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  • 151. Caddick, Jenny
    et al.
    Kingham, Paul J
    Gardiner, Natalie J
    Wiberg, Mikael
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi, Anatomi. Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Handkirurgi.
    Terenghi, Giorgio
    Phenotypic and functional characteristics of mesenchymal stem cells differentiated along a Schwann cell lineage.2006Inngår i: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 54, nr 8, s. 840-849Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have investigated the phenotypic and bioassay characteristics of bone marrow mesenchymal stromal cells (MSCs) differentiated along a Schwann cell lineage using glial growth factor. Expression of the Schwann cell markers S100, P75, and GFAP was determined by immunocytochemical staining and Western blotting. The levels of the stem cell markers Stro-1 and alkaline phosphatase and the neural progenitor marker nestin were also examined throughout the differentiation process. The phenotypic properties of cells differentiated at different passages were also compared. In addition to a phenotypic characterization, the functional ability of differentiated MSCs has been investigated employing a co-culture bioassay with dissociated primary sensory neurons. Following differentiation, MSCs underwent morphological changes similar to those of cultured Schwann cells and stained positively for all three Schwann cell markers. Quantitative Western blot analysis showed that the levels of S100 and P75 protein were significantly elevated upon differentiation. Differentiated MSCs were also found to enhance neurite outgrowth in co-culture with sensory neurons to a level equivalent or superior to that produced by Schwann cells. These findings support the assertion that MSCs can be differentiated into cells that are Schwann cell-like in terms of both phenotype and function.

  • 152.
    Carlsson, Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    The muscle cytoskeleton of mice and men: Structural remodelling in desmin myopathies2001Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The muscle fibre cytoskeleton of skeletal and heart muscle cells is composed mainly of intermediate filaments (IFs), that surround the myofibrils and connect the peripheral myofibrils with the sarcolemma and the nuclear membrane. Desmin is the first muscle specific IF protein to be produced in developing muscles and is the main IF protein in mature muscles. In skeletal muscle, desmin is particularly abundant at myotendinous and neuromuscular junctions. In the heart an increased amount of desmin is found at intercalated discs and in Purkinje fibres of the conduction system. Interactions between the IFs themselves, and between IFs and other structures such as Z-discs and the sarcolemma, are mediated by intermediate filament associated proteins (IFAPs). A transgenic mice model, which lacks the desmin gene have been developed to study the function of desmin. In these mice, morphological abnormalities are observed in both heart and skeletal muscles. Similar defects have been observed in human myopathies, caused by different mutations in the desmin gene. In the present thesis, skeletal and heart muscles of both wild type and desmin knock-out (K/O) mice have been investigated. Furthermore the cytoskeletal organisation in skeletal muscles from human controls and from a patient with desmin myopathy was examined.

    In the desmin K/O mice, no morphological alterations were observed during embryogenesis. These mice postnatally developed a cardiomyopathy and a muscle dystrophy in highly used skeletal muscles. Ruptures of the sarcolemma appear to be the primary event leading to muscle degeneration and fibrosis both in cardiac and affected skeletal muscles. In the heart the muscle degeneration gave rise to calcifications, whereas in skeletal muscles regeneration of affected muscle was seen.

    In mature wild type mice, the IF proteins synemin and paranemin, and the IFAP plectin were present together with desmin at the myofibrillar Z-discs, the sarcolemma, the neuromuscular junctions and the myotendinous junctions. Nestin was only found in these junctional regions. In desmin K/O mice, all four proteins were detected at neuromuscular and myotendinous junctions. The normal network of synemin and paranemin were not observed, whereas the distribution of plectin was preserved.

    In normal human muscles, synemin, paranemin, plectin and αB-crystallin were colocalised with desmin in between the myofibrils, at the sarcolemma and at myotendinous and neuromuscular junctions. In the human desmin myopathy, the distribution of desmin varied considerably. A normal pattern was seen in some fibres areas, whereas other regions either contained large subsarcolemmal and intermyofibrillar accumulations of desmin or totally lacked desmin. Nestin, synemin, paranemin, plectin and αB-crystallin also exhibited an abnormal distribution. They were often aggregated in the areas that contained accumulations of desmin.

    In cultured satellite cells from the patient, a normal network of desmin was present in early passages, whereas aggragates of desmin occurred upon further culturing. In the latter, also the nestin network was disrupted, whereas vimentin showed a normal pattern. αB-crystallin was only present in cells with a disrupted desmin network. Plectin was present in a subset of cells, irrespective of whether desmin was aggregated or showed a normal network.

    From the present study it can be concluded that an intact desmin network is needed to maintain the integrity of muscle fibres. Desmin may be an important component in the assembly of proteins, which connect the extrasarcomeric cytoskeleton with the extracellular matrix.

  • 153.
    Carlsson, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Fischer, Christine
    Karoloinska Institute.
    Sjöberg, Gunnnar
    Karoloinska Institute.
    Robson, Richard M
    Iowa Statte University.
    Sejersen, Thomas
    Karoloinska Institute.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Cytoskeletal derangements in hereditary myopathy with a desmin L345P mutation2002Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 104, nr 5, s. 493-504Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Patients with abnormal accumulations of desmin have been described in myopathies with or without cardiac involvement. Desmin deposits were sometimes associated with abnormal aggregates of other cytoskeletal proteins. In the present study we present how the cytoskeletal organisation of desmin, nestin, synemin, paranemin, plectin and alphaB-crystallin is altered in skeletal muscles from a patient with a L345P mutation in the desmin gene. In general, accumulations of desmin together with synemin, nestin, plectin and alphaB-crystallin were present between myofibrils and beneath the sarcolemma. However, as the biopsy samples were very myopathic, large variability in fibre size and fibre maturation was seen, thus the myofibrillar content and the cytoskeletal organisation varied considerably. In cultured satellite cells from the patient, desmin aggregates were not observed in initial passages, but occurred over time in culture in the form of perinuclear, peripheral or cytoplasmic deposits. Nestin colocalised to the abnormal desmin deposits to a larger extent than did vimentin. alphaB-Crystallin was only present in cells with a disrupted desmin network. Plectin was altered in a subset of cells with a disrupted desmin network, whereas synemin and paranemin were not detected. We conclude that the L345P desmin mutation has a profound influence on the cytoskeletal organisation both in vivo and in vitro, which reflects the pathogenesis of the desmin myopathy.

  • 154.
    Carlsson, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Li, Z L
    Université Paris.
    Paulin, D
    Université Paris.
    Price, M G
    Baylor College of Medicine.
    Breckler, J
    San Fransisco State University.
    Robson, R M
    Iowa State University.
    Wiche, G
    University of Vienna.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Differences in the distribution of synemin, paranemin, and plectin in skeletal muscles of wild-type and desmin knock-out mice2000Inngår i: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 114, nr 1, s. 39-47Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mice lacking the gene encoding for the intermediate filament protein desmin have a surprisingly normal myofibrillar organization in skeletal muscle fibers, although myopathy develops in highly used muscles. In the present study we examined how synemin, paranemin, and plectin, three key cytoskeletal proteins related to desmin, are organized in normal and desmin knock-out (K/O) mice. We show that in wild-type mice, synemin, paranemin, and plectin were colocalized with desmin in Z-disc-associated striations and at the sarcolemma. All three proteins were also present at the myotendinous junctions and in the postsynaptic area of motor endplates. In the desmin K/O mice the distribution of plectin was unaffected, whereas synemin and paranemin were partly affected. The Z-disc-associated striations were in general no longer present in between the myofibrils. In contrast, at the myotendinous and neuromuscular junctions synemin and paranemin were still present. Our study shows that plectin differs from synemin and paranemin in its binding properties to the myofibrillar Z-discs and that the cytoskeleton in junctional areas is particularly complex in its organization.

  • 155.
    Carlsson, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Desmin-related myopathies in mice and man2001Inngår i: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 171, nr 3, s. 341-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Desmin, the main intermediate filament (IF) protein in skeletal and heart muscle cells, is of great importance as a part of the cytoskeleton. The IFs surround and interlink myofibrils, and connect the peripheral myofibrils with the sarcolemma. In myotendinous junctions and neuromuscular junctions of skeletal muscle fibres, desmin is enriched. In the heart, desmin is increased at intercalated discs, the attachment between cardiomyocytes, and it is the main component in Purkinje fibres of the conduction system. Desmin is the first muscle-specific protein to appear during myogenesis. Nevertheless, lack of desmin, as shown from experiments with desmin knockout (K/O) mice, does not influence myogenesis or myofibrillogenesis. However, the desmin knock-out mice postnatally develop a cardiomyopathy and a muscle dystrophy in highly used skeletal muscles. In other skeletal muscles the organization of myofibrils is remarkably unaffected. Thus, the main consequence of the lack of desmin is that the muscle fibres become more susceptible to damage. The loss of membrane integrity leads to a dystrophic process, with degeneration and fibrosis. In the heart cardiac failure develops, whereas in affected skeletal muscles regenerative attempts are seen. In humans, accumulations of desmin have been a hallmark for presumptive desmin myopathies. Recent investigations have shown that some families with such a myopathy have a defect in the gene coding for alphaB-crystallin, whereas others have mutations in the desmin gene. Typical features of these patients are cardiac affections and muscle weakness. Thus, mutations in the desmin gene is pathogenic for a distinct type of muscle disorder.

  • 156.
    Carlsson, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Yu, Ji-Guo
    Department of Natural and Environmental Physiology, Mid Sweden University.
    Moza, Monica
    Department of Pathology and Neuroscience Program, Biomedicum Helsinki, University of Helsinki and University Central Hospital, Finland.
    Carpén, Olli
    Department of Pathology, University of Turku and Turku University Central Hospital, Finland.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Myotilin: a prominent marker of myofibrillar remodelling2007Inngår i: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 17, nr 1, s. 61-68Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Myofibrillar remodelling with insertion of sarcomeres is a typical feature of biopsies taken from persons suffering of exercise-induced delayed onset muscle soreness. Here we studied the presence of the sarcomeric protein myotilin in eccentric exercise related lesions. Myotilin is a component of sarcomeric Z-discs and it binds several other Z-disc proteins, i.e. alpha-actinin, filamin C, F-actin and FATZ. Myotilin has previously been shown to be present in nemaline rods and central cores and to be mutated in limb girdle muscular dystrophy 1A (LGMD1A) and in a subset of myofibrillar myopathies, indicating an important role in Z-disc maintenance. Our findings on non-diseased muscle affected by eccentric exercise give new information on how myotilin is associated to myofibrillar components upon remodelling. We show that myotilin was present in increased amount in lesions related to Z-disc streaming and events leading to insertion of new sarcomeres in pre-existing myofibrils and can therefore be used as a marker for myofibrillar remodelling. Interestingly, myotilin is preferentially associated with F-actin rather than with the core Z-disc protein alpha-actinin during these events. This suggests that myotilin has a key role in the dynamic molecular events mediating myofibrillar assembly in normal and diseased skeletal muscle.

