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  • 1. Abat, F
    et al.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. Alfredson Tendon Clinic Inc, Umeå, Sweden; Pure Sports Medicine Clinic, ISEH, UCLH, London, UK.
    Cucchiarini, M
    Madry, H
    Marmotti, A
    Mouton, C
    Oliveira, J M
    Pereira, H
    Peretti, G M
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Stephen, J
    van Bergen, C J A
    de Girolamo, L
    Current trends in tendinopathy: consensus of the ESSKA basic science committee. Part II2018In: Journal of experimental orthopaedics, ISSN 2197-1153, Vol. 5, no 38Article in journal (Refereed)
    Abstract [en]

    The treatment of painful chronic tendinopathy is challenging. Multiple non-invasive and tendon-invasive methods are used. When traditional non-invasive treatments fail, the injections of platelet-rich plasma autologous blood or cortisone have become increasingly favored. However, there is little scientific evidence from human studies supporting injection treatment. As the last resort, intra- or peritendinous open or endoscopic surgery are employed even though these also show varying results. This ESSKA basic science committee current concepts review follows the first part on the biology, biomechanics and anatomy of tendinopathies, to provide a comprehensive overview of the latest treatment options for tendinopathy as reported in the literature.

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  • 2.
    Abat, F.
    et al.
    Department of Orthopaedic Sports Medicine, ReSport Clinic, Passeig Fabra i Puig 47, Barcelona, Spain.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports Medicine. Alfredson Tendon Clinic Inc, Umeå, Sweden; Pure Sports Medicine Clinic, ISEH, UCLH, London, United Kingdom.
    Cucchiarini, M.
    Molecular Biology, Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr Bldg 37, Homburg/Saar, Germany.
    Madry, H.
    Lehrstuhl für Experimentelle Orthopädie und Arthroseforschung, Universität des Saarlandes, Gebäude 37, Kirrbergerstr 1, Homburg, Germany.
    Marmotti, A.
    Department of Orthopaedics and Traumatology, San Luigi Gonzaga Hospital, Orbassano, University of Turin, Turin, Italy.
    Mouton, C.
    Department of Orthopedic Surgery, Clinique d’Eich-Centre Hospitalier de Luxembourg, 76, rue d’Eich, Luxembourg, Luxembourg.
    Oliveira, J.M.
    3B’s Research Group – Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Zona Industrial da Gandra, GMR, Barco, Portugal; ICVS/3B’s - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
    Pereira, H.
    3B’s Research Group University of Minho, ICVS/3B’s–PT Government Associate Laboratory, Braga, Guimarães, Portugal; Orthopedic Department Centro Hospitalar Póvoa de Varzim, Vila do Conde, Portugal; Ripoll y De Prado Sports Clinic – FIFA Medical Centre of Excellence, Madrid, Murcia, Spain.
    Peretti, G.M.
    IRCCS Istituto Ortopedico Galeazzi, Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.
    Romero-Rodriguez, D.
    Department of Physical Therapy and Sports Rehabilitation, ReSport Clinic Barcelona, Barcelona, Spain; EUSES Sports Science, University of Girona, Girona, Spain.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Stephen, J.
    Fortius Clinic, 17 Fitzhardinge St, London, United Kingdom; The Biomechanics Group, Department of Mechanical Engineering, Imperial College, London, United Kingdom.
    van Bergen, C.J.A.
    Department of Orthopedic Surgery, Amphia Hospital Breda, Breda, Netherlands.
    de Girolamo, L.
    Orthopaedic Biotechnology Laboratory, Galeazzi Orthopaedic Institute, Milan, Italy.
    Current trends in tendinopathy: consensus of the ESSKA basic science committee. Part I: biology, biomechanics, anatomy and anexercise-based approach2017In: Journal of Experimental Orthopaedics, E-ISSN 2197-1153, Vol. 4, no 1, article id 18Article, review/survey (Refereed)
    Abstract [en]

    Chronic tendinopathies represent a major problem in the clinical practice of sports orthopaedic surgeons, sports doctors and other health professionals involved in the treatment of athletes and patients that perform repetitive actions. The lack of consensus relative to the diagnostic tools and treatment modalities represents a management dilemma for these professionals. With this review, the purpose of the ESSKA Basic Science Committee is to establish guidelines for understanding, diagnosing and treating this complex pathology.

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  • 3.
    Abdelmalek, George
    et al.
    Rutgers New Jersey Medical School, NJ, Newark, United States.
    Mina, George Ehab
    Rutgers New Jersey Medical School, NJ, Newark, United States.
    Pant, Krittika
    Rutgers New Jersey Medical School, NJ, Newark, United States.
    Zheng, Zheshi
    Department of Statistics, Rutgers University, NJ, Piscataway, United States.
    Mahajan, Jasmine
    Rutgers New Jersey Medical School, NJ, Newark, United States.
    Srinivasan, Nivetha
    Rutgers New Jersey Medical School, NJ, Newark, United States.
    Gupta, Shivani
    Rutgers New Jersey Medical School, NJ, Newark, United States.
    Shafei, Jasmine
    Rutgers New Jersey Medical School, NJ, Newark, United States.
    Levidy, Michael F.
    Rutgers New Jersey Medical School, NJ, Newark, United States.
    McGrath, Aleksandra M
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Department of Hand Surgery, Norrland’s University Hospital, Umeå, Sweden.
    Chu, Alice
    Division of Pediatric Orthopedics, Department of Orthopedic Surgery, Rutgers New Jersey Medical School, NJ, Newark, United States.
    Intercostal nerve transfer for biceps reinnervation in obstetrical brachial plexus palsy: a preferred reporting items for systematic reviews and meta-analysis for individual patient data systematic review using individualized fusion and comparison to supraclavicular exploration and nerve grafting2024In: Journal of Children's Orthopaedics, ISSN 1863-2521, E-ISSN 1863-2548, Vol. 18, no 1, p. 54-63Article, review/survey (Refereed)
    Abstract [en]

    Introduction: The objective of this study was to search existing literature on nerve reconstruction surgery in patients with obstetric brachial plexus palsy to determine whether treatment with supraclavicular exploration and nerve grafting produced better elbow flexion outcomes compared to intercostal nerve transfer.

    Methods: This study was a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Individual Patient Data guidelines. A systematic search was conducted using multiple databases. An ordinal regression model was used to analyze the effect of using supraclavicular exploration and nerve grafting or intercostal nerve on elbow flexion with the two scores measured: elbow flexion Medical Research Council scores and Toronto active movements scale scores for elbow flexion.

    Results: A final patient database from 6 published articles consisted of 83 supraclavicular exploration and nerve grafting patients (73 patients with Medical Research Council and 10 patients with Toronto score) and 7 published articles which consisted of 131 intercostal nerve patients (84 patients with Medical Research Council and 47 patients with Toronto scores). Patients who underwent supraclavicular exploration and nerve grafting presented with an average Medical Research Council score of 3.9 ± 0.72 and an average Toronto score of 6.2 ± 2.2. Patients who underwent intercostal nerve transfer presented with an average Medical Research Council score of 3.9 ± 0.71 and an average Toronto score of 6.4 ± 1.2. There was no statistical difference between supraclavicular exploration and nerve grafting and intercostal nerve transfer when utilizing Medical Research Council elbow flexion scores (ordinal regression: 0.3821, standard error: 0.4590, p = 0.2551) or Toronto Active Movement Scale score for elbow flexion (ordinal regression: 0.7154, standard error: 0.8487, p = 0.2188).

    Conclusion: Regardless of surgical intervention utilized (supraclavicular exploration and nerve grafting or intercostal nerve transfers), patients had excellent outcomes for elbow flexion following obstetric brachial plexus palsy when utilizing Medical Research Council or Toronto scores for elbow flexion. The difference between these scores was not statistically significant.

    Type of study/Level of evidence: Therapeutic Study: Investigating the Result of Treatment/level III.

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  • 4.
    Agarkova, Irina
    et al.
    ETH-Zurich Hoenggerberg.
    Schoenauer, Roman
    ETH-Zurich Hoenggerberg.
    Ehler, Elisabeth
    King×s College London,.
    Carlsson, Lena
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Carlsson, Eva
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Perriard, Jean-Claude
    ETH-Zurich Hoenggerberg.
    The molecular composition of the sarcomeric M-band correlates with muscle fiber type2004In: European Journal of Cell Biology, ISSN 0171-9335, Vol. 83, no 5, p. 193-204Article in journal (Refereed)
    Abstract [en]

    The M-band is the transverse structure that cross-links the thick filaments in the center and provides a perfect alignment of the A-band in the activated sarcomere. The molecular composition of the M-bands in adult mouse skeletal muscle is fiber-type dependent. All M-bands in fast fibers contain M-protein while M-bands in slow fibers contain a significant proportion of the EH-myomesin isoform, previously detected only in embryonic heart muscle. This fiber-type specificity develops during the first postnatal weeks. However, the ratio between the amounts of myosin and of myomesin, taken as sum of both isoforms, remains nearly constant in all studied muscles. Ultrastructural analysis demonstrates that some of the soleus fibers show a diffuse appearance of the M-band, resembling the situation in the embryonic heart. A model is proposed to explain the functional consequence of differential M-band composition for the physiological and morphological properties of sarcomeres in different muscle types.

