of key neurotrophic factors (NTFs) and Wnt proteins in EOMs and limb muscles from ALS donors and from SOD1G93A transgenic mice. Comparisons were made with age-matched controls to distinguish between changes related to ALS and to ageing.

    Results: Brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4) were present in EOMs and limb muscles at both mRNA and protein levels in control mice. The mRNA levels of BDNF, NT-3 and NT-4 were significantly lower in EOMs than in limb muscles of early and/or late control mice, indicating an intrinsic difference in NTFs expression between EOMs and limb muscles. qRT-PCR analysis showed significantly upregulated mRNA levels of NT-3 and GDNF in EOMs but significantly downregulated mRNA levels of NT-4 in limb muscles from SOD1G93A transgenic mice at early stage. The NTFs were detected immunohistochemically in NMJs, nerve axons and muscle fibres. The expression of BDNF, GDNF and NT-4 on NMJs of limb muscles, but not of EOMs, was significantly decreased in terminal stage ALS animals as compared to the limb muscles of the age-matched controls. In contrast, NTFs expression in intramuscular nerve axons did not present significant changes in either muscle group of early or late ALS mice. NTFs, especially BDNF and NT-4 were upregulated in some small-sized muscle fibres in limb muscles of late stage ALS mice. All the four Wnt isoforms, Wnt1, Wnt3a, Wnt5a and Wnt7a were detected in most axon profiles in all human EOMs with ALS, whereas significantly fewer axon profiles were positive in the human limb muscles except for Wnt5a. Similar differential patterns were found in myofibres, except for Wnt7a, where its expression was elevated within sarcolemma of limb muscle fibres. β-catenin, a marker of the canonical Wnt pathway was activated in a subset of myofibres in the EOMs and limb muscle in all ALS patients. In the SOD1G93A mouse, all four Wnt isoforms were significantly decreased in the NMJs at the terminal stage compared to age matched controls.

    Conclusions: There were clear differences in NTF and Wnt expression patterns between EOM and limb muscle, suggesting that they may play a role in the distinct susceptibility of these two muscle groups to ALS. In particular, the early upregulation of GDNF and NT-3 in the EOMs might play a role in the preservation of the EOMs in ALS. Further studies are needed to determine whether these proteins and the pathways they control may be have a future potential as protecting agents for other muscles.

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