  • 157.
    Carlsson, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Yu, Ji-Guo
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    New aspects of obscurin in human striated muscles.2008Inngår i: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 130, nr 1, s. 91-103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obscurin is a giant protein (700-800 kDa) present in both skeletal muscles and myocardium. According to animal studies, obscurin interacts with myofibrillar Z-discs during early muscle development, but is translocalised to be predominantly associated with the M-bands in mature muscles. The proposed function for obscurin is in the assembly and organisation of myosin into regular A-bands during formation of new sarcomeres. In the present study, the precise localisation of obscurin in developing and mature normal human striated muscle is presented for the first time. We show that obscurin surrounded myofibrils at the M-band level in both developing and mature human skeletal and heart muscles, which is partly at variance with that observed in animals. At maturity, obscurin also formed links between the peripheral myofibrils and the sarcolemma, and was a distinct component of the neuromuscular junctions. Obscurin should therefore be regarded as an additional component of the extrasarcomeric cytoskeleton. To test this function of obscurin, biopsies from subjects with exercise-induced delayed onset muscle soreness (DOMS) were examined. In these subjects, myofibrillar alterations related to sarcomerogenesis are observed. Our immunohistochemical analysis revealed that obscurin was never lacking in myofibrillar alterations, but was either preserved at the M-band level or diffusely spread over the sarcomeres. As myosin was absent in such areas but later reincorporated in the newly formed sarcomeres, our results support that obscurin also might play an important role in the formation and maintenance of A-bands.

  • 158.
    Carlsöö, Bengt
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Studies on submandibular salivary gland peroxidase, its cellular localization and release mechanisms1974Doktoravhandling, med artikler (Annet vitenskapelig)
  • 159. Cenci, M. Angela
    et al.
    Jörntell, Henrik
    Petersson, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). The Group for Integrative Neurophysiology and Neurotechnology, Neuronano Research Centre, Department Experimental Medical Science, Lund University, Lund, Sweden.
    On the neuronal circuitry mediating l-DOPA-induced dyskinesia2018Inngår i: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 125, nr 8, s. 1157-1169Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    With the advent of rodent models of l-DOPA-induced dyskinesia (LID), a growing literature has linked molecular changes in the striatum to the development and expression of abnormal involuntary movements. Changes in information processing at the striatal level are assumed to impact on the activity of downstream basal ganglia nuclei, which in turn influence brain-wide networks, but very little is actually known about systems-level mechanisms of dyskinesia. As an aid to approach this topic, we here review the anatomical and physiological organisation of cortico-basal ganglia-thalamocortical circuits, and the changes affecting these circuits in animal models of parkinsonism and LID. We then review recent findings indicating that an abnormal cerebellar compensation plays a causal role in LID, and that structures outside of the classical motor circuits are implicated too. In summarizing the available data, we also propose hypotheses and identify important knowledge gaps worthy of further investigation. In addition to informing novel therapeutic approaches, the study of LID can provide new clues about the interplay between different brain circuits in the control of movement.

  • 160.
    Chandra, Naresh
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
    Liu, Yan
    Liu, Jing-Xia
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Frängsmyr, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
    Wu, Nian
    Silva, Lisete M
    Lindström, Mona
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Chai, Wengang
    Domellöf, Fatima Pedrosa
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Feizi, Ten
    Arnberg, Niklas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
    Sulfated Glycosaminoglycans as Viral Decoy Receptors for Human Adenovirus Type 372019Inngår i: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 11, nr 3, artikkel-id E247Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glycans on plasma membranes and in secretions play important roles in infection by many viruses. Species D human adenovirus type 37 (HAdV-D37) is a major cause of epidemic keratoconjunctivitis (EKC) and infects target cells by interacting with sialic acid (SA)-containing glycans via the fiber knob domain of the viral fiber protein. HAdV-D37 also interacts with sulfated glycosaminoglycans (GAGs), but the outcome of this interaction remains unknown. Here, we investigated the molecular requirements of HAdV-D37 fiber knob:GAG interactions using a GAG microarray and demonstrated that fiber knob interacts with a broad range of sulfated GAGs. These interactions were corroborated in cell-based assays and by surface plasmon resonance analysis. Removal of heparan sulfate (HS) and sulfate groups from human corneal epithelial (HCE) cells by heparinase III and sodium chlorate treatments, respectively, reduced HAdV-D37 binding to cells. Remarkably, removal of HS by heparinase III enhanced the virus infection. Our results suggest that interaction of HAdV-D37 with sulfated GAGs in secretions and on plasma membranes prevents/delays the virus binding to SA-containing receptors and inhibits subsequent infection. We also found abundant HS in the basement membrane of the human corneal epithelium, which may act as a barrier to sub-epithelial infection. Collectively, our findings provide novel insights into the role of GAGs as viral decoy receptors and highlight the therapeutic potential of GAGs and/or GAG-mimetics in HAdV-D37 infection.

  • 161.
    Chang, Yanhai
    et al.
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Wang, Xiao
    Department of Galactophore, Shaanxi Provincial Cancer Hospital, Xi’an, PR China.
    Sun, Zhengming
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Jin, Zhankui
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Chen, Ming
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Wang, Xiaoqing
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Lammi, Mikko
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Guo, Xiong
    School of Public Health, Xi’an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, Ministry of Health, Xi’an, China.
    Inflammatory cytokine of IL-1β is involved in T-2 toxin-triggered chondrocyte injury and metabolism imbalance by the activation of Wnt/β-catenin signaling2017Inngår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 91, s. 195-201Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mycotoxin T-2 exerts a causative role in Kashin-Beck disease (KBD) suffering chondrocyte apoptosis and cartilage matrix homeostasis disruption. Recent research corroborated the aberrant levels of pro-inflammatory cytokine IL-1ß in KBD patients and mycotoxin environment. In the present study, we investigated the relevance of IL-1ß in T-2 toxin-evoked chondrocyte cytotoxic injury and aberrant catabolism. High levels of IL-1ß were detected in serum and cartilages from KBD patients and in T-2-stimulated chondrocytes. Moreover, knockdown of IL-1ß antagonized the adverse effects of T-2 on cytotoxic injury by enhancing cell viability and inhibiting apoptosis. However, exogenous supplementation of IL-1β further aggravated cell damage in response to T-2. Additionally, cessation of IL-1β rescued T-2-elicited tilt of matrix homeostasis toward catabolism by elevating the transcription of collagen II and aggrecan, promoting release of sulphated glycosaminoglycans (sGAG) and TIMP1, and suppressing matrix metalloproteinases production including MMP-1, MMP-3 and MMP-13. Conversely, IL-1β stimulation deteriorated T-2-induced disruption of matrix metabolism balance toward catabolism. Mechanistic analysis found the high activation of Wnt/β-catenin in KBD patients and chondrocytes upon T-2. Furthermore, this activation was mitigated after IL-1β inhibition, but further enhanced following IL-1β precondition. Importantly, blocking this pathway by transfection with β-catenin alleviated the adverse roles of IL-1β on cytotoxic injury and metabolism disorders under T-2 conditioning. Together, this study elucidates a new insight into how T-2 deteriorates the pathological progression of KBD by regulating inflammation-related pathways, indicating a promising anti-inflammation strategy for KBD therapy.

  • 162.
    Chen, Jialin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Chen, Peng
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Zhou, Qingjun
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Ciliary Neurotrophic Factor Promotes the Migration of Corneal Epithelial Stem/progenitor Cells by Up-regulation of MMPs through the Phosphorylation of Akt2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 25870Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The migration of limbal epithelial stem cells is important for the homeostasis and regeneration of corneal epithelium. Ciliary neurotrophic factor (CNTF) has been found to promote corneal epithelial wound healing by activating corneal epithelial stem/progenitor cells. However, the possible effect of CNTF on the migration of corneal epithelial stem/progenitor cells is not clear. This study found the expression of CNTF in mouse corneal epithelial stem/progenitor cells (TKE2) to be up-regulated after injury, on both gene and protein level. CNTF promoted migration of TKE2 in a dose-dependent manner and the peak was seen at 10 ng/ml. The phosphorylation level of Akt (p-Akt), and the expression of MMP3 and MMP14, were up-regulated after CNTF treatment both in vitro and in vivo. Akt and MMP3 inhibitor treatment delayed the migration effect by CNTF. Finally, a decreased expression of MMP3 and MMP14 was observed when Akt inhibitor was applied both in vitro and in vivo. This study provides new insights into the role of CNTF on the migration of corneal epithelial stem/progenitor cells and its inherent mechanism of Up-regulation of matrix metalloproteinases through the Akt signalling pathway.

  • 163.
    Chen, Jialin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Lan, Jie
    Liu, Dongle
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Zhang, Wei
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Zhou, Qingjun
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Ascorbic Acid Promotes the Stemness of Corneal Epithelial Stem/Progenitor Cells and Accelerates Epithelial Wound Healing in the Cornea2017Inngår i: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 6, nr 5, s. 1356-1365Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High concentration of ascorbic acid (vitamin C) has been found in corneal epithelium of various species. However, the specific functions and mechanisms of ascorbic acid in the repair of corneal epithelium are not clear. In this study, it was found that ascorbic acid accelerates corneal epithelial wound healing in vivo in mouse. In addition, ascorbic acid enhanced the stemness of cultured mouse corneal epithelial stem/progenitor cells (TKE2) in vitro, as shown by elevated clone formation ability and increased expression of stemness markers (especially p63 and SOX2). The contribution of ascorbic acid on the stemness enhancement was not dependent on the promotion of Akt phosphorylation, as concluded by using Akt inhibitor, nor was the stemness found to be dependent on the regulation of oxidative stress, as seen by the use of two other antioxidants (GMEE and NAC). However, ascorbic acid was found to promote extracellular matrix (ECM) production, and by using two collagen synthesis inhibitors (AzC and CIS), the increased expression of p63 and SOX2 by ascorbic acid was decreased by around 50%, showing that the increased stemness by ascorbic acid can be attributed to its regulation of ECM components. Moreover, the expression of p63 and SOX2 was elevated when TKE2 cells were cultured on collagen I coated plates, a situation that mimics the in vivo situation as collagen I is the main component in the corneal stroma. This study shows direct therapeutic benefits of ascorbic acid on corneal epithelial wound healing and provides new insights into the mechanisms involved.