  • 5.
    Ahlgren, Christina
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Waling, Kerstin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Kadi, Fawzi
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Djupsjöbacka, Mats
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Centre for Musculoskeletal Research, National Institute for Working Life, Umeå , Sweden.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Sundelin, Gunnevi
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Effects on physical performance and pain from three dynamic training programs for women with work-related trapezius myalgia2001In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 33, no 4, p. 162-9Article in journal (Refereed)
    Abstract [en]

    To compare training programs for women with trapezius myalgia regarding physical performance and pain, 102 women were randomized to strength, endurance, co-ordination and non-training groups. Before and after the intervention, static strength and dynamic muscular endurance in shoulder muscles were measured on a Cybex II dynamometer. Muscle activity in shoulder muscles was monitored via surface EMG. The signal amplitude ratio between the active and passive phase of repeated contractions indicated the ability to relax. Pain at present, pain in general and pain at worst were measured on visual analogue scales. After training, within group comparisons showed that the training groups rated less pain, and in the strength training group ratings of pain at worst differed from the non-training group. Using the non-training group as a reference, static strength increased in the strength and endurance training groups and muscular endurance in all training groups. The study indicates that regular exercises with strength, endurance or co-ordination training of neck/shoulder muscles might alleviate pain for women with work-related trapezius myalgia.

  • 6.
    Ahmadi, Mahboobah
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Human extraocular muscles in ALS2010In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 51, no 7, p. 3494-3501Article in journal (Refereed)
    Abstract [en]

    PURPOSE. To investigate the general morphology, fiber type content, and myosin heavy chain (MyHC) composition of extraocular muscles (EOMs) from postmortem donors with amyotrophic lateral sclerosis (ALS) and to evaluate whether EOMs are affected or truly spared in this disease. METHODS. EOM and limb muscle samples obtained at autopsy from ALS donors and EOM samples from four control donors were processed for immunohistochemistry with monoclonal antibodies against distinct MyHC isoforms and analyzed by SDS-PAGE. In addition, hematoxylin and eosin staining and nicotinamide tetrazolium reductase (NADH-TR) activity were studied. RESULTS. Wide heterogeneity was observed in the appearance of the different EOMs from each single donor and between donors, irrespective of ALS type or onset. Pathologic morphologic findings in ALS EOMs included presence of atrophic and hypertrophic fibers, either clustered in groups or scattered; increased amounts of connective tissue; and areas of fatty replacement. The population of fibers stained with anti-MyHCslow tonic was smaller than that of MyHCIpositive fibers and was mostly located in the orbital layer in most of the ALS EOM samples, whereas an identical staining pattern for both fiber populations was observed in the control specimens. MyHCembryonic was notably absent from the ALS EOMs. CONCLUSIONS. The EOMs showed signs of involvement with altered fiber type composition, contractile protein content, and cellular architecture. However, when compared to the limb muscles, the EOMs were remarkably preserved. EOMs are a useful model for the study of the pathophysiology of ALS.

  • 7.
    Albiin, Nils
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Middle ear structure in relation to function: the rat in middle ear research1985Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The present study was undertaken to evaluate the rat as a model for middle ear re­search. The rat was chosen primarily because the gross structure of its middle ear shows several similarities to that of man. It was considered of great importance to make a thorough structural study of the rat middle ear and to compare the results with those reported for the human middle ear. The thesis therefore includes indepen­dent studies on various aspects of rat middle ear structure and function as well as a review of the literature. The most pertinent findings in the experimental part of this study were the following.

    The rat Eustachian tube consists of a nasopharyngeal, and a cartilaginous and bony portion. The orifice of the nasopharyngeal portion is composed of two soft tissue lips, which appear to be opened mainly by the action of the salpingopharyngeal mus­cle, but also by the levator and tensor veli palatini muscles. The cartilaginous por­tion appears to be opened solely by the tensor veli palatini muscle. The tensor tympani muscle seems to have no effect on the tube.

    A ciliated and secretory epithelium lines the inferomedial walls of the tube throughout its length. In the tympanic cavity these thelial cell types extend as two tracts - one anterior and the other inferoposterior to  the promontory - which communicate with the epitympanic/attic compartments. The remaining parts of the tube and the tympanic cavity are covered by a squamous/cuboidal, non-ciliated epithelium. The subepithelial loose connective tissue contains vessels, nerves, and connective tissue cells, among these mast cells. The mast cells are confined to areas covered by the ciliated epithelium, and in the floor of the bulla, in the pars flaccida, and along the manubrial vessels. Glands are restricted to the Eustachian tube.

    In the clearance/transport of serum-like material, from the epitympanum towards the tube, hydrostatic forces appear to be important.

    The tympanic membrane is vascularized from meatal and tympanal vessels. Meatal ves­sels branch in the pars flaccida and along the handle of the malleus, where they are localized directly beneath the outer, keratinizing, stratified, squamous epithelium. Furthermore, meatal vessels form a vascular network at the junction between the fi­brocartilaginous annulus and the tympanic sulcus. Tympanal vessels send branches to the periphery of the pars tensa, where they run immediately beneath the tympanal, simple, squamous epithelium. In the major portion of the pars tensa, no blood vessels were found.

    The rat stapedial artery is a thin-walled vessel with a wide lumen. Without branch­ing, it runs through the tympanic cavity to the extratympanal regions it supplies. In contrast to the corresponding artery in man, the rat stapedial artery persists throughout life. The artery does not seem to be affected by the fluid produced during experimentally induced otitis media with effusion.

    The middle ear structure in the rat and in man show both similarities and differ­ences. If the differences are kept in mind and considered, it would seem that the rat is indeed a suitable model for experimental middle ear research.

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  • 8. Al-Bishri, Awwad
    et al.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Al-Thobaiti, Yasser
    Sunzel, Bo
    Rosenquist, Jan
    Effect of betamethasone on the degree of macrophage recruitment and nerve growth factor receptor p75 immunoreaction during recovery of the sciatic nerve after injury: an experimental study in rats.2008In: British Journal of Oral & Maxillofacial Surgery, ISSN 0266-4356, E-ISSN 1532-1940, Vol. 46, no 6, p. 455-9Article in journal (Refereed)
    Abstract [en]

    PURPOSE: This study was designed to explain our previous findings of beneficial effects of betamethasone given perioperatively on decreasing the incidence of neurosensory disturbance after sagittal split osteotomy and improving functional recovery after crush injury to rat sciatic nerves. We analysed the pattern of macrophage recruitment and expression of nerve growth factor p75. MATERIAL AND METHODS: The sciatic nerve was crushed in each of 42 animals by tying the nerve against a glass rod for 30s. Half the rats were given betamethasone and half were not. The effect of betamethasone was evaluated immunohistochemically in a double blind manner after 2, 7 and 17 days using antibodies against macrophage marker (ED1) and p75. RESULTS: We found an initial and significant decrease in the number of macrophages recruited after two days in the group treated with betamethasone compared with controls (p=0.001). By 7 days there were significantly more macrophages in the steroid group than in the control group (p=0.001). There was however, a tendency for the number of p75R to be higher in the in the steroid group but the difference was not significant. At 17 days, there were significantly fewer macrophages in the steroid group (p=0.008) than in the control. CONCLUSION: We conclude that the beneficial effect of a moderate perioperative dose of betamethasone on recovery of a nerve is reflected in the recruitment of macrophages but to only a small extent in expression of p75.

  • 9.
    Alfredson, H.
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Öhberg, L.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Is vasculo-neural ingrowth the cause of pain in chronic Achilles tendinosis?: An investigation using US and colour Doppler, immunohistochemistry, and diagnostic injections2003In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, Vol. 11, no 5, p. 334-338Article in journal (Refereed)
  • 10.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Thorsen, Kim
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Fahlström, Martin
    Umeå University, Faculty of Medicine, Community Medicine and Rehabilitation, Rehabilitation Medicine. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Johansson, Håkan
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Glutamate NMDAR1 receptors localised to nerves in human Achilles tendons. Implications for treatment?2001In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 9, no 2, p. 123-126Article in journal (Refereed)
    Abstract [en]

    In this investigation, we show the presence of both free glutamate (microdialysis) and glutamate NMDAR1 receptors (immunohistochemical analyses of tendon biopsies), in tendons from patients with chronic Achilles tendon pain (Achilles tendinosis) and in controls (pain-free tendons). The NMDAR1 immunoreaction was usually confined to acetylcholinesterase-positive structures, implying that the reaction is present in nerves. Glutamate is a potent pain mediator in the human central nervous system, and in animals it has been shown that peripherally administered glutamate NMDA receptor antagonists diminish the response to formalin-induced nociception. Our present finding of glutamate NMDA receptors in human Achilles tendons might have implications for pain treatment.

  • 11.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Thorsen, Kim
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    In vivo microdialysis and immunohistochemical analyses of tendon tissue demonstrated high amounts of free glutamate and glutamate NMDAR1 receptors, but no signs of inflammation, in Jumper's knee.2001In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 19, no 5, p. 881-886Article in journal (Refereed)
    Abstract [en]

    This investigation describes, to our knowledge, the first experiment where the microdialysis technique was used to study certain metabolic events in human patellar tendons in combination with immunohistochemical analyses of tendon biopsies. In five patients (four men and one woman) with a long duration (range 12-36 months) of pain symptoms from Jumper's knee (localized tenderness in the patellar tendon verified as tendon changes with ultrasonography or MRI), and in five controls (four men and one woman) with normal patellar tendons, a standard microdialysis catheter was inserted into the patellar tendon under local anestesia. The local concentrations of glutamate (excitatory neurotransmitter) and prostaglandin E2 (PGE2) were registered under resting conditions. Samplings were done every 15 min during a 2 h period. In all individuals (patients and controls) biopsies were taken for immunohistochemical analyses. The results showed that it was possible to detect and measure the concentrations of glutamate and PGE2 in the patellar tendon with the use of microdialysis technique. There were significantly higher concentrations of free glutamate, but not PGE2, in tendons with tendinosis compared to normal tendons. In the biopsies, there were no inflammatory cell infiltrates, but, for the first time, it was shown that there was immunoreaction for the glutamate receptor NMDAR1 in association with nerve structures in human patellar tendons. These findings altogether indicate that glutamate might be involved in painful Jumper's knee, and further emphasizes that there is no chemical inflammation (normal PGE2 levels) in this chronic condition.