  • 164.
    Chen, Jialin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, Zhejiang; Zhejiang Provincial Key Lab forTissue Engineering and Regenerative Medicine, Hangzhou, Zhejiang, People’s Republic of China.
    Zhang, Erchen
    Zhang, Wei
    Liu, Zeyu
    Lu, Ping
    Zhu, Ting
    Yin, Zi
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Liu, Huanhuan
    Chen, Xiao
    Ouyang, Hongwei
    Fos Promotes Early Stage Teno-Lineage Differentiation of Tendon Stem/Progenitor Cells in Tendon2017Inngår i: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 6, nr 11, s. 2009-2019Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stem cells have been widely used in tendon tissue engineering. The lack of refined and controlled differentiation strategy hampers the tendon repair and regeneration. This study aimed to find new effective differentiation factors for stepwise tenogenic differentiation. By microarray screening, the transcript factor Fos was found to be expressed in significantly higher amounts in postnatal Achilles tendon tissue derived from 1 day as compared with 7-days-old rats. It was further confirmed that expression of Fos decreased with time in postnatal rat Achilles tendon, which was accompanied with the decreased expression of multiply tendon markers. The expression of Fos also declined during regular in vitro cell culture, which corresponded to the loss of tendon phenotype. In a cell-sheet and a three-dimensional cell culture model, the expression of Fos was upregulated as compared with in regular cell culture, together with the recovery of tendon phenotype. In addition, significant higher expression of tendon markers was found in Fos-overexpressed tendon stem/progenitor cells (TSPCs), and Fos knock-down gave opposite results. In situ rat tendon repair experiments found more normal tendon-like tissue formed and higher tendon markers expression at 4 weeks postimplantation of Fos-overexpressed TSPCs derived nonscaffold engineering tendon (cell-sheet), as compared with the control group. This study identifies Fos as a new marker and functional driver in the early stage teno-lineage differentiation of tendon, which paves the way for effective stepwise tendon differentiation and future tendon regeneration.

  • 165.
    Chen, Jialin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Zhang, Wei
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Kelk, Peyman
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Mechanical stress potentiates the differentiation of periodontal ligament stem cells into keratocytes2018Inngår i: British Journal of Ophthalmology, ISSN 0007-1161, E-ISSN 1468-2079, Vol. 102, nr 4, s. 562-569Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims To explore the role of corneal-shaped static mechanical strain on the differentiation of human periodontal ligament stem cells (PDLSCs) into keratocytes and the possible synergistic effects of mechanics and inducing medium. Methods PDLSCs were exposed to 3% static dome-shaped mechanical strain in a Flexcell Tension System for 3 days and 7 days. Keratocyte phenotype was determined by gene expression of keratocyte markers. Keratocyte differentiation (inducing) medium was introduced in the Flexcell system, either continuously or intermittently combined with mechanical stimulation. The synergistic effects of mechanics and inducing medium on keratocyte differentiation was evaluated by gene and protein expression of keratocyte markers. Finally, a multilamellar cell sheet was assembled by seeding PDLSCs on a collagen membrane and inducing keratocyte differentiation. The transparency of the cell sheet was assessed, and typical markers of native human corneal stroma were evaluated by immunofluorescence staining. Results Dome-shaped mechanical stimulation promoted PDLSCs to differentiate into keratocytes, as shown by the upregulation of ALDH3A1, CD34, LUM, COL I and COL V. The expression of integrins were also upregulated after mechanical stimulation, including integrin alpha 1, alpha 2, beta 1 and non-muscle myosin II B. A synergistic effect of mechanics and inducing medium was found on keratocyte differentiation. The cell sheets were assembled under the treatment of mechanics and inducing medium simultaneously. The cell sheets were transparent, multilamellar and expressed typical markers of corneal stroma. Conclusion Dome-shaped mechanical stimulation promotes differentiation of PDLSCs into keratocytes and has synergistic effects with inducing medium. Multilamellar cell sheets that resemble native human corneal stroma show potential for future clinical applications.

  • 166.
    Chen, Jialin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Zhang, Wei
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kelk, Peyman
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Fysioterapi.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Substance P and patterned silk biomaterial stimulate periodontal ligament stem cells to form corneal stroma in a bioengineered three-dimensional model2017Inngår i: Stem Cell Research & Therapy, E-ISSN 1757-6512, Vol. 8, artikkel-id 260Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: We aimed to generate a bioengineered multi-lamellar human corneal stroma tissue in vitro by differentiating periodontal ligament stem cells (PDLSCs) towards keratocytes on an aligned silk membrane.

    Methods: Human PDLSCs were isolated and identified. The neuropeptide substance P (SP) was added in keratocyte differentiation medium (KDM) to evaluate its effect on keratocyte differentiation of PDLSCs. PDLSCs were then seeded on patterned silk membrane and cultured with KDM and SP. Cell alignment was evaluated and the expression of extracellular matrix (ECM) components of corneal stroma was detected. Finally, multi-lamellar tissue was constructed in vitro by PDLSCs seeded on patterned silk membranes, which were stacked orthogonally and stimulated by KDM supplemented with SP for 18 days. Sections were prepared and subsequently stained with hematoxylin and eosin or antibodies for immunofluorescence observation of human corneal stroma-related proteins.

    Results: SP promoted the expression of corneal stroma-related collagens (collagen types I, III, V, and VI) during the differentiation induced by KDM. Patterned silk membrane guided cell alignment of PDLSCs, and important ECM components of the corneal stroma were shown to be deposited by the cells. The constructed multi-lamellar tissue was found to support cells growing between every two layers and expressing the main type of collagens (collagen types I and V) and proteoglycans (lumican and keratocan) of normal human corneal stroma.

    Conclusions: Multi-lamellar human corneal stroma-like tissue can be constructed successfully in vitro by PDLSCs seeded on orthogonally aligned, multi-layered silk membranes with SP supplementation, which shows potential for future corneal tissue engineering.

  • 167.
    Chen, Jialin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Zhang, Wei
    Liu, Zeyu
    Zhu, Ting
    Shen, Weiliang
    Ran, Jisheng
    Tang, Qiaomei
    Gong, Xiaonan
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Chen, Xiao
    Chen, Xiaowen
    Wen, Feiqiu
    Ouyang, Hongwei
    Characterization and comparison of post-natal rat Achilles tendon-derived stem cells at different development stages2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 22946Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tendon stem/progenitor cells (TSPCs) are a potential cell source for tendon tissue engineering. The striking morphological and structural changes of tendon tissue during development indicate the complexity of TSPCs at different stages. This study aims to characterize and compare post-natal rat Achilles tendon tissue and TSPCs at different stages of development. The tendon tissue showed distinct differences during development: the tissue structure became denser and more regular, the nuclei became spindle-shaped and the cell number decreased with time. TSPCs derived from 7 day Achilles tendon tissue showed the highest self-renewal ability, cell proliferation, and differentiation potential towards mesenchymal lineage, compared to TSPCs derived from 1 day and 56 day tissue. Microarray data showed up-regulation of several groups of genes in TSPCs derived from 7 day Achilles tendon tissue, which may account for the unique cell characteristics during this specific stage of development. Our results indicate that TSPCs derived from 7 day Achilles tendon tissue is a superior cell source as compared to TSPCs derived from 1 day and 56 day tissue, demonstrating the importance of choosing a suitable stem cell source for effective tendon tissue engineering and regeneration.

  • 168.
    Chermenina, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    GDNF and alpha-synuclein in nigrostriatal degeneration2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Parkinson’s disease is a common neurological disorder with a complex etiology. The disease is characterized by a progressive loss of dopaminergic cells in the substantia nigra, which leads to motor function and sometimes cognitive function disabilities. One of the pathological hallmarks in Parkinson’s disease is the cytoplasmic inclusions called Lewy bodies found in the dopamine neurons. The aggregated protein α-synuclein is a main component of Lewy bodies. In view of severe symptoms and the upcoming of problematic side effects that are developed by the current most commonly used treatment in Parkinson’s disease, new treatment strategies need to be elucidated. One such strategy is replacing the lost dopamine neurons with new dopamine-rich tissue. To improve survival of the implanted neurons, neurotrophic factors have been used. Glial cell line-derived neurotrophic factor (GDNF), which was discovered in 1993, improves survival of ventral mesencephalic dopamine neurons and enhances dopamine nerve fiber formation according to several studies. Thus, GDNF can be used to improve dopamine-rich graft outgrowth into the host brain as well as inducing sprouting from endogenous remaining nerve fibers. This study was performed on Gdnf gene-deleted mice to investigate the role of GDNF on the nigrostriatal dopamine system. The transplantation technique was used to create a nigrostriatal microcircuit from ventral mesencephalon (VM) and the lateral ganglionic eminence (LGE) from different Gdnf gene-deleted mice. The tissue was grafted into the lateral ventricle of wildtype mice. The results revealed that reduced concentrations of GDNF, as a consequence from the Gdnf gene deletion, had effects on survival of dopamine neurons and the dopamine innervation of the nigrostriatal microcircuit. All transplants had survived at 3 months independently of Gdnf genotype, however, the grafts derived from Gdnf gene-deleted tissue had died at 6 months. Transplants with partial Gdnf gene deletion survived up to 12 months after transplantation. Moreover, the dopaminergic innervation of striatal co-grafts was impaired in Gdnf gene-deleted tissue. These results highlight the role of GDNF for long-term maintenance of the nigrostriatal dopamine system. To further investigate the role of GDNF expression on survival and organization of the nigrostriatal dopamine system, VM and LGE as single or combined to double co-grafts created from mismatches in Gdnf genotypes were transplanted into the lateral ventricle of wildtype mice. Survival of the single grafts was monitored over one year using a 9.4T MR scanner. The size of single LGE transplants was significantly reduced by the lack of GDNF already at 2 weeks postgrafting while the size of single VM was maintained over time, independently of GDNF expression. The double grafts were evaluated at 2 months, and the results revealed that lack of GDNF in LGE reduced the dopamine cell survival, while no loss of dopamine neurons was found in VM single grafts. The dopaminergic innervation of LGE was affected by absence of GDNF, which also caused a disorganization of the striatal portion of the co-grafts. Small, cytoplasmic inclusions were frequently found in the dopamine neurons in grafts lacking GDNF expression. These inclusions were not possible to classify as Lewy bodies by immunohistochemistry and the presence of phospho-α-synuclein and ubiquitin; however, mitochondrial dysfunction could not be excluded. To further study the death of the dopamine neurons by the deprivation of GDNF, the attention was turned to how Lewy bodies are developed. With respect to the high levels of α-synuclein that was found in the striatum, this area was selected as a target to inject the small molecule – FN075, which stimulates α-synuclein aggregation, to further investigate the role of α-synuclein in the formation of cytoplasmic inclusions. The results revealed that cytoplasmic inclusions, similar to those found in the grafts, was present at 1 month after the injection, while impairment in sensorimotor function was exhibited, the number of dopamine neurons was not changed at 6 months after the injection. Injecting the templator to the substantia nigra, however, significantly reduced the number of TH-positive neurons at 3 months after injection. In conclusion, these studies elucidate the role of GDNF for maintenance and survival of the nigrostriatal dopamine system and mechanisms of dopamine cell death using small molecules that template the α-synuclein aggregation.