  • 12.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Section of Sports Medicine.
    Masci, Lorenzo
    Institute of Sports Exercise and Health, University College Hospital London, London, United Kingdom; Sports & Exercise Medicine, Queen Mary University of London, London, United Kingdom.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Private Orthopaedic Spine Center, Würzburg, Germany.
    Is There a Relationship Between Quadriceps Tendinopathy and Suprapatellar Plica? An Observational Case Series2022In: International Medical Case Reports Journal, E-ISSN 1179-142X, Vol. 15, p. 81-84Article in journal (Refereed)
    Abstract [en]

    Purpose: Chronic painful quadriceps tendinopathy is a relatively rare condition known to be difficult to manage. Conservative management is first-line treatment and if that fails open intra-tendinous revision surgery followed by a long rehabilitation period is used. There is sparse research on etiology and new treatment methods. This observational study aimed to evaluate the intra-articular findings in patients with chronic painful quadriceps tendinopathy resistant to conservative management.

    Patients and Methods: Seven male athletes (mean age 33 years, range 22–40) suffering from chronic painful quadriceps tendinopathy in altogether 10 tendons, not responding to conservative management including heavy strength training, were included. Clinical examination and ultrasound scanning were used for diagnosis. Arthroscopy was used for evaluation of the inside of the knee.

    Results: In all 10 knees, there were obliterating major plica formations in the suprapatellar pouch.

    Conclusion: Obliterating plica formations in the suprapatellar pouch may be involved in the aetiology and pathology in quadriceps tendinopathy.

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  • 13.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Section of Sports Medicine. Institute of Sports Exercise and Health, University College Hospital London, London, United Kingdom.
    Masci, Lorenzo
    Institute of Sports Exercise and Health, University College Hospital London, London, United Kingdom; Sports and Exercise Medicine, Queen Mary University of London, London, United Kingdom.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Private Orthopaedic Spine Center Dr. Alfen, Würzburg, Germany.
    Sharp pain in a normal Achilles tendon of a professional female football player was related to a plantaris tendon in a rare position: a case report2021In: Journal of Medical Case Reports, E-ISSN 1752-1947, Vol. 15, no 1, article id 513Article in journal (Refereed)
    Abstract [en]

    Background: Plantaris tendinopathy and plantaris-associated Achilles tendinopathy can be responsible for chronic pain in the Achilles tendon midportion, often accompanied by medial tenderness. As conservative treatments are less successful for this patient group, proper diagnosis is important for decision making. This report presents a case with plantaris tendinopathy in a rare (superficial) location.

    Case presentation: This article describes a pain history and treatment timeline of a professional Swedish female soccer player (32 years old, Northern European ethnicity, white) who suffered from sharp pain in the Achilles tendon midportion and tenderness on the medial and superficial side for about 2 years. Conservative treatments, including eccentric exercises, were not successful and, to some extent, even caused additional irritation in that region. Ultrasound showed a wide and thick plantaris tendon located on the superficial side of the Achilles tendon midportion. The patient was surgically treated with local removal of the plantaris tendon. After surgery there was a relatively quick (4–6 weeks) rehabilitation, with immediate weight bearing, gradual increased loading, and return to running activities after 4 weeks. At follow-up at 8 weeks, the patient was running and had not experienced any further episodes of sharp pain during change of direction or sprinting.

    Conclusions: The plantaris tendon should be considered as a possible source of Achilles tendon pain. This case study demonstrates that the plantaris tendon can be found in unexpected (superficial) positions and needs to be carefully visualized during clinical and imaging examinations.

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  • 14.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. ISEH, UCLH, London, UK; Pure Sports Medicine Clinic, London, UK.
    Masci, Lorenzo
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Surgical plantaris tendon removal for patients with plantaris tendon-related pain only and a normal Achilles tendon: a case series2018In: BMJ Open Sport & Exercise Medicine, ISSN 2055-7647, Vol. 4, no 1, article id e000462Article in journal (Refereed)
    Abstract [en]

    Objectives: Surgical removal of the plantaris tendon can cure plantaris-associated Achilles tendinopathy, a condition in which Achilles and plantaris tendinopathy coexist. However, rare cases with plantaris tendinopathy alone are often misdiagnosed due to a normal Achilles tendon.

    Design and setting: Prospective case series study at one centre.

    Participants: Ten consecutive patients (9 men and one woman, mean age 35 years, range 19–67) with plantaris tendon-related pain alone in altogether 13 tendons were included. All had had a long duration (median 10 months, range 3 months to 10 years) of pain symptoms on the medial side of the Achilles tendon mid-portion. Preoperative ultrasound showed thickened plantaris tendon but a normal Achilles tendon.

    Interventions: Operative treatment consisting of ultrasound-guided excision of the plantaris tendon.

    Primary and secondary outcome measures: Scores from Victorian Institute of Sports Assessment-Achilles questionnaire (VISA-A)were taken preoperatively and postoperatively (median duration 10 months). Patient satisfaction and time until full return to sports activity level was asked by a questionnaire.

    Results: The VISA-A scores increased from 61 (range 45–81) preoperatively to 97 (range 94–100) postoperatively (p<0.01). Follow-up results at 10 months (range 7–72 months) on 9/10 patients showed full satisfaction and return to their preinjury sports or recreational activity

    Conclusion: The plantaris tendon should be kept in mind when evaluating painful conditions in the Achilles tendon region, especially when no Achilles tendinopathy is present. Excision of the plantaris tendon via a minor surgical procedure in local anaesthesia results in a good outcome.

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  • 15.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Section of Sports Medicine. Institute of Sports, Exercise and Health, University College Hospital, London, UK.
    Masci, Lorenzo
    Department of Sports and Exercise Medicine, Queen Mary University, London, United Kingdom.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Research Unit, Orthopaedic Spine Center, Dr. Alfen, Würzburg, Germany.
    Ultrasound and surgical inspection of plantaris tendon involvement in chronic painful insertional Achilles tendinopathy: A case series2021In: BMJ Open Sport and Exercise Medicine, ISSN 2055-7647, Vol. 7, no 1, article id e000979Article in journal (Refereed)
    Abstract [en]

    Objectives: Chronic painful insertional Achilles tendinopathy is known to be difficult to manage. The diagnosis is not always easy because multiple different tissues can be involved. The plantaris tendon has recently been described to frequently be involved in chronic painful mid-portion Achilles tendinopathy. This study aimed to evaluate possible plantaris tendon involvement in patients with chronic painful insertional Achilles tendinopathy.

    Methods: Ninety-nine consecutive patients (74 males, 25 females) with a mean age of 40 years (range 24-64) who were surgically treated for insertional Achilles tendinopathy, were included. Clinical examination, ultrasound (US)+Doppler examination, and surgical findings were used to evaluate plantaris tendon involvement.

    Results: In 48/99 patients, there were clinical symptoms of plantaris tendon involvement with pain and tenderness located medially at the Achilles tendon insertion. In all these cases, surgical findings showed a thick and wide plantaris tendon together with a richly vascularised fatty infiltration between the plantaris and Achilles tendon. US examination suspected plantaris involvement in 32/48 patients.

    Conclusion: Plantaris tendon involvement can potentially be part of the pathology in chronic painful insertional Achilles tendinopathy and should be considered for diagnosis and treatment when there is distinct and focal medial pain and tenderness.

    Level of evidence: IV case series.

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  • 16.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bilateral Achilles tendinosis: the similar morphological appearance and the benefit of unilateral treatment has benefits for the contralateral tendon2013In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 94, no 4, p. A18-A18Article in journal (Other academic)
  • 17.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Unilateral surgical treatment for patients with midportion Achilles tendinopathy may result in bilateral recovery2014In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 48, no 19, p. 1421-1424Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bilateral midportion Achilles tendinopathy/tendinosis is not unusual, and treatment of both sides is often carried out. Experiments in animals suggest of the potential involvement of central neuronal mechanisms in Achilles tendinosis. OBJECTIVES: To evaluate the outcome of surgery for Achilles tendinopathy. METHODS: This observational study included 13 patients (7 men and 6 women, mean age 53 years) with a long duration (6-120 months) of chronic painful bilateral midportion Achilles tendinopathy. The most painful side at the time for investigation was selected to be operated on first. Treatment was ultrasound-guided and Doppler-guided scraping procedure outside the ventral part of the tendon under local anaesthetic. The patients started walking on the first day after surgery. Follow-ups were conducted and the primary outcome was pain by visual analogue scale. In an additional part of the study, specimens from Achilles and plantaris tendons in three patients with bilateral Achilles tendinosis were examined. RESULTS: Short-term follow-ups showed postoperative improvement on the non-operated side as well as the operated side in 11 of 13 patients. Final follow-up after 37 (mean) months showed significant pain relief and patient satisfaction on both sides for these 11 patients. In 2 of 13 patients operation on the other, initially non-operated side, was instituted due to persisting pain. Morphologically, it was found that there were similar morphological effects, and immunohistochemical patterns of enzyme involved in signal substance production, bilaterally. CONCLUSION: Unilateral treatment with a scraping operation can have benefits contralaterally; the clinical implication is that unilateral surgery may be a logical first treatment in cases of bilateral Achilles tendinopathy.