  • 169.
    Chermenina, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Henrik, Antti
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Strömberg, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    A novel animal model for Parkinson's disease based on in vivo effects of small-molecule of alpha-synucleinManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Amyloid fibrils of alpha-synuclein are major constituents of Lewy bodies, the pathological hallmark of Parkinson’s disease. Monomeric α-synuclein is involved in synaptic vesicle trafficking and long-term maintenance of neurons. The underlying mechanisms of Parkinson’s disease are not known but it has been proposed that oligomers of α-synuclein, formed during the aggregation process, are toxic to neurons. To search for a new animal model of Parkinson’s disease, here we capitalized on the in vitro discovery of a small-molecule templator of α-synuclein fibrillization, the 2-pyridone, FN075. FN075 and MS382, another 2-pyridone variant that act as an inhibitor of amyloids in vitro, were injected into the striatum or substantia nigra of normal C57Bl/6 mice. No acute toxicity of the compounds was detected, as there was 100 % survival of the injected mice. At 6 months after the striatal injection, sensorimotor functions were impaired with no reduction in TH-positive neurons in the substantia nigra in mice injected with FN075, whereas mice injected with MS382 or vehicle had no dysfunctions. Injection of FN075 into the substantia nigra revealed a significant loss of TH-positive neurons already at 3 months and TH-negative inclusion-like structures were detected in substantia nigra neurons of these mice. Thus, the results suggest that injection of a templator of α-synuclein aggregation into the brain of normal mice can serve as a novel experimental design for an animal model of Parkinson’s disease.

  • 170.
    Chermenina, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pokrzywa, Malgorzata
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Strömberg, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Single injection of small-molecule amyloid accelerator results in cell death of nigral dopamine neurons in mice2015Inngår i: Parkinson's Disease, ISSN 2090-8083, E-ISSN 2042-0080, Vol. 1, artikkel-id 15024Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The assembly process of a-synuclein toward amyloid fibers is linked to neurodegeneration in Parkinson´s disease. In the present study, we capitalized on the in vitro discovery of a small-molecule accelerator of a-synuclein amyloid formation and assessed its effects when injected in brains of normal mice. An accelerator and an inhibitor of a-synuclein amyloid formation, as well as vehicle only, were injected into the striatum of normal mice and follwed by behavioral evaluation, immunohistochemistry, and metabolomics up to six months later. The effects of molecules injected into the substansia nigra of normal and a-synuclein knockout mice were also analyzed. When accelerator or inhibitor was injected into the brain of normal mice no acute compound toxicity was found. However, 6 months after single striatal injection of accelerator, mice sensorimotor functions were impaired, whereas mice injected with inhibitor had no dysfunctions. Injection of accelerator (but not inhibitor or vehicle) into the substantia nigra revealed singificant loss of tyrosine hydroxylase (TH)-positive neurons after 3 months. No loss of TH-positive neurons was found in a-synuclein knock-out mice injected with accelerator intor the substantia nigra. Metabolic serum profiles from accelerator-injected normal mice matched those of newly diagnosed Parkinson´s disease patients, whereas the profiles from inhibitor-injected normal mice matched controls. Single inoculation of a small-molecule amyloid accelerator may be a new approach for studies of early events during dopamine neurodegeneration in mice.

  • 171.
    Chermenina, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Schouten, P
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Nevalainen, Nina
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Johansson, F
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Orädd, Greger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Strömberg, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    GDNF is important for striatal organization and maintenance of dopamine neurons grown in the presence of the striatum2014Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 270, s. 1-11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glial cell-derived neurotrophic factor (GDNF) exerts neuroprotective and neurorestorative effects on neurons and GDNF plays a significant role in maintenance of the dopamine neurons utilizing grafting to create a nigrostriatal microcircuit of Gdnf knockout (Gdnf(-/-)) tissue. To further evaluate the role of GDNF on organization of the nigrostriatal system, single or double grafts of ventral mesencephalon (VM) and lateral ganglionic eminence (LGE) with mismatches in Gdnf genotypes were performed. The survival of single grafts was monitored utilizing magnetic resonance imaging (MRI) and cell survival and graft organization were evaluated with immunohistochemistry. The results revealed that the size of VM single grafts did not change over time independent of genotype, while the size of the LGE transplants was significantly reduced already at 2weeks postgrafting when lacking GDNF. Lack of GDNF did not significantly affect the survival of tyrosine hydroxylase (TH)-positive neurons in single VM grafts. However, the survival of TH-positive neurons was significantly reduced in VM derived from Gdnf(+/+) when co-grafted with LGE from the Gdnf(-/-) tissue. In contrast, lack of GDNF in the VM portion of co-grafts had no effect on the survival of TH-positive neurons when co-grafted with LGE from Gdnf(+/+) mice. The TH-positive innervation of co-grafts was sparse when the striatal co-grafts were derived from the Gdnf(-/-) tissue while dense and patchy when innervating LGE producing GDNF. The TH-positive innervation overlapped with the organization of dopamine and cyclic AMP-regulated phosphoprotein-relative molecular mass 32,000 (DARPP-32)-positive neurons, that was disorganized in LGE lacking GDNF production. In conclusion, GDNF is important for a proper striatal organization and for survival of TH-positive neurons in the presence of the striatal tissue.

  • 172.
    Ching, Rosanna C.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    The role of exosomes in peripheral nerve regeneration2015Inngår i: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 10, nr 5, s. 743-747Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Peripheral nerve injuries remain problematic to treat, with poor functional recovery commonly observed. Injuries resulting in a nerve gap create specific difficulties for axonal regeneration. Approaches to address these difficulties include autologous nerve grafts (which are currently the gold standard treatment) and synthetic conduits, with the latter option being able to be impregnated with Schwann cells or stem cells which provide an appropriate micro-environment for neuronal regeneration to occur. Transplanting stem cells, however, infers additional risk of malignant transformation as well as manufacturing difficulties and ethical concerns, and the use of autologous nerve grafts and Schwann cells requires the sacrifice of a functioning nerve. A new approach utilizing exosomes, secreted extracellular vesicles, could avoid these complications. In this review, we summarize the current literature on exosomes, and suggest how they could help to improve axonal regeneration following peripheral nerve injury.

  • 173.
    Ching, Rosanna C.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Schwann cell-like differentiated adipose stem cells promote neurite outgrowth via secreted exosomes and RNA transfer2018Inngår i: Stem Cell Research & Therapy, E-ISSN 1757-6512, Vol. 9, artikkel-id 266Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Adipose derived stem cells can be stimulated to produce a growth factor rich secretome which enhances axon regeneration. In this study we investigated the importance of exosomes, extracellular vesicles released by many different cell types, including stem cells and endogenous nervous system Schwann cells (SCs), on neurite outgrowth.

    Methods: Adipose derived stem cells were differentiated towards a Schwann cell-like phenotype (dADSCs) by in vitro stimulation with a mix of factors (basic fibroblast growth factor, platelet derived growth factor-AA, neuregulin-1 and forskolin). Using a precipitation and low-speed centrifugation protocol the extracellular vesicles were isolated from the medium of the stem cells cultures and also from primary SCs. The conditioned media or concentrated vesicles were applied to neurons in vitro and computerised image analysis was used to assess neurite outgrowth. Total RNA was purified from the extracellular vesicles and investigated using qRT-PCR.

    Results: Application of exosomes derived from SCs significantly enhanced in vitro neurite outgrowth and this was replicated by the exosomes from dADSCs. qRT-PCR demonstrated that the exosomes contained mRNAs and miRNAs known to play a role in nerve regeneration and these molecules were up-regulated by the Schwann cell differentiation protocol. Transfer of fluorescently tagged exosomal RNA to neurons was detected and destruction of the RNA by UV-irradiation significantly reduced the dADSCs exosome effects on neurite outgrowth. In contrast, this process had no significant effect on the SCs-derived exosomes.

    Conclusions: In summary, this work suggests that stem cell-derived exosomes might be a useful adjunct to other novel therapeutic interventions in nerve repair.