  • 18.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Section of Sports Medicine. Capio Ortho Center Skåne, Malmö, Sweden.
    Waldén, Markus
    Capio Ortho Center Skåne, Malmö, Sweden; Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Roberts, David
    Capio Ortho Center Skåne, Malmö, Sweden.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Department of Sports Science, University of Würzburg, Sanderring, Germany.
    Combined midportion achilles and plantaris tendinopathy: a 1-year follow-up study after ultrasound and color-doppler-guided walant surgery in a private setting in Southern Sweden2023In: Medicina, ISSN 1010-660X, E-ISSN 1648-9144, Vol. 59, no 3, article id 438Article in journal (Refereed)
    Abstract [en]

    Background and Objectives: Chronic painful midportion Achilles combined with plantaris tendinopathy can be a troublesome condition to treat. The objective was to prospectively follow patients subjected to ultrasound (US)- and color doppler (CD)-guided wide awake, local anesthetic, no-tourniquet (WALANT) surgery in a private setting.

    Material and Methods: Twenty-six Swedish patients (17 men and 9 women, mean age 50 years (range 29-62)) and eight international male patients (mean age of 38 years (range 25-71)) with combined midportion Achilles and plantaris tendinopathy in 45 tendons altogether were included. All patients had had >6 months of pain and had tried non-surgical treatment with eccentric training, without effect. US + CD-guided surgical scraping of the ventral Achilles tendon and plantaris removal under local anesthesia was performed on all patients. A 4-6-week rehabilitation protocol with an immediate full-weight-bearing tendon loading regime was used. The VISA-A score and a study-specific questionnaire evaluating physical activity level and subjective satisfaction with the treatment were used for evaluation.

    Results: At the 1-year follow-up, 32/34 patients (43 tendons) were satisfied with the treatment result and had returned to their pre-injury Achilles tendon loading activity. There were two dropouts (two tendons). For the Swedish patients, the mean VISA-A score increased from 34 (0-64) before surgery to 93 (61-100) after surgery (p < 0.001). There were two complications, one wound rupture and one superficial skin infection.

    Conclusions: For patients suffering from painful midportion Achilles tendinopathy and plantaris tendinopathy, US + CD-guided surgical Achilles tendon scraping and plantaris tendon removal showed a high satisfaction rate and good functional results 1 year after surgery.

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  • 19.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Willberg, Lotta
    Öhberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ultrasound and doppler-guided artthroscopic shaving for the treatment of patellar tendinopathy/jumper´s knee: biological background and description of method2011In: Anterior knee pain and patellar instability / [ed] Sanchis-Alfonso, Vicente, London: Springer London, 2011, p. 367-371Chapter in book (Refereed)
    Abstract [en]

    Treatment with ultrasound and Doppler-guided arthroscopic shaving of the region with vessels and nerves outside the dorsal tendon has shown promising clinical results in patients with proximal patellar tendinopathy/Jumper´s knee. The results concerning only a limited patient material has been published in a scientific paper. Results on larger materials are under evaluation for later publication. Proper understanding of the ultrasound and Doppler findings, to enable for a precise and minimal arthroscopic shaving procedure on the dorsal side of the tendon, are cornerstones using this new type of treatment.

  • 20.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Influences of paratendinous innervation and non-neuronal substance P in tendinopathy: studies on human tendon tissue and an experimental model of Achilles tendinopathy2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pain of the musculoskeletal system is one of the most common reasons for people seeking medical attention, and is also one of the major factors that prevent patients from working. Chronic tendon pain, tendinopathy, affects millions of workers world-wide, and the Achilles tendon is an important structure often afflicted by this condition. The pathogenesis of tendinopathy is poorly understood, but it is thought to be of multifactoral aetiology. It is known that tendon pain is often accompanied not only by impaired function but also by structural tissue changes, like vascular proliferation, irregular collagen organisation, and hypercellularity, whereby the condition is called tendinosis. In light of the poor knowledge of tendinosis pathophysiology and recent findings of a non-neuronal signalling system in tendon tissue, the contributory role of neuropeptides such as substance P (SP) has gained increased interest. SP, known for afferent pain signalling in the nervous system, also has multiple efferent functions and has been described to be expressed by non-neuronal cells. As pain is the most prominent symptom of tendinopathy, the focus of the studies in this thesis was the innervation patterns of the tissue ventral to the Achilles tendon (i.e. the tissue targeted in many contemporary treatment methods) as well as the distribution of SP and its preferred receptor, the neurokinin-1 receptor (NK-1R), in the tendon tissue itself. It was hereby hypothesised that the source of SP affecting the Achilles tendon might be the main cells of the tendon tissue (the tenocytes) as well as paratendinous nerves, and that SP might be involved in tendinosis- development. The studies were conducted, via morphological staining methods including immunohistochemistry and in situ hybridisation, on tendon biopsies from patients suffering from Achilles tendinosis and on those from healthy volunteers. The hypothesis of the thesis was furthermore tested using an experimental animal model (rabbit) of Achilles tendinopathy, which was first validated. The model was based on a previously established overuse protocol of repetitive exercise. In the human biopsies of the tissue ventral to the Achilles tendon, there was a marked occurrence of sympathetic innervation, but also sensory, SP-containing, nerve fibres. NK-1R was expressed on blood vessels and nerve fascicles of the paratendinous tissue, but also on the tenocytes of the tendon tissue proper itself, and notably more so in patients suffering from tendinosis. Furthermore, the human tenocytes displayed not only NK-1R mRNA but also mRNA for SP. The animal model was shown to produce objectively verified tendinosis-like changes, such as hypercellularity and increased vascularity, in the rabbit Achilles tendons, after a minimum of three weeks of the exercise protocol. The contralateral leg of the animals in the model was found to be an unreliable control, as bilateral changes occured. The model furthermore demonstrated that exogenously administered SP triggers an inflammatory response in the paratendinous tissue and accelerates the intratendinous tendinosis-like changes such that they now occur after only one week of the protocol. Injections of saline as a control showed similar results as SP concerning hypercellularity, but did not lead to vascular changes or pronounced paratendinous inflammation. In summary, this thesis concludes that interactions between the peripheral sympathetic and sensory nervous systems may occur in Achilles tendinosis at the level of the ventral paratendinous tissue, a region thought to be of great importance in chronic tendon pain since many successful treatments are directed toward it. Furthermore, the distribution of NK-1R:s in the Achilles tendon described in these studies gives a basis for SP, whether produced by nerves mainly outside the tendon or by tenocytes within the tendon, to affect blood vessels, nerve structures, and/or tendon cells, especially in tendinosis patients. In light of this and of previously known SP-effects, such as stimulation of angiogenesis, pain signalling, and cell proliferation, the proposed involvement of SP in tendinosis development seems likely. Indeed, the animal model of Achilles tendon overuse confirms that SP does induce vascular proliferation and hypercellularity in tendon tissue, thus strengthening theories of SP playing a role in tendinosis pathology.

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  • 21.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Christensen, Jens
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nerve distributions in insertional Achilles tendinopathy - a comparison of bone, bursae and tendon2017In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 32, no 3, p. 263-270Article in journal (Refereed)
    Abstract [en]

    Background/Aim. In a condition of pain in the Achilles tendon insertion there are multiple structures involved, such as the Achilles tendon itself, the retrocalcaneal bursa and a bony protrusion at the calcaneal tuberosity called Haglund's deformity. The innervation patterns of these structures are scarcely described, and the subcutaneous calcaneal bursa is traditionally not considered to be involved in the pathology. This study aimed at describing the innervation patterns of the four structures described above to provide a better understanding of possible origins of pain at the Achilles tendon insertion.

    Methods. Biopsies were taken from 10 patients with insertional Achilles tendinopathy, which had pathological changes in the subcutaneous and retrocalcaneal bursae, a Haglund deformity and Achilles tendon tendinopathy as verified by ultrasound. The biopsies were stained using immunohistochemistry in order to delineate the innervation patterns in the structures involved in insertional Achilles tendinopathy.

    Results. Immunohistochemical examinations found that the subcutaneous bursa scored the highest using a semi-quantitative evaluation of the degree of innervation when compared to the retrocalcaneal bursa, the Achilles tendon, and the calcaneal bone.

    Conclusions. These findings suggest that the subcutaneous bursa, which is traditionally not included in surgical treatment, may be a clinically important factor in insertional Achilles tendinopathy.

  • 22.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    Department of Physical Therapy, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Hip Health and Mobility, Vancouver Coastal Health and Research Institute, Vancouver, British Columbia, Canada.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Substance P accelerates hypercellularity and angiogenesis in tendon tissue and enhances paratendinitis in response to Achilles tendon overuse in a tendinopathy model2011In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 45, no 13, p. 1017-1022Article in journal (Refereed)
    Abstract [en]

    Background Tenocytes produce substance P (SP) and its receptor (neurokinin-1 receptor (NK-1R) is expressed throughout the tendon tissue, expecially in patients with tendinopathy and tissue changes (tendinosis) including hypercellularity and vascular proliferation. Considering the known effects of SP, one might ask whether SP contributes to these canges.

    Objectives To test whether development of tendinosislike changes (hypercellularity and angiogenesis) is accelerated during a 1-week course of ecercise with local administration of SP in an establish Achilles tendinopathy model.

    Methods Rabbits were subjected to a protocol of Achilles tendon overuse for 1 week, in conjunction with SP injections in the paratenon. Exercised control animals received NaCl injections or no injections, and unexercised, uninjected controls were also used. Tenocyte number and vascular density, as well as paratendinous inflammation, were evaluated. Immunohistochemistry and in sity hybridisation to detect NK-1R were conducted.

    Results There was a significant increase in tenocyte number in the SP-injected and NaCl-injected groups compared with both unexercised and exercised, uninjected controls. Tendon blood vessels increased in number in the SP-injected group compared with unexercised controls, a finding not seen in NaCl-injected controls or in uninjected, exercised animals. Paratendinous inflammation was more pronounced in the SP-injected group than in the NaCl controls. NK-1R was detected in blood vessel walls, nerves, inflammatory cells and tenocytes.