  • 174.
    Chizhov, Anton V
    et al.
    Computational Physics Laboratory, Division of Plasma Physics, Atomic Physics and Astrophysics, A.F. Ioffe Physical-Technical Institute of the Russian Academy of Sciences, St. Petersburg, Russia.
    Malinina, Evgenia
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Druzin, Michael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi. Department of Neurodynamics and Neurobiology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia.
    Graham, Lyle J
    Neurophysiology and New Microscopies Laboratory, INSERM U603 - CNRS UMR 8154, Université Paris Descartes, Paris, France.
    Johansson, Staffan
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Firing clamp: a novel method for single-trial estimation of excitatory and inhibitory synaptic neuronal conductances.2014Inngår i: Frontiers in cellular neuroscience, ISSN 1662-5102, Vol. 8, nr 86, s. 86-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Understanding non-stationary neuronal activity as seen in vivo requires estimation of both excitatory and inhibitory synaptic conductances from a single trial of recording. For this purpose, we propose a new intracellular recording method, called "firing clamp." Synaptic conductances are estimated from the characteristics of artificially evoked probe spikes, namely the spike amplitude and the mean subthreshold potential, which are sensitive to both excitatory and inhibitory synaptic input signals. The probe spikes, timed at a fixed rate, are evoked in the dynamic-clamp mode by injected meander-like current steps, with the step duration depending on neuronal membrane voltage. We test the method with perforated-patch recordings from isolated cells stimulated by external application or synaptic release of transmitter, and validate the method with simulations of a biophysically-detailed neuron model. The results are compared with the conductance estimates based on conventional current-clamp recordings.

  • 175.
    Christensen, Jens
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Idrottsmedicin. UCLH, ISEH, London, England; Pure Sports Clin, London, England.
    Andersson, Gustav
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Protease-activated receptors in the Achilles tendon-a potential explanation for the excessive pain signalling in tendinopathy2015Inngår i: Molecular Pain, ISSN 1744-8069, E-ISSN 1744-8069, Vol. 11, artikkel-id 13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background/Aim: Tendinopathies are pathological conditions of tissue remodelling occurring in the major tendons of the body, accompanied by excessive nociceptive signalling. Tendinopathies have been shown to exhibit an increase in the number of mast cells, which are capable of releasing histamine, tryptase and other substances upon activation, which may play a role in the development of tendinopathies. This study set out to describe the distribution patterns of a family of receptors called protease-activated receptors (PARs) within the Achilles tendon. These four receptors (PAR1, PAR2, PAR3, PAR4) are activated by proteases, including tryptase released from mast cells, and are involved in fibrosis, hyperalgesia and neovascularisation, which are changes seen in tendinopathies. Method: In order to study which structures involved in tendinopathy that these proteases can affect, biopsies from patients suffering of mid-portion Achilles tendinosis and healthy controls were collected and examined using immunohistochemistry. Tendon cells were cultured to study in vitro expression patterns. Results: The findings showed a distribution of PARs inside the tendon tissue proper, and in the paratendinous tissue, with all four being expressed on nerves and vascular structures. Double staining showed co-localisation of PARs with nociceptive fibres expressing substance P. Concerning tenocytes, PAR2, PAR3, and PAR4, were found in both biopsies of tendon tissue and cultured tendon cells. Conclusions: This study describes the expression patterns of PARs in the mid-portion of the Achilles tendon, which can help explain the tissue changes and increased pain signalling seen in tendinopathies. These findings also show that in-vitro studies of the effects of these receptors are plausible and that PARs are a possible therapeutic target in the future treatment strategies of tendinopathy.

  • 176. Cipriani, Christian
    et al.
    Segil, Jacob L.
    Clemente, Francesco
    Weir, Richard F. Ff.
    Edin, Benoni
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Humans can integrate feedback of discrete events in their sensorimotor control of a robotic hand2014Inngår i: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 232, nr 11, s. 3421-3429Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Providing functionally effective sensory feedback to users of prosthetics is a largely unsolved challenge. Traditional solutions require high band-widths for providing feedback for the control of manipulation and yet have been largely unsuccessful. In this study, we have explored a strategy that relies on temporally discrete sensory feedback that is technically simple to provide. According to the Discrete Event-driven Sensory feedback Control (DESC) policy, motor tasks in humans are organized in phases delimited by means of sensory encoded discrete mechanical events. To explore the applicability of DESC for control, we designed a paradigm in which healthy humans operated an artificial robot hand to lift and replace an instrumented object, a task that can readily be learned and mastered under visual control. Assuming that the central nervous system of humans naturally organizes motor tasks based on a strategy akin to DESC, we delivered short-lasting vibrotactile feedback related to events that are known to forcefully affect progression of the grasp-lift-and-hold task. After training, we determined whether the artificial feedback had been integrated with the sensorimotor control by introducing short delays and we indeed observed that the participants significantly delayed subsequent phases of the task. This study thus gives support to the DESC policy hypothesis. Moreover, it demonstrates that humans can integrate temporally discrete sensory feedback while controlling an artificial hand and invites further studies in which inexpensive, noninvasive technology could be used in clever ways to provide physiologically appropriate sensory feedback in upper limb prosthetics with much lower band-width requirements than with traditional solutions.

  • 177. Clemente, Francesco
    et al.
    D'Alonzo, Marco
    Controzzi, Marco
    Edin, Benoni B.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Cipriani, Christian
    Non-Invasive, Temporally Discrete Feedback of Object Contact and Release Improves Grasp Control of Closed-Loop Myoelectric Transradial Prostheses2016Inngår i: IEEE transactions on neural systems and rehabilitation engineering, ISSN 1534-4320, E-ISSN 1558-0210, Vol. 24, nr 12, s. 1314-1322Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human grasping and manipulation control critically depends on tactile feedback. Without this feedback, the ability for fine control of a prosthesis is limited in upper limb amputees. Although various approaches have been investigated in the past, at present there is no commercially available device able to restore tactile feedback in upper limb amputees. Based on the Discrete Event-driven Sensory feedback Control (DESC) policy we present a device able to deliver short-lasting vibrotactile feedback to transradial amputees using commercially available myoelectric hands. The device (DESC-glove) comprises sensorized thimbles to be placed on the prosthesis digits, a battery-powered electronic board, and vibrating units embedded in an arm-cuff being transiently activated when the prosthesis makes and breaks contact with objects. The consequences of using the DESC-glove were evaluated in a longitudinal study. Five transradial amputees were equipped with the device for onemonth at home. Through a simple test proposed here for the first time-the virtual eggs test-we demonstrate the effectiveness of the device for prosthetic control in daily life conditions. In the future the device could be easily exploited as an add-on to complement myoelectric prostheses or even embedded in prosthetic sockets to enhance their control by upper limb amputees.

  • 178. Cotrufo, Stefano
    et al.
    Dabernig, Joerg
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Department of Surgical and Perioperative Science, Section for Hand and Plastic Surgery, University Hospital, Umea, Sweden.
    Vascular supply of the tensor fasciae latae flap revised2009Inngår i: Plastic and reconstructive surgery (1963), ISSN 0032-1052, E-ISSN 1529-4242, Vol. 123, nr 4, s. 161e-162eArtikkel i tidsskrift (Annet vitenskapelig)
  • 179.
    Cotrufo, Stefano
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; .
    Dabernig, Joerg
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Laboratory of Human Anatomy, University of Glasgow, Glasgow, United Kingdom.
    Russell, David
    Laboratory of Human Anatomy, University of Glasgow, Glasgow, United Kingdom.
    Payne, Anthony
    Laboratory of Human Anatomy, University of Glasgow, Glasgow, United Kingdom.
    Hart, Andrew
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; .
    The Vascular Anatomy of the Rat Superficial Epigastric Flap by Vascular Corrosion Casting and Technical Refinement for the Study of Choke Vessels in Cadaveric Flap Models2010Inngår i: Annals of Plastic Surgery, ISSN 0148-7043, E-ISSN 1536-3708, Vol. 64, nr 1, s. 93-97Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Accurate depiction of cutaneous vascular microanatomy is of relevance to plastic surgical flap research, and to descriptive anatomy. Yet current techniques have not permitted full visualization of the subdermal plexus, or potential angiosomal connections. Nor has endothelial visualization been facilitated. Vascular corrosion casting techniques are promising in that regard, and were applied in an extended lateral thoracoabdominal suprafascial adipocutancous flap in the rat (based on the superficial epigastric bundle). Technical refinements for application to further study of human cadaveric flap models are presented. The intraflap vascular branching pattern of the superficial epigastric artery is described, with filling of the lateral thoracic, intercostals, and iliolumbar angiosomes found when coagulation of vessels at the periphery was delayed until after clearance. The vascular casting protocol presented is an effective and promising tool for the study of macro- and microvascular anatomy.

  • 180. Crea, Simona
    et al.
    Edin, Benoni B.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Knaepen, Kristel
    Meeusen, Romain
    Vitiello, Nicola
    Time-Discrete Vibrotactile Feedback Contributes to Improved Gait Symmetry in Patients With Lower Limb Amputations: Case Series2017Inngår i: Physical Therapy, ISSN 0031-9023, E-ISSN 1538-6724, Vol. 97, nr 2, s. 198-207Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Reduced sensory feedback from lower leg prostheses results in harmful gait patterns and entails a significant cognitive burden because users have to visually monitor their locomotion. Objectives. The purpose of this study was to validate a sensory feedback device designed to help elderly patients with transfemoral amputation to improve their temporal gait symmetry after a training program aimed at associating the vibrotactile patterns with symmetrical walking. Design. This was a prospective quasi-experimental study including 3 elderly patients walking with lower leg prostheses. Methods. During training sessions, participants walked on a treadmill equipped with feedback device that controlled vibrotactile stimulators based on signals from a sensorized insole while provided with visual feedback about temporal gait symmetry. The vibrotactile stimulators delivered short-lasting, low-intensity vibrations synchronously with certain gait phase transitions. During pretraining and posttraining sessions, participants walked without visual feedback about gait symmetry under 4 conditions: with or without vibrotactile feedback while performing or not performing a secondary cognitive task. The primary outcome measure was temporal gait symmetry. Results. with <= 52 hours of training,the participants improved their temporal gait symmetry from 0.82 to 0.84 during the pretraining evaluation session to 0.98 to 1.02 during the follow-up session across all conditions. Following training, participants were able to maintain good temporal gait synmsetry, without any evidence of an increased cognitive burden. Limitations. The small sample size and short follow-up time do not allow straightforward extrapolations to larger populations or extended time periods. Conclusions. Low-cost, gait phase-specific vibrotactile feedback after training combined with visual feedback may improve the temporal gait synmsetry in patients with transfemoral amputation without representing an additional cognitive burden.

  • 181.
    Dabernig, Jörg
    et al.
    Glasgow Royal Infirmary.
    Ong, Keh O
    Glasgow Royal Infirmary.
    McGowan, Robert
    Glasgow Royal Infirmary.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Payne, Anthony P
    University of Glasgow.
    Hart, Andrew M
    Glasgow Royal Infirmary.
    The anatomic and radiologic basis of the circumflex scapular artery perforator flap2010Inngår i: Annals of Plastic Surgery, ISSN 0148-7043, E-ISSN 1536-3708, Vol. 64, nr 6, s. 784-788Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Microsurgical development has recently focused upon the perforator paradigm and primary thinning. Existing perforator flaps may require intramuscular dissection or lack reliable surface markings, whereas traditional scapular/parascapular flaps have low donor morbidity and reliable anatomy, but can be excessively bulky. Clinical application of a new flap based on a perforator from the circumflex scapular axis (CSA) has recently been published, but the vessel's anatomy has not been adequately characterized. The CSA was dissected in 115 sites in 69 cadavers. The number, external vessel diameter, and site of origin of perforators were measured relative to the CSA bifurcation. Color Doppler ultrasound was used to delineate the CSA and its perforators bilaterally in 40 volunteers. The number, origin relative to CSA bifurcation, diameter, length, and flow velocity of cutaneous perforators were determined. A CSA perforator was always present, running into the subdermal plexus, arising within 2.4 cm of the bifurcation. Cadaver studies: mean perforator diameter, 1.3 mm (SD, 0.66); 13% arose at bifurcation, 36% arose proximal (mean, 1.1 mm; SD, 0.63), and 52% distal to bifurcation (mean, 1.5 mm; SD, 0.88). Ultrasound: mean perforator diameter, 1.18 mm (SD, 0.41); mean flow velocity, 16.3 cm/s (SD, 3.65); perforator arose in 36% proximal, in 40% distal to bifurcation, and in 24% from the bifurcation. We definitively describe the anatomy of the perforator from the circumflex scapular artery upon which a new flap has been based. Its origin and dimensions are anatomically and radiologically reliable. The flap has certain potential benefits over existing perforator flaps.

  • 182.
    Dabernig, Jörg
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Sorensen, K
    Shaw-Dunn, J
    Hart, Andrew McKay
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    The thin circumflex scapular artery perforator flap2007Inngår i: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1532-1959, Vol. 60, nr 10, s. 1082-1096Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The development of microsurgery has most recently been focused upon the evolution of perforator flaps, with the aim of minimising donor site morbidity, and avoiding the transfer of functionally unnecessary tissues. The vascular basis of perforator flaps also facilitates radical primary thinning prior to flap transfer, when appropriate. Based upon initial clinical observations, cadaveric, and radiological studies, we describe a new, thin, perforator flap based upon the circumflex scapular artery (CSA). A perforator vessel was found to arise within 1.5cm of the CSA bifurcation (arising from the main trunk, or the descending branch). The perforator arborises into the sub-dermal vascular plexus of the dorsal scapular skin, permitting the elevation and primary thinning of a skin flap. This thin flap has been employed in a series of five clinical cases to reconstruct defects of the axilla (two cases of hidradenitis suppurativa; pedicled transfers), and upper limb (one sarcoma, one brachial to radial artery flowthrough revascularisation plus antecubital fossa reconstruction, and one hand reconstruction with a chimeric flap incorporating vascularised bone, fascia, and thin skin flaps; free tissue transfers). No intramuscular perforator dissection is required; pedicle length is 8-10cm and vessel diameter 2-4mm. There was no significant peri-operative complication or flap failure, all donor sites were closed primarily, patient satisfaction was high, and initial reconstructive aims were achieved in all cases. Surgical technique, and the vascular basis of the flap are described. The thin circumflex scapular artery perforator flap requires no intramuscular dissection yet provides high quality skin (whose characteristics can be varied by orientation of the skin paddle), and multiple chimeric options. The donor site is relatively hair-free, has favourable cosmesis and no known functional morbidity. This flap represents a promising addition to the existing range of perforator flaps.

  • 183.
    Dagberg, Björn
    et al.
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi, Fysiologi.
    Alstermark, Bror
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi, Fysiologi.
    Improved organotypic cell culture model for analysis of the neuronal circuit involved in the monosynaptic stretch reflex.2006Inngår i: Journal of Neuroscience Research, ISSN 0360-4012, Vol. 84, nr 2, s. 460-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Knowledge regarding neuronal circuit formation is central for the understanding of the vast network making up the brain. It is therefore necessary to find novel ways to analyze the mechanisms involved in well-defined neural circuits. We present an improved in vitro model of the monosynaptic stretch reflex circuit, based on primary organotypic cell cultures. By using limb tissue as a source of muscle fibers instead of circumspinal tissue we could make the in vitro system more in vivo like in the sense that it focuses on the stretch reflex involving limb muscles. Furthermore, our analyses showed that this procedure allows muscle fibers to follow the normal developmental pattern. Particularly interesting was the finding of slow tonic myosin heavy chain expressing muscle fibers, a developmental marker for muscle spindles, in the cultures showing that this system has the potential to contain the complete reflex circuits.

  • 184.
    Dahl, Morten
    et al.
    Institute of Sports Medicine, Department 8, Bispebjerg Hospital and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Hansen, Philip
    Institute of Sports Medicine, Department 8, Bispebjerg Hospital and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Stål, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Edmundsson, David
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Magnusson, S. Peter
    Institute of Sports Medicine, Department 8, Bispebjerg Hospital and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Stiffness and thickness of Fascia do not explain chronic exertional compartment syndrome2011Inngår i: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, Vol. 469, nr 12, s. 3495-3500Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background   Chronic exertional compartment syndrome is diagnosed based on symptoms and elevated intramuscular pressure and often is treated with fasciotomy. However, what contributes to the increased intramuscular pressure remains unknown.

    Questions/purposes   We investigated whether the stiffness or thickness of the muscle fascia could help explain the raised intramuscular pressure and thus the associated chronic compartment syndrome symptoms.

    Patients and Methods   We performed plain radiography, bone scan, and intramuscular pressure measurement to diagnose chronic compartment syndrome and to exclude other disorders. Anterior tibialis muscle fascial biopsy specimens from six healthy individuals, 11 patients with chronic compartment syndrome, and 10 patients with diabetes mellitus and chronic compartment syndrome were obtained. Weight-normalized fascial stiffness was assessed mechanically in a microtensile machine, and fascial thickness was analyzed microscopically.

    Results   Mean fascial stiffness did not differ between healthy individuals (0.120 N/mg/mm; SD, 0.77 N/mg/mm), patients with chronic compartment syndrome (0.070 N/mg/mm; SD, 0.052 N/mg/mm), and patients with chronic compartment syndrome and diabetes (0.097 N/mg/mm; SD, 0.073 N/mg/mm). Similarly, no differences in fascial thickness were present. There was a negative correlation between fascial stiffness and intramuscular pressure in the patients with chronic compartment syndrome and diabetes.

    Conclusions   The lack of difference in fascial thickness and stiffness in patients with chronic compartment syndrome and patients with chronic compartment syndrome and diabetes compared with healthy individuals suggests structural and mechanical properties are unlikely to explain chronic compartment syndrome. To prevent chronic exertional compartment syndrome, it is necessary to address aspects other than the muscle fascia.

  • 185.
    Dahlin, Erika
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi. Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    Train your brain: updating, transfer, and neural changes2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    An initial aim of this thesis was to determine whether training of a specific executive function (updating) produces improvements in performance on trained and transfer tasks, and whether the effects are maintained over time. Neural systems underlying training and transfer effects were also investigated and one question considered is whether transfer depends on general or specific neural overlap between training and transfer tasks. An additional aim was to identify how individual differences in executive functioning are mapped to functional brain changes. In Study I, significant training-related changes in performance on the letter memory criterion task were found in both young and older adults after 5 weeks of updating training. Transfer to a 3-back test of updating was also demonstrated in the young adults. Functional Magnetic Resonance Imaging (fMRI) revealed overlapping activity in letter memory and 3-back tasks in fronto-parietal areas and striatum pre-training, and a joint training-related activity increase for the tasks in a striatal region. No transfer was observed to a task (Stroop) that engaged fronto-parietal areas, but not the striatal region and updating per se. Moreover, age-related striatal changes imposed constraints on transfer. In Study II, additional transfer tasks and a test of long-term maintenance were included. Results revealed that training-related gains in performance were maintained 18 months post-training in both young and older adults, whereas transfer effects were limited to tasks requiring updating and restricted to young participants. In Study III, analyses of brain activity and performance during n-back (1/2/3-back) were executed. This task enables manipulation of executive demand, which permits examination of how individual differences in executive functioning can be mapped to functional brain changes. Relative to a young high-

    performing group, capacity constraints in executive functioning were apparent between 1–2-back for the elderly participants and between 2–3-back for a young low-performing group. Capacity constraints in neural activity followed this pattern by showing a monotonically increasing response in the parietal cortex and the thalamus for young high performers, whereas activity levelled off at 1-back for elderly performers and at 2-back for young low performers. The response in the dorsal frontal cortex followed a similar pattern. Together, these findings indicate that fronto-parietal as well as sub-cortical areas are important for individual differences in executive functioning, training of updating and transfer effects.

  • 186.
    Dahlin, Erika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Bäckman, Lars
    Aging Research Center, Karolinska institutet,Stockholm.
    Stigsdotter Neely, Anna
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Training of the executive component of working memory: subcortial areas mediate transfer effects2009Inngår i: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 27, nr 5, s. 405-419Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Several recent studies show that training can improve working memory (WM) performance. In this review, many issues related to WM training, such as neural basis, transfer effects, and age-related changes are addressed.

    Method: We focus on our own studies investigating training on tasks taxing the executive updating function and discuss our findings in relation to results from other studies investigating training of the executive component of WM.

    Results: The review confirms positive behavioral effects of training on working memory. The most common neural pattern following training is fronto-parietal activity decreases. Increases in sub-cortical areas are also frequently reported after training, and we suggest that such increases indicate changes in the underlying skill following training. Transfer effects are in general difficult to demonstrate. Some studies show that older adults increase their performance after WM training. However, transfer effects are small or nonexistent in old age.