    Conclusions SP accelerated the development of tendinosis-like changes in the rabbit. Achilles tendon, which supports theories of a potential role of SP in tendinosis development; a fact of clinical interest since SP effects can be effectively blocked. The angiogenic response to SP injections seems related to parateninitis.

  • 23.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    Department of Physical Therapy, University of British Columbia, Vancouver, BC, Canada.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Substance P induces tendinosis-like changes in a rabbit model of Achilles tendon overuseManuscript (preprint) (Other academic)
    Abstract [en]

    BACKGROUND: In previous studies we found evidence favouring that human Achilles tendon cells (tenocytes) are capable of producing the neuropeptide substance P (SP). Furthermore, the preferred receptor for SP (the neurokinin-1 receptor, NK-1 R) was widely expressed throughout the tendon, especially in patients suffering from chronic tendon pain (tendinopathy) with tissue changes (tendinosis) including hypercellularity and vascular proliferation. Considering known effects of SP, one might ask whether SP contributes to tendon cell proliferation and neovascularisation in tendinosis. We have an established animal (rabbit) model of Achilles tendinopathy based on overuse in the form of repetitive exercise. Recent studies with this model have shown that tendinosis-like changes are present after 3 weeks of exercise, but not after only 1 week. The current study aimed to test whether the development of tendinosis-like changes would be accelerated during a 1 week course of exercise with repetitive local administration of SP.

    MATERIAL AND METHODS: Four groups of animals (5-6 New Zealand white rabbits per group) were used. Three groups were subjected to the previously established protocol of Achilles tendon overuse for 1 week. One of these groups was given repetitive SP injections in the paratendinous tissue of the Achilles tendon, whereas one group (‘NaCl controls’) was given an equivalent schedule of saline injections. Two additional control groups existed: One in which the animals were neither subjected to the overuse protocol nor to any injections (‘untrained controls’), and one in which the animals trained for 1 week but were not given any injections (‘1 week controls’). Tenocyte number, vascular density, and the possible occurrence of paratendinous inflammation were evaluated. Immunohistochemistry and in situ hybridisation to detect NK-1 R were also conducted.

    RESULTS: There was a significant increase in tenocyte number in the SP-injected group compared to both untrained controls and 1 week controls. However, the same phenomenon was noticed for NaCl controls, i.e. tenocyte number was significantly increased in response to NaCl injections compared to untrained controls. There was an increase in the number of tendon blood vessels in the SP-injected group as compared to untrained controls, and this increase in vascularity was not seen for the NaCl controls or the 1 week controls. Paratendinous inflammation, as evidenced by invasion of inflammatory cells in the paratenon, was clearly more pronounced in the SP-injected group than in the NaCl controls. NK-1 R was detected in blood vessel walls, on nerves, on inflammatory cells, and on tenocytes.

    DISCUSSION AND CONCLUSIONS: The observations suggest that SP induces tenocyte proliferation and angiogenesis in the rabbit Achilles tendon, thus supporting a potential role of this neuropeptide in the processes that occur in tendinosis. The study corroborates findings on the human Achilles tendon in that NK-1 R was expressed on tenocytes and tendon blood vessel walls, thereby providing a potential anatomic basis for the observed effects of SP on the development of tendinosis. The hypercellularity observed in response to NaCl injections might be due increased tissue pressure or to stimulation of endogenous SPproduction, a phenomenon not unheard of. The angiogenic effect of SP injections, on the other hand, appeared to be more specifically related to an induction of inflammation in the paratendon.

  • 24.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Arteries in the area targeted with successful sclerosing injections for Achilles tendinosis are under distinct neural control2006Conference paper (Refereed)
    Abstract [en]

    It has been scientifically demonstrated that there are blood vessels with pathologically high blood flow inside and outside the ventral part of the Achilles tendon in chronic painful tendinosis, but not in pain-free normal Achilles tendons. Injections of local anaesthesia on the outside of the ventral part of the tendon have been found to temporarily abolish the tendon pain, and this has been an inspiration in the development of a new approach in the treatment of tendinosis: Based on ultrasound- (US) and colour Doppler- (CD) guidance, the sclerosing substance polidocanol, for many years used in treatment of varicose veins, was injected targeting the area of high-flow blood vessels just outside the ventral part of the Achilles tendon. The treatment has in pilot studies and a randomized controlled clinical study been shown to cure the pain in about 70-80 % of the patients. Also, follow up examinations, using US and CD, have shown a possible remodeling potential of the tendon. There is some previous information available on the innervation patterns of the human Achilles tendon itself. However, the innervation patterns of the area just outside the ventral part of the tendon, i.e. the area that is targeted by the sclerosing injections (target area), are unknown. This includes a lack of information concerning the nerve-related characteristics of the blood vessels in the area. In this study, therefore, tissue specimens from this target area, obtained during surgical treatment of patients with chronic painful mid-portion Achilles tendinosis, were examined. Histological and immunohistochemical examinations were performed. In the tissue of the target area, in which loose connective tissue and fat cells were frequent constituents, there was a presence of arteries and nerve fascicles. The arteries were of varying dimensions, some being very large. The nerve fascicles were distinguished in sections processed for the pan-neural marker protein gene-product 9.5 (PGP 9.5).  Some of the arteries were supplied by an extensive perivascular innervation, as seen via PGP 9.5 staining. As seen via processing for the rate limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), sympathetic innervation was found to be a constituent of this innervation. There was furthermore a marked occurrence of immunoreactions for the α1-adrenoreceptor in arterial walls. Also, there was a presence of immunoreactions for the substance P (SP)-preferred receptor, the neurokinin-1 (NK-1) receptor in arterial walls. This receptor was particularly detected in the endothelial parts. The study shows that the arteries in the target area are accompanied by nerve fascicles and that there is a presence of a perivascular innervation, as well as a presence of adrenergic and NK-1 receptors in arterial walls, in this region. Thus, arteries in this area are under distinct neural control. The nerve-related characteristics of the area targeted in the successful polidicanol injection treatment for Achilles tendinosis are here for the first time shown.

  • 25.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Nerve-related characteristics of ventral paratendinous tissue in chronic Achilles tendinosis2007In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 15, no 10, p. 1272-1279Article in journal (Refereed)
    Abstract [en]

    Ultrasound and Doppler examination has shown high blood flow-neovascularisation inside and outside the ventral Achilles tendon in chronic painful tendinosis, but not in pain-free normal Achilles tendons. In patients with Achilles tendinosis, injections with the sclerosing substance polidocanol, targeting the areas with increased blood flow, have been demonstrated to give pain relief. A drawback when interpreting these findings is the fact that the pattern of nerve supply in the target area, i.e. the ventral area of the tendon, is so far unknown. In this study, therefore, tissue specimens from this area, obtained during surgical treatment of patients with chronic painful midportion Achilles tendinosis, were examined. In the examined area, containing loose connective tissue, the general finding was a presence of large and small arteries and nerve fascicles. The nerve fascicles were distinguished in sections processed for the pan-neural marker protein gene-product 9.5. The nerve fascicles contain sensory nerve fibers, as shown via staining for the sensory markers substance P (SP) and calcitonin gene-related peptide, and sympathetic nerve fibers as seen via processing for tyrosine hydroxylase. In addition, there were immunoreactions for the SP-preferred receptor, the neurokinin-1 receptor, in blood vessel walls and nerve fascicles. Some of the blood vessels were supplied by an extensive peri-vascular innervation, sympathetic nerve fibers being a distinct component of this innervation. There was also a marked occurrence of immunoreactions for the alpha1-adrenoreceptor in arterial walls as well as in the nerve fascicles. Altogether, these findings suggest that the area investigated is under marked influence by the nervous system, including sympathetic and sensory components. Thus, sympathetic/sensory influences may be involved in the pain mechanisms from this area. In conclusion, the nerve-related characteristics of the area targeted by the polidicanol injection treatment for Achilles tendinosis, are shown here for the first time.

  • 26.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of substance P and the neurokinin-1 receptor in tenocytes of the human Achilles tendon2008In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 150, no 1-3, p. 81-87Article in journal (Refereed)
    Abstract [en]

    Nerve signal substances, such as the tachykinin substance P (SP), may be involved in the changes that occur in response to tendinopathy (tendinosis). It is previously known that the level of SP innervation within tendon tissue is limited, but results of experimental studies have suggested that SP may have stimulatory, angiogenetic and healing effects in injured tendons. Therefore, it would be of interest to know if there is a local SP-supply in tendon tissue. In the present study, the patterns of expression of SP and its preferred receptor, the neurokinin-1 receptor (NK-1 R), in normal and tendinosis human Achilles tendons were analyzed by use of both immunohistochemistry and in situ hybridization. We found that there was expression of SP mRNA in tenocytes, and that tenocytes showed expression of NK-1 R at protein as well as mRNA levels. The observations concerning both SP and NK-1 R were most evident for tenocytes in tendinosis tendons. Our findings suggest that SP is produced in tendinosis tendons, and furthermore that SP has marked effects on the tenocytes via the NK-1 R. It cannot be excluded that the SP effects are of importance concerning the processes of reorganization and healing that occur for tendon tissue in tendinosis. In conclusion, it appears as if SPergic autocrine/paracrine effects occur in tendon tissue during the processes of tendinosis, hitherto unknown effects for human tendons.