    Conclusions: The main finding in this review is that sub-cortical areas seem to have a critical role in mediating transfer effects to untrained tasks after at least some forms of working memory training (such as updating).

  • 187.
    Dahlin, Erika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Bäckman, Lars
    Stigsdotter Neely, Anna
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Plasticity of executive functioning in young and older adults: immediative training gains, transfer, and long-term maintenance2008Inngår i: Psychology and Aging, ISSN 0882-7974, E-ISSN 1939-1498, Vol. 23, nr 4, s. 720-730Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The authors investigated immediate training gains, transfer effects, and 18-month maintenance after 5 weeks of computer-based training in updating of information in working memory in young and older subjects. Trained young and older adults improved significantly more than controls on the criterion task (letter memory), and these gains were maintained 18 months later. Transfer effects were in general limited and restricted to the young participants, who showed transfer to an untrained task that required updating (3-back). The findings demonstrate substantial and durable plasticity of executive functioning across adulthood and old age, although there appear to be age-related constraints in the ability to generalize the acquired updating skill.

  • 188.
    Dahlin, Erika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Stigsdotter-Neely, Anna
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Larsson, Anne
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Bäckman, Lars
    Aging Research Center, Karolinska Institute, 11330 Stockholm, Sweden.
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Transfer of learning after updating training mediated by the striatum2008Inngår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 320, nr 5882, s. 1510-1512Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Process-specific training can improve performance on untrained tasks, but the magnitude of gain is variable and often there is no transfer at all. We demonstrate transfer to a 3-back test of working memory after 5 weeks of training in updating. The transfer effect was based on a joint training-related activity increase for the criterion (letter memory) and transfer tasks in a striatal region that also was recruited pretraining. No transfer was observed to a task that did not engage updating and striatal regions, and age-related striatal changes imposed constraints on transfer. These findings indicate that transfer can occur if the criterion and transfer tasks engage specific overlapping processing components and brain regions.

  • 189. Dahlin, Lars B.
    et al.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). 2 Department of Surgical and Perioperative Science, University Hospital, Umeå.
    Nerve injuries of the upper extremity and hand2017Inngår i: EFORT OPEN REVIEWS, ISSN 2058-5241, Vol. 2, nr 5, s. 158-170Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A nerve injury has a profound impact on the patient's daily life due to the impaired sensory and motor function, impaired dexterity, sensitivity to cold as well as eventual pain problems. To perform an appropriate treatment of nerve injuries, a correct diagnosis must be made, where the injury is properly classified, leading to an optimal surgical approach and technique, where timing of surgery is also important for the outcome. Knowledge about the nerve regeneration process, where delicate processes occur in neurons, non-neuronal cells (i. e. Schwann cells) and other cells in the peripheral as well as the central nervous systems, is crucial for the treating surgeon. The surgical decision to perform nerve repair and/or reconstruction depends on the type of injury, the condition of the wound as well as the vascularity of the wound. To reconnect injured nerve ends, various techniques can be used, which include both epineurial and fascicular nerve repair, and if a nerve defect is caused by the injury, a nerve reconstruction procedure has to be performed, including bridging the defect using nerve-grafts or nerve transfer techniques. The patients must be evaluated properly and regularly after the surgical procedure and appropriate rehabilitation programmes are useful to improve the final outcome.

  • 190.
    Damber, Jan-Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Testicular blood flow: methodological and functional studies in the rat1978Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Different methods of measuring testicular blood flow in the rat were compared in an attempt to find an accurate method for measuring physiological testicular blood flow. It was found that both the Xenon- 133 clearance technique and the radioactive microsphere technique probably reflect true physiological blood flow in the testis.

    The microsphere method was used to study some functional aspects of testicular blood flow. There was a significant positive correla­tion between the testicular blood flow and the outflow of testosterone in the spermatic vein, indicating that testicular hormone secretion may be affected indirectly via a primary effect on testicular blood flow. Intra-arterial infusion of LH caused a significant decrease in the vascular resistance of the testis. However, the effect was small in comparison with the simultaneous effect of LH on plasma testosterone concentration, indicating that blood flow changes are not critically involved in the acute effect of LH on testicular endocrine function. Infusion of epinephrine or norepinephrine did not induce any absolute changes in testicular blood flow, but norepinephrine caused an in­crease in testicular vascular resistance. Both catecholamines caused significant depressions in plasma testosterone concentration. It was concluded that the catecholamine induced reductions in testosterone concentration were not due to a vascular effect on the testis.

    Testicular blood flow and Leydig cell function in the cryptorchid and heated testis were also studied. There was a significant increase in relative blood flow in the cryptorchid testis, probably due to an highly altered morphology consisting of a relative increase in inter­stitial tissue containing blood vessels. Furthermore, it was found that the testosterone levels, in spermatic vein blood from the cryptor­chid testis, were highly reduced in comparison to the corresponding values for the scrotal testis and the outflow of testosterone from the cryptorchid testis was estimated to be only 13% of that from the scrotal one. This result suggested that the Leydig cell function was greatly impaired in the cryptorchid testis. The vasculature of the testis is relatively insensitive to local heating since no effects on vascular resistance were observed when warming the testis to ab­dominal temperature. On the other hand, there was a significant in­crease in blood flow in the testis at 41 and 43° C, which are tempera­tures known to induce cessation of spermatogenesis in the rat. The acute response of the testis to LH stimulation was reduced when warm­ing the scrotum to 41 and 43° C. This strongly indicates an impaired Leydig cell function at these temperatures. Since blood flow was in­creased at these temperatures it was concluded that the reduced Leydig cell responsiveness to LH was unrelated to testicular perfusion.

  • 191.
    Dan, Gustafsson
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    A model for investigating microcircuit changes underlying functional recovery after brain lesion in vivo2016Independent thesis Advanced level (degree of Master (Two Years)), 30 poäng / 45 hpOppgave
  • 192.
    Danielson, Patrik
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi.
    Innervation patterns and locally produced signal substances in the human patellar tendon: of importance when understanding the processes of tendinosis2007Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Tendinosis is a condition of chronic pain that afflicts several human tendons, not least the patellar tendon, in which case it is often clinically referred to as ‘jumper’s knee’. The exact mechanisms behind tendinosis are yet not fully understood. One draw-back in the case of patellar tendinosis has been the lack of knowledge of the innervation patterns of the human patellar tendon. It cannot be excluded that the processes of tendinosis are influenced by nerve mediators, released from nerve endings or from stimulated cells inside the tendon.

    Thus, the studies of the present thesis aimed to 1) map the general, sensory, cholinergic and sympathetic innervation patterns of the human patellar tendon, in both the tendon tissue proper and the loose paratendinous connective tissue surrounding the tendon, and 2) investigate the possible existence of a production of signal substances, traditionally associated with neurons, in non-neuronal tendon cells, and to see if there are signs of local cholinergic and catecholaminergic signaling pathways. Biopsies of both normal pain-free patellar tendons and patellar tendons from patients with chronic painful tendinosis were collected and investigated. The main method utilized was immunohistochemistry, using antibodies directed against synthesizing enzymes for acetylcholine and catecholamines, against muscarinic and adrenergic receptors, and against markers of general and sensory innervation. In situ hybridization (ISH) to detect mRNA for the cholinergic/catecholaminergic synthesizing enzymes was also used.

    It was found that the loose paratendinous connective tissue of the patellar tendon was rather richly innervated by nerve structures. These consisted of large nerve fascicles, as well as perivascular innervation in the walls of some of the larger arteries and smaller blood vessels. It was found that part of the nerve structures corresponded to sensory afferents, and that some conformed to cholinergic and, especially, sympathetic nerve fibers. The tendon tissue proper was strikingly less innervated than the paratendinous tissue. The sparse innervation that was found in the tendon tissue proper was seen in narrow zones of loose connective tissue and blood vessels, interspersed between the collagen bundles. The overall impression was that the patterns of distribution of the general, sensory, and autonomic innervations of tendinosis tendon tissue were similar to those of normal tendon tissue proper.

    The most pioneering findings were the immunohistochemical observations of an expression of enzymes related to production of both acetylcholine and catecholamines within the tendon cells (tenocytes) themselves, as well as of a presence of the receptors for these substances on the same cells; features that were predominantly seen in tendinosis tendons. The observations of the synthesizing enzymes for acetylcholine and catecholamines in tenocytes were confirmed by ISH findings of mRNA for these enzymes in the tenocytes. Immunoreactions for muscarinic and adrenergic receptors were also found in blood vessel walls and in some of the nerve fascicles.

    In summary, this thesis presents novel information on the innervation patterns of the human patellar tendon, in healthy individuals with pain-free tendons as well as in patients with chronic painful tendinosis. Furthermore, it gives the first evidence of the presence of a local, non-neuronal production in the tendon tissue of signal substances normally seen in neurons, and a basis for these substances to affect the tenocytes as these cells also display muscarinic and adrenergic receptors. Thus, the results indicate an existence of autocrine and/or paracrine cholinergic/catecholaminergic systems in the tendon tissue; systems that seem to be up-regulated in tendinosis. This is of great interest as it is known that stimulation of receptors for both catecholamines and acetylcholine can lead to cell proliferation, interfere with pain sensation, influence collagen production, and take part in vasoregulation, as well as, in the case of adrenergic receptors, promote cell degeneration and apotosis. All these processes represent biological functions/events that are reported to be affected in tendinosis.

    In conclusion, despite the fact that there is very limited innervation within the patellar tendon tissue proper, it is here shown that effects of signal substances traditionally associated with neurons seem to occur in the tissue, via a local production of these substances in tenocytes.

  • 193.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Reviving the "biochemical" hypothesis for tendinopathy: new findings suggest the involvement of locally produced signal substances2009Inngår i: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 43, nr 4, s. 265-268Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Studies of recent years on human tendinopathies have provided us with evidence of a local, non-neuronal production in tendon cells (tenocytes) of signal substances traditionally confined to neurons. These substances include acetylcholine, catecholamines, substance P, and glutamate. Furthermore, the receptors for several of these substances have been found on nerve fascicles and in blood vessel walls, as well as on the tenocytes themselves, of the tendon tissue. The findings provide the basis for locally produced signal substances to influence pain signaling, vascular regulation, and/or tissue changes in tendinopathy. This reinforces a previously presented "biochemical" hypothesis for tendinopathy, suggesting that biochemical mediators in the tendon tissue might influence/irritate nociceptors, in or around the tendon, to cause chronic tendon pain. The potential clinical implications of the studies are considerable.