  • 27.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    University of British Columbia, Vancouver, Vancouver Coastal Health and Research Institute.
    Gaida, James Edmund
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Stjernfeldt, Johanna Elgestad
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Backman, Clas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Tenocyte hypercellularity and vascular proliferation in a rabbit model of tendinopathy: contralateral effects suggest the involvement of central neuronal mechanisms2011In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 45, no 5, p. 399-406Article in journal (Refereed)
    Abstract [en]

    Objective To determine whether there are objective findings of tendinosis in a rabbit tendinopathy model on exercised and contralateral (non-exercised) Achilles tendons. Design Four groups of six New Zealand white rabbits per group were used. The animals of one (control) group were not subjected to exercise/stimulation. Interventions Animals were subjected to a protocol of electrical stimulation and passive flexion-extension of the right triceps surae muscle every second day for 1, 3 or 6 weeks. Main Outcome Measures Tenocyte number and vascular density were calculated. Morphological evaluations were also performed as well as in-situ hybridisation for vascular endothelial growth factor (VEGF) messenger RNA. Results There was a significant increase in the tenocyte number after 3 and 6 weeks of exercise, but not after 1 week, in comparison with the control group. This was seen in the Achilles tendons of both legs in experimental animals, including the unexercised limb. The pattern of vascularity showed an increase in the number of tendon blood vessels in rabbits that had exercised for 3 weeks or more, compared with those who had exercised for 1 week or not at all. VEGF-mRNA was detected in the investigated tissue, with the reactions being more clearly detected in the tendon tissue with tendinosis-like changes (6-week rabbits) than in the normal tendon tissue (control rabbits). Conclusions There were bilateral tendinosis-like changes in the Achilles tendons of rabbits in the current model after 3 weeks of training, suggesting that central neuronal mechanisms may be involved and that the contralateral side is not appropriate as a control.

  • 28.
    Andersson, Magnus N.
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Svensson, Johan
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Björkgren, Annika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wiberg, Rebecca
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Prophylactic mastectomy – Correlation between skin flap thickness and residual glandular tissue evaluated postoperatively by imaging2022In: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1878-0539, Vol. 75, no 6, p. 1813-1819Article in journal (Refereed)
    Abstract [en]

    Background: Women with an increased hereditary risk of breast cancer can undergo risk-reducing prophylactic mastectomy. However, there is a balance between how much subcutaneous tissue should be resected to achieve maximal reduction of glandular tissue, while leaving viable skin flaps.

    Methods: Forty-five women previously operated with prophylactic mastectomy underwent magnetic resonance tomography (MRT) and ultrasound (US) to investigate the correlation between skin flap thickness and residual glandular tissue. Residual glandular tissue was documented as being present or not present, but not quantified, as the amount of residual glandular tissue in many cases was considered too small to make reliable volume quantifications with available tools. Since a mastectomy skin flap thickness of 5 mm is discussed as an oncologically safe thickness in the literature, this was used as a cut-off.

    Results: Following prophylactic mastectomy, residual glandular tissue was detected in 39.3% of all breasts and 27.9% of all the breast quadrants examined by MRT, and 44.1% of all breasts and 21.7% of all the breast quadrants examined by US. Residual glandular tissue was detected in 6.9% of the quadrants in skin flaps ≤ 5 mm and in 37.5% of the quadrants in skin flaps > 5 mm (OR 3.07; CI = 1.41–6.67; p = 0.005). Furthermore, residual glandular tissue increased significantly already when the skin flap thickness exceeded 7 mm.

    Conclusions: This study highlights that complete removal of glandular breast tissue during a mastectomy is difficult and suggests that this is an unattainable goal. We demonstrate that residual glandular tissue is significantly higher in skin flaps > 5 mm in comparison to skin flaps ≤ 5 mm, and that residual glandular tissue increases significantly already when the flap thickness exceeds 7 mm.

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  • 29. Armstrong, Stephanie J
    et al.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
    Terenghi, Giorgio
    Kingham, Paul J
    Laminin activates NF-kappaB in Schwann cells to enhance neurite outgrowth.2008In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 439, no 1, p. 42-6Article in journal (Refereed)
    Abstract [en]

    Extracellular matrix (ECM) molecules and Schwann cells (SCs) are important components of peripheral nerve regeneration. In this study, the role of the transcription factor nuclear factor kappa B (NF-kappaB) in SC activation in response to laminin and the subsequent effect on in vitro neurite outgrowth was investigated. Immunocytochemistry and Western blot analysis showed that compared with poly-d-lysine (PDL), laminin enhanced the phosphorylation of IkappaB and p65 NF-kappaB signalling proteins in SCs. Phospho NF-kappaB-p65 was localised to the nucleus indicating activation of NF-kappaB. To assess the functional effect of NF-kappaB activation, SCs plated on PDL or laminin were pre-treated with NF-kappaB inhibitors, 6-amino-4-(4-phenoxyphenylethylamino)quinazoline (QNZ) or Z-leu-leu-leu-CHO (MG-132) before NG108-15 neuronal cells were seeded on the SC monolayer. After 24h co-culture in the absence of inhibitors, SCs seeded on laminin enhanced the mean number and length of neurites extended by NG108-15 cells (1.87+/-0.13 neurites; 238.74+/-8.53microm) compared with those cultured in the presence of SCs and PDL (1.26+/-0.07 neurites; 157.57+/-9.80microm). At 72h, neurite length had further increased to 321.83+/-6.60microm in the presence of SCs and laminin. Inhibition of NF-kappaB completely abolished the effect of laminin on SC evoked neurite outgrowth at 24h and reduced the enhancement of neurite length by over 60% at 72h. SC proliferation was unaffected by NF-kappaB inhibition suggesting that the NF-kappaB signalling pathway plays a discrete role in the activation of SCs and their neurotrophic potential.

  • 30.
    Backman, Ludvig
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Neuropeptide and catecholamine effects on tenocytes in tendinosis development: studies on two model systems with focus on proliferation and apoptosis2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Achilles tendinopathy is a common clinical syndrome of chronic Achilles tendon pain combined with thickening of the tendon and impaired tendon function. Tendinopathy is often, but not always, induced by mechanical overload, and is frequently accompanied by abnormalities at the tissue level, such as hypercellularity and angiogenesis, in which case the condition is called tendinosis. In tendinosis, there are no signs of intratendinous inflammation, but occasionally increased apoptosis is observed. Tendinosis is often hard to treat and its pathogenesis is still not clear. Recently, a new hypothesis has gained support, suggesting a biochemical model based on the presence of a non-neuronal production of classically neuronal signal substances by the primary tendon cells (tenocytes) in tendinosis. The possible functional importance of these signal substances in tendons is unknown and needs to be studied. In particular, the neuropeptide substance P (SP) and catecholamines are of interest in this regard, since these substances have been found to be up-regulated in tendinosis. As both SP and catecholamines are known to exert effects in other tissues resulting in changes similar to those characteristic of tendinosis, it is possible that they have a role in tendinosis development. It is furthermore unknown what elicits the increased intratendinous neuropeptide production in tendinosis, but given that tendon overload is a prominent riskfactor, it is possible that mechanical stimuli are involved.

    The hypothesis of this thesis work was that intratendinous production of SP is up-regulated in response to load of Achilles tendons/tenocytes, and thatstimulation of the preferred SP receptor, the neurokinin-1 receptor (NK-1 R), aswell as stimulation of the catecholamine α2 adrenoreceptors, contribute to the hypercellularity seen in tendinosis, via increased proliferation and/or decreased apoptosis, and that SP stimulates tendon angiogenesis. The purpose of the studies was to test this hypothesis. To achieve this, two model systems were used: One in vivo (rabbit Achilles tendon overload model of tendinosis) and one in vitro (human primary Achilles tendon cell culture model).

    Results: In the rabbit Achilles tendon tissue, SP and NK-1 R expression was extensive in the blood vessel walls, but also to some extent seen in the tenocytes. Quantification of endogenously produced SP in vivo confirmed intratendinous production of the peptide. The production of SP by human tendon cells in vitro was furthermore demonstrated. The catecholamine synthesizing enzyme tyrosine hydroxylase (TH), as well as the α2A adrenoreceptor (α2A AR), were detected in the tenocytes, both in vivo in the rabbit tissue and in vitro in the human tendon cells. As a response to mechanical loading in the in vivo model, the intratendinous levels of SP increased, and this elevation was found to precede distinct tendinosis changes. The in vitro model demonstrated the same response to load, i.e. an increased SP expression, but in this case also a decrease in the NK-1 R expression. In the in vivo model, exogenously administered SP, as well as clonidine (an α2 AR agonist), accelerated tenocyte hypercellularity, an effect that was not seen when administrating a specific α2A AR antagonist. Exogenous administration of SP also resulted in intratendinous angiogenesis and paratendinous inflammation. In the in vitro model, both SP and clonidine had proliferative effects on the human tenocytes, specifically mediated via NK-1R and α2A AR, respectively; both of which in turn involved activation/phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2). Exogenously administered SP, in Anti-Fas induced apoptosis of the tenocytes in vitro, confirmed SP to have an anti-apoptotic effect on these cells. This effect was specifically mediated via NK-1 R and the known anti-apoptotic Akt pathway.

    Conclusions: In summary, this thesis concludes that stimulation of NK-1 R and α2A AR on tenocytes, both in vitro and in vivo, mediates significant cell signalling effects leading to processes known to occur in tendinosis, including hypercellularity. The pathological role of the hypercellularity in tendinosis is still unclear, but it is likely to affect collagen metabolism/turnover and arrangement, and thereby indirectly tendon biomechanical function. Additional evidence is here provided showing that SP not only causes tenocyte proliferation, but also contributes to anti-apoptotic events. Furthermore, it was concluded that SP may be involved in the development of tendinosis, since its production is increased in response to load, preceding tendinosis, and since SP accelerates tendinosis changes, through some mechanistic pathways here delineated. These findings suggest that inhibition of SP, and possibly also catecholamines, could be beneficial in the reconstitution/normalization of tendon structure in tendinosis.

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  • 31.
    Backman, Ludvig
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wennstig, Gabriel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Endogenous substance P production in the Achilles tendon increases with loading in an in vivo model of tendinopathy: peptidergic elevation preceding tendinosis-like tissue changes2011In: Journal of Musculoskeletal and Neuronal Interactions - JMNI, ISSN 1108-7161, Vol. 11, no 2, p. 133-140Article in journal (Refereed)
    Abstract [en]

    Objectives: To quantify the intratendinous levels of substance P (SP) at different stages of overload in an established modelfor Achilles tendinopathy (rabbit). Also, to study the distribution of the SP-receptor, the NK-1R, and the source of SP, in thetendon. 

    Methods: Animals were subjected to the overuse protocol for 1, 3 or 6 weeks. One additional group served as unexercisedcontrols. Immunoassay (EIA), immunohistochemistry (IHC), and in situ hybridisation (ISH) were performed.

    Results: EIA revealedincreased SP-levels in the Achilles tendon of the exercised limb in all the experimental groups as compared to in thecontrols (statistically significant; p=0.01). A similar trend in the unexercised Achilles tendon was observed but was not statisticallysignificant (p=0.14). IHC and in ISH illustrated reactions of both SP and NK-1R mainly in blood vessel walls, but the receptorwas also found on tenocytes.

    Conclusions: Achilles tendon SP-levels are elevated already after 1 week of loading. This showsthat increased SP-production precedes tendinosis, as tendinosis-like changes occur only after a minimum of 3 weeks of exercise,as shown in a recent study using this model. We propose that central neuronal mechanism may be involved as similar trends wereobserved in the contralateral Achilles tendon.

  • 32.
    Backman, Ludvig
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Fong, Gloria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    Vancouver Coastal Health and Research Institute, University of British Columbia, Vancouver.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Substance P is a mechanoresponsive, autocrine regulator of human tenocyte proliferation2011In: PLOS ONE, E-ISSN 1932-6203, Vol. 6, no 11, p. e27209-Article in journal (Refereed)
    Abstract [en]

    It has been hypothesised that substance P (SP) may be produced by primary fibroblastic tendon cells (tenocytes), and that this production, together with the widespread distribution of the neurokinin-1 receptor (NK-1 R) in tendon tissue, could play an important role in the development of tendinopathy, a condition of chronic tendon pain and thickening. The aim of this study was to examine the possibility of endogenous SP production and the expression of NK-1 R by human tenocytes. Because tendinopathy is related to overload, and because the predominant tissue pathology (tendinosis) underlying early tendinopathy is characterized by tenocyte hypercellularity, the production of SP in response to loading/strain and the effects of exogenously administered SP on tenocyte proliferation were also studied. A cell culture model of primary human tendon cells was used. The vast majority of tendon cells were immunopositive for the tenocyte/fibroblast markers tenomodulin and vimentin, and immunocytochemical counterstaining revealed that positive immunoreactions for SP and NK-1 R were seen in a majority of these cells. Gene expression analyses showed that mechanical loading (strain) of tendon cell cultures using the FlexCell (R) technique significantly increased the mRNA levels of SP, whereas the expression of NK-1 R mRNA decreased in loaded as compared to unloaded tendon cells. Reduced NK-1 R protein was also observed, using Western blot, after exogenously administered SP at a concentration of 10(-7) M. SP exposure furthermore resulted in increased cell metabolism, increased cell viability, and increased cell proliferation, all of which were found to be specifically mediated via the NK-1 R; this in turn involving a common mitogenic cell signalling pathway, namely phosphorylation of ERK1/2. This study indicates that SP, produced by tenocytes in response to mechanical loading, may regulate proliferation through an autocrine loop involving the NK-1 R.

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  • 33.
    Backman, Ludvig J
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Fong, Gloria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Department of Physical Therapy, University of British Columbia and Centre for Hip Health and Mobility, Vancouver Coastal Health and Research Institute, Vancouver, British Columbia, Canada.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Scott, A
    University of British Columbia, Vancouver, Vancouver Coastal Health and Research Institute.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alpha-2 adrenergic stimulation triggers Achilles tenocyte hypercellularity: comparison between two model systems2013In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 23, no 6, p. 687-696Article in journal (Refereed)
    Abstract [en]

    The histopathology of tendons with painful tendinopathy is often tendinosis, a fibrosis-like condition of unclear pathogenesis characterized by tissue changes including hypercellularity. The primary tendon cells (tenocytes) have been shown to express adrenoreceptors (mainly alpha-2A) as well as markers of catecholamine production, particularly in tendinosis. It is known that adrenergic stimulation can induce proliferation in other cells. The present study investigated the effects of an exogenously administered alpha-2 adrenergic agonist in an established in vivo Achilles tendinosis model (rabbit) and also in an in vitro human tendon cell culture model. The catecholamine producing enzyme tyrosine hydroxylase and the alpha-2A-adrenoreceptor (α(2A) AR) were expressed by tenocytes, and alpha-2 adrenergic stimulation had a proliferative effect on these cells, in both models. The proliferation was inhibited by administration of an α(2A) AR antagonist, and the in vitro model further showed that the proliferative alpha-2A effect was mediated via a mitogenic cell signaling pathway involving phosphorylation of extracellular-signal-regulated kinases 1 and 2. The results indicate that catecholamines produced by tenocytes in tendinosis might contribute to the proliferative nature of the pathology through stimulation of the α(2A) AR, pointing to a novel target for future therapies. The study furthermore shows that animal models are not necessarily required for all aspects of this research.

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  • 34.
    Backman, Ludvig J
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Akt-mediated anti-apoptotic effects of substance P in Anti-Fas-induced apoptosis of human tenocytes2013In: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 17, no 6, p. 723-733Article in journal (Refereed)
    Abstract [en]

    Substance P (SP) and its receptor, the neurokinin-1 receptor (NK-1 R), are expressed by human tenocytes, and they are both up-regulated incases of tendinosis, a condition associated with excessive apoptosis. It is known that SP can phosphorylate/activate the protein kinase Akt,which has anti-apoptotic effects. This mechanism has not been studied for tenocytes. The aims of this study were to investigate if Anti-Fastreatment is a good apoptosis model for human tenocytes in vitro, if SP protects from Anti-Fas-induced apoptosis, and by which mechanismsSP mediates an anti-apoptotic response. Anti-Fas treatment resulted in a time- and dose-dependent release of lactate dehydrogenase (LDH), i.e.induction of cell death, and SP dose-dependently reduced the Anti-Fas-induced cell death through a NK-1 R specific pathway. The same trendwas seen for the TUNEL assay, i.e. SP reduced Anti-Fas-induced apoptosis via NK-1 R. In addition, it was shown that SP reduces Anti-Fas-induced decrease in cell viability as shown with crystal violet assay. Protein analysis using Western blot confirmed that Anti-Fas inducescleavage/activation of caspase-3 and cleavage of PARP; both of which were inhibited by SP via NK-1 R. Finally, SP treatment resulted in phosphorylation/activation of Akt as shown with Western blot, and it was confirmed that the anti-apoptotic effect of SP was, at least partly, inducedthrough the Akt-dependent pathway. In conclusion, we show that SP reduces Anti-Fas-induced apoptosis in human tenocytes and that this antiapoptoticeffect of SP is mediated through NK-1 R and Akt-specific pathways.

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  • 35.
    Backman, Ludvig J
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Low range of ankle dorsiflexion predisposes for patellar tendinopathy in junior elite basketball players: a 1-year prospective study2011In: American Journal of Sports Medicine, ISSN 0363-5465, E-ISSN 1552-3365, Vol. 39, no 12, p. 2626-2633Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patellar tendinopathy (PT) is one of the most common reasons for sport-induced pain of the knee. Low ankle dorsiflexion range might predispose for PT because of load-bearing compensation in the patellar tendon.

    PURPOSE: The purpose of this 1-year prospective study was to analyze if a low ankle dorsiflexion range increases the risk of developing PT for basketball players. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2.

    METHODS: Ninety junior elite basketball players were examined for different characteristics and potential risk factors for PT, including ankle dorsiflexion range in the dominant and nondominant leg. Data were collected over a 1-year period and follow-up, including reexamination, was made at the end of the year.

    RESULTS: Seventy-five players met the inclusion criteria. At the follow-up, 12 players (16.0%) had developed unilateral PT. These players were found to have had a significantly lower mean ankle dorsiflexion range at baseline than the healthy players, with a mean difference of -4.7° (P = .038) for the dominant limb and -5.1° (P = .024) for the nondominant limb. Complementary statistical analysis showed that players with dorsiflexion range less than 36.5° had a risk of 18.5% to 29.4% of developing PT within a year, as compared with 1.8% to 2.1% for players with dorsiflexion range greater than 36.5°. Limbs with a history of 2 or more ankle sprains had a slightly less mean ankle dorsiflexion range compared to those with 0 or 1 sprain (mean difference, -1.5° to -2.5°), although this was only statistically significant for nondominant legs.

    CONCLUSION: This study clearly shows that low ankle dorsiflexion range is a risk factor for developing PT in basketball players. In the studied material, an ankle dorsiflexion range of 36.5° was found to be the most appropriate cutoff point for prognostic screening. This might be useful information in identifying at-risk individuals in basketball teams and enabling preventive actions. A history of ankle sprains might contribute to reduced ankle dorsiflexion range.

  • 36.
    Backman, Ludvig J.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Eriksson, Daniella E.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Substance P reduces TNF-α-induced apoptosis in human tenocytes through NK-1 receptor stimulation2014In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 48, no 19, p. 1414-1420Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: It has been hypothesised that an upregulation of the neuropeptide substance P (SP) and its preferred receptor, the neurokinin-1 receptor (NK-1 R), is a causative factor in inducing tenocyte hypercellularity, a characteristic of tendinosis, through both proliferative and antiapoptotic stimuli. We have demonstrated earlier that SP stimulates proliferation of human tenocytes in culture.