  • 194.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    What are the nerve related changes in tendinopathies and their implications for the cause and/or treatment of pain?2007Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Three theoretical models for possible nerve-related changes that occur in tendinopathies, either as cause or effects of the condition, are suggested: 1) changes in innervation patterns, 2) changes in nerve signaling/responsiveness, and 3) changes in production of (non-neuronal) signal substances. The scientific literature on the subject is reviewed, and studies in support of all three theories are presented. The conclusions are as follows: Changes in innervation patterns in tendinopathies are not fully verified, and not sufficient to explain the pain that occurs in tendinopathy. Changes in nerve sensitization/responsiveness cannot be ruled out, since there is a clear morphological basis in the form of several types of receptors demonstrated on nerves in tendons. Finally, there is novel evidence in favor of a biochemical explanation model, including a local, non-neuronal, production of signal substances, and also findings of receptors for these substances on nerves (and tenocytes). In summary, many possible sites for intervention in treatment of tendinopathy are suggested.

  • 195.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Är "nervsignalsubstanser utan nerver" svaret på tendinopatins gåta?: Om en muskelsenas förvandling vid kroniska smärttillstånd2009Inngår i: Svensk Idrottsforskning: Organ för Centrum för Idrottsforskning, ISSN 1103-4629, Vol. 18, nr 1, s. 50-52Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Forskare har i många år gäckats av frågan om vad som är orsaken till smärtan och vävnadsförändringarna vid kroniska senbesvär, s.k. tendinopati eller tendinos. Många teorier har framlagts, men få har kunnat bekräftas med forskningsresultat. I en aktuell serie studier från Umeå universitet, delvis i samarbete med kanadensiska forskare, har oväntade fynd kastat nytt ljus över gåtan. Helt överraskande har det visat sig att de sjuka muskelsenornas egna celler, de s.k. tenocyterna, producerar signalämnen som normalt bildas i nerver b ämnen som kan ha betydelse både för vävnadsnedbrytning och smärta

  • 196.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Anatomi.
    Distribution of general (PGP 9.5) and sensory (substance P/CGRP) innervations in the human patellar tendon.2006Inngår i: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 14, nr 2, s. 125-132Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is no information on the pattern of blood vessel innervation, and in principle no information on innervation in general, in the human patellar tendon. In the present study, biopsies from the proximal part of normal and pain-free patellar tendons (11 men, mean age 33 years) were examined. The specimens were evaluated by using antibodies against the general nerve marker protein gene-product 9.5 (PGP 9.5) and the sensory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP), and immunohistochemistry. It was observed that the arteries, and to some extent the small vessels, in the loose paratendinous connective tissue were supplied with PGP 9.5- as well as SP- and CGRP-innervations. There was a marked PGP 9.5-like immunoreaction (LI), and to some extent also SP- and CGRP-LI, in the large nerve fascicles in this tissue. In the tendon tissue proper, PGP 9.5-LI was detected in nerve fibers located in the vicinity of some of the blood vessels and in thin nerve fascicles. There was a low degree of SP- and CGRP-innervation in the tendon tissue proper. The observations give a morphologic correlate for the occurrence of nerve-mediated effects in the patellar tendon. Particularly it seems as if there is a marked nerve-mediated regulation of the blood vessels supplying the tendon, at the level where they course in the loose paratendinous connective tissue.

  • 197.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Extensive expression of markers for acetylcholine synthesis and of M2 receptors in tenocytes in therapy-resistant chronic painful patellar tendon tendonosis - a case study2006Konferansepaper (Fagfellevurdert)
    Abstract [en]

    We have recently, in a study of a group of patients with chronic painful patellar tendon tendinosis (“jumper’s knee”), obtained evidence favoring the occurrence of an upregulation of a non-neuronal cholinergic system in this condition. Today, there is a new line of treatment of patellar tendinosis in the form of doppler guided sclerosing injections (Polidokanol), a treatment that has turned out to be very successful. However, the mechanisms for this therapy remain somewhat unclear. After an average of three treatments, a majority of the patients experience a significant decrease of pain symptoms. Nevertheless, a few patients seem resistant to this therapy, exhibiting no clear decrease in pain sensation.

    Therefore, we have in this pilot study investigated biopsies from the patellar tendon of one such therapy-resistant patient (male, exhibiting long duration of pain symptoms and showing radiological findings confirming tendinosis), using immunohistochemical methods examining both chemically fixed and unfixed tissue. The results were compared with our previous findings of both normal and tendinosis tendons.

    Morphologically, there was hypercellularity in the tendon tissue. The immunohistochemical studies showed that there were marked immunoreactions for choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) (fixed tissue), as well as for the M2 muscarinic acetylcholine receptor (unfixed tissue), in the overwhelming majority of the tenocytes. The levels of immunoreactions were more pronounced than those obtained in the tendinosis tissue of the previously studied patients and clearly more pronounced than those of tendon tissue of controls.

    In conclusion, our theory is that cases of severe tendinosis, exhibiting therapy-resistance, are related to the occurrence of an excessive local acetylcholine (ACh) production that appears to be even more prominent than in tendinosis in general. This case study emphasizes the need for further investigation regarding the role of non-neuronal ACh in therapy-resistant patellar tendon tendinosis.

  • 198.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Findings favoring production of non-neuronal acetylcholine with possible autocrine/paracrine effects in chronic painful patellar tendon tendinosis.2006Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The innervation pattern of the human patellar tendon is largely unknown. That includes the situation for patients suffering from patellar tendon tendinosis (“jumper’s knee”). Concerning the possible occurrence of a cholinergic system in the human patellar tendon, very little information is available.

    In the present study, specimens of pain-free normal (n=16) and chronically painful tendinosis (n=7) tendons were examined by different immunohistochemical and histochemical methods.

    It was found that parts of the tenocytes of the tendinosis tendons displayed immunoreactions for choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT). Furthermore, immunoreactions for the M2 muscarinic acetylcholine receptor could be detected in both blood vessel cells and tenocytes, especially in tendinosis specimens. Acetylcholinesterase activity was shown for scarce nerve fibers associated with small blood vessels in both the normal and the tendinosis tendons.

    The observations suggest that, besides the occurrence of a scanty nerve related cholinergic system in the human patellar tendon, there is a local non-neuronal cholinergic system as well, at least in tendinosis tendons. As ChAT and VAChT were detected in tenocytes of these tendons, such tenocytes are likely to produce acetylcholine (ACh) locally, and as both tenocytes and blood vessel cells were found to express the M2 receptor, it is likely that both of these cell types may be influenced by ACh.

    Thus, in conclusion, there appears to be an upregulation of the cholinergic system, and an occurrence of autocrine/paracrine effects in this system, in the tendinosis patellar tendon. This observation is of importance, not only related to the fact that tendinosis patients exhibit marked pain, but also as stimulation of ACh receptors can lead to cell proliferation, effects on collagen accumulation and angiogenesis, all of which are phenomena that occur in tendinosis.

  • 199.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin. Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Anatomi.
    Immunohistochemical and histochemical findings favoring the occurrence of autocrine/paracrine as well as nerve-related cholinergic effects in chronic painful patellar tendon tendinosis.2006Inngår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 69, nr 10, s. 808-819Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pathogenesis of the pain in patellar tendon tendinosis ("jumper's knee") is unclear. We have recently presented new information about the sensory nervous system in the human patellar tendon, but there is very little information regarding the possible occurrence of a cholinergic system in this tendon. In the present study, specimens of pain-free normal tendons and chronically painful tendinosis tendons were examined by different immunohistochemical and histochemical methods. Antibodies against the M(2) receptor, choline acetyltransferase (ChAT), and vesicular acetylcholine transporter (VAChT) were applied, and staining for demonstration of activity of acetylcholinesterase (AChE) was also utilized. It was found that immunoreactions for the M(2) receptor could be detected intracellularly in both blood vessel cells and tenocytes, especially in tendinosis specimens. Furthermore, in the tendinosis specimens, some tenocytes were seen to exhibit immunoreaction for ChAT and VAChT. AChE reactions were seen in fine nerve fibers associated with small blood vessels in both the normal control tendons and the tendinosis tendons. The observations suggest that there is both a nerve related and a local cholinergic system in the human patellar tendon. As ChAT and VAChT immunoreactions were detected in tenocytes of tendinosis tendons, these cells might be a source of local acetylcholine (Ach) production. As both tenocytes and blood vessel cells were found to exhibit immunoreactions for the M(2) receptor, it is likely that both of these tissue cells may be influenced by ACh. Thus, in conclusion, there appears to be an upregulation of the cholinergic system, and an occurrence of autocrine/paracrine effects in this system, in the tendinosis patellar tendon.

  • 200.
    Danielson, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    In situ hybridization studies confirming recent findings of the existence of a local nonneuronal catecholamine production in human patellar tendinosis.2007Inngår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 70, nr 10, s. 908-911Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    We have in recent studies presented unexpected immunohistochemical evidence favoring the existence of a local production of catecholamines, and an occurrence of adrenergic receptors on the tendon cells (tenocytes), in the human patellar tendon. This was particularly noticed for tendons from patients suffering from tendinosis (chronic tendon pain), which has led us to propose an involvement of this autocrine/paracrine system in the development of tendinosis, especially since catecholamines have been reported to be modulators of tissue remodeling and pain processes. However, the findings concerning catecholamine production have so far only been noted at the level of protein detection, and for this reason, the aim of the present study was to confirm the previous immunohistochemical results by using in situ hybridization (ISH) technique. A ssDNA probe detecting human mRNA for the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) was applied. The ISH results revealed that there were clear reactions indicating the existence of mRNA for TH in tenocytes of tendinosis specimens. It was generally noted that disfigured tenocytes were the ones with the most distinct reactions, while normally looking tenocytes hardly displayed any reactions at all. In conclusion, this study presents the first evidence at the mRNA level of the existence of a local nonneuronal production of catecholamines in human patellar tendon tissue. The findings add to recent observations of the occurrence of a local production in tendons of signal substances traditionally related to neurons.

    (c) 2007 Wiley-Liss, Inc.

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