    AIM: The aim of this study was to investigate whether SP can mediate an antiapoptotic effect in tumour necrosis factor-α (TNF-α)-induced apoptosis of human tenocytes in vitro.

    RESULTS: A majority (approximately 75%) of tenocytes in culture were immunopositive for TNF Receptor-1 and TNF Receptor-2. Exposure of the cells to TNF-α significantly decreased cell viability, as shown with crystal violet staining. TNF-α furthermore significantly increased the amount of caspase-10 and caspase-3 mRNA, as well as both BID and cleaved-poly ADP ribosome polymerase (c-PARP) protein. Incubation of SP together with TNF-α resulted in a decreased amount of BID and c-PARP, and in a reduced lactate dehydrogenase release, as compared to incubation with TNF-α alone. The SP effect was blocked with a NK-1 R inhibitor.

    DISCUSSION: This study shows that SP, through stimulation of the NK-1 R, has the ability to reduce TNF-α-induced apoptosis of human tenocytes. Considering that SP has previously been shown to stimulate tenocyte proliferation, the study confirms SP as a potent regulator of cell-turnover in tendon tissue, capable of stimulating hypercellularity through different mechanisms. This gives further support for the theory that the upregulated amount of SP seen in tendinosis could contribute to hypercellularity.

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  • 37.
    Bagge, J.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Nerve ingrowth into tendon tissue in Achilles tendinosis: a Case Report2013In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 94, no 4, p. A8-A8Article in journal (Other academic)
  • 38.
    Bagge, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    TNF-α and neurotrophins in Achilles tendinosis2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tenocytes are the principal cells of the human Achilles tendon. In tendinosis, changes in the metabolism and morphology of these cells occur. Neurotrophins are growth factors essential for the development of the nervous system. Tumour necrosis factor alpha (TNF-α) has been found to kill sarcomas but has destructive effects in several major diseases. The two systems have interaction effects and are associated with apoptosis, proliferation, and pain signalling in various diseases. Whether these systems are present in the Achilles tendon and in Achilles tendinosis is unknown. The hypothesis is that the tenocytes produce substances belonging to these systems. In Studies I–III, we show that the potent effects of these substances are also likely to occur in the Achilles tendon. We found tenocyte immunoreactions for the neurotrophins brain-derived neurotrophic factor (BDNF), the nerve growth factor (NGF), the neurotrophin receptor p75, and for TNF-α and both of its receptors, TNFR1 and TNFR2. This occurred in both subjects with painful mid-portion Achilles tendinosis, and in controls. Furthermore, we found mRNA expression for BDNF and TNF-α in tenocytes, which proves that these cells produce these substances. TNFR1 mRNA was also detected for the tenocytes, and TNFR1 immunoreactions were upregulated in tendinosis tendons. This might explain why tenocytes in tendinosis undergo apoptosis more often than in normal tendons. Total physical activity (TPA) level and blood concentration of both soluble TNFR1 and BDNF were measured in Study IV. The results showed that the blood concentration of both factors were similar in subjects with tendinosis and in controls. Nevertheless, the TPA level was related to the blood concentration of sTNFR1 in tendinosis, but not in controls. This relationship should be studied further. The findings of this doctoral thesis show that neurotrophin and TNF-α systems are expressed in the Achilles tendon. We believe that the functions include tissue remodelling, proliferation and apoptosis.

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  • 39.
    Bagge, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    In situ hybridization studies favouring the occurrence of a local production of BDNF in the human Achilles tendon2012In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 27, no 9, p. 1239-1246Article in journal (Refereed)
    Abstract [en]

    Brain derived neurotrophic factor (BDNF) is a multipotent neurotrophin known for its growth-influencing and apoptosis-modulating functions, as well as for its function to interact with neurotransmitters/neuromodulators. BDNF is reported to be mainly produced in the brain. BDNF can be absorbed into peripheral tissue from the blood stream. Expression of this neurotrophin at the protein level, as well as of the neurotrophin receptor p75, has been previously shown for the principal cells (tenocytes) of the Achilles tendon. However, there is no proof at the mRNA level that BDNF is produced by the tenocytes. As the Achilles tendon tenocytes show "neuronal-like" characteristics, in the form of expressions favouring synthesis of several neuromodulators/neurotransmitters, and as BDNF especially is produced in neurons, it is of interest to confirm this. In the present study, therefore, in situ hybridization for demonstration of BDNF mRNA was performed on biopsies from Achilles tendons of patients with tendinosis and pain-free non-tendinosis individuals. The results showed that the tenocytes of both groups exhibited BDNF mRNA reactions. These observations indeed favour the idea that BDNF is produced by tenocytes in the human Achilles tendon, why Achilles tendon tissue is a tissue in which BDNF can be locally produced. BDNF can have modulatory functions for the tenocytes, including apoptosis-modifying effects via actions on the p75 receptor and interactive effects with neurotransmitters/neuromodulators produced in these cells. This possibility should be further studied for Achilles tendon tissue.

  • 40.
    Bagge, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Gaida, JE
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Physical activity level in Achilles tendinosis is associated with blood levels of pain-related factors: a pilot study2011In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 21, no 6, p. E430-E438Article in journal (Refereed)
    Abstract [en]

    Physical activity affects the pain symptoms for Achilles tendinosis patients. Brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-alpha) and their receptors have been detected in human Achilles tendon. This pilot study aimed to compare serum BDNF and soluble tumor necrosis factor receptor I (sTNFRI) levels in Achilles tendinosis patients and healthy controls and to examine the influence of physical activity, and BMI and gender, on these levels. Physical activity was measured with a validated questionnaire, total physical activity being the parameter analyzed. Physical activity was strongly correlated with BDNF among tendinosis women [Spearman's rho (rho) = 0.90, P < 0.01] but not among control women (rho = -0.08, P = 0.83), or among tendinosis and control men. Physical activity was significantly correlated with sTNFRI in the entire tendinosis group and among tendinosis men (rho = 0.65, P = 0.01), but not in the entire control group or among control men (rho = 0.04, P = 0.91). Thus, the physical activity pattern is related to the TNF and BDNF systems for tendinosis patients but not controls, the relationship being gender dependent. This is new information concerning the relationship between physical activity and Achilles tendinosis, which may be related to pain for the patients. This aspect should be further evaluated using larger patient materials.

  • 41.
    Bagge, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Unexpected presence of the neurotrophins NGF and BDNF and the neurotrophin receptor p75 in the tendon cells of the human Achilles tendon2009In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 24, no 7, p. 839-848Article in journal (Refereed)
    Abstract [en]

    Neurotrophins are substances that have been shown to be important in growth and remodelling phases in different types of tissue. There is no information concerning the possible occurrences of neurotrophins and their receptors in tendons. In this study, sections of both chronic painful (tendinosis) and pain-free (non-tendinosis) human Achilles tendons were immunohistochemically stained with antibodies against the neurotrophins NGF and BDNF, and their receptors TrkA, TrkB and p75. There were marked immunoreactions for NGF and BDNF in the tendon cells (tenocytes) of both tendinosis and non-tendinosis specimens. The tenocytes were also reactive for the receptor p75, but not for the receptors TrkA and TrkB. In addition, p75 immunoreactions were seen in nerve fascicles and in the walls of arterioles. This is the first study to identify neurotrophins in the tenocytes of human tendon. It is clear from this study that the local cells of tendons are sources of neurotrophins. The neurotrophins may play an important role in the tendon through their interaction with the receptor p75 in the tenocytes. These interactions may regulate tropic modulatory, and apoptotic effects. In conclusion, the observations show a new concept concerning production and function of neurotrophins, namely in the tenocytes of tendons.

  • 42.
    Bain, G. I.
    et al.
    Australia .
    Polites, N.
    Australia .
    Higgs, B. G.
    Australia .
    Heptinstall, R. J.
    Unaffiliated .
    McGrath, Aleksandra
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The functional range of motion of the finger joints2015In: Journal of Hand Surgery, European Volume, ISSN 1753-1934, E-ISSN 2043-6289, Vol. 40, no 4, p. 406-411Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to measure the functional range of motion of the finger joints needed to perform activities of daily living. Using the Sollerman hand grip function test, 20 activities were assessed in ten volunteers. The active and passive range of motion was measured with a computerized electric goniometer. The position of each finger joint was evaluated in the pre-grasp and grasp positions. The functional range of motion was defined as the range required to perform 90% of the activities, utilizing the pre-grasp and grasp measurements. The functional range of motion was 19 degrees-71 degrees, 23 degrees-87 degrees, and 10 degrees-64 degrees at the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints, respectively. This represents 48%, 59%, and 60% of the active motion of these joints, respectively. There was a significant difference in the functional range of motion between the joints of the fingers, with the ulnar digits having greater active and functional range. The functional range of motion is important for directing indications for surgery and rehabilitation, and assessing outcome of treatment.

  • 43. Bain, Gregory I
    et al.
    McGuire, Duncan T
    McGrath, Aleksandra M
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    A Simplified Lateral Hinge Approach to the Proximal Interphalangeal Joint2015In: Techniques in Hand & Upper Extremity Surgery, ISSN 1089-3393, E-ISSN 1531-6572, Vol. 19, no 3, p. 129-132Article in journal (Refereed)
    Abstract [en]

    Proximal interphalangeal joint replacement is an effective treatment for painful arthritis affecting the joint. However, the complication rate is relatively high, with many of these complications related to soft-tissue imbalance or instability. Volar, dorsal, and lateral approaches have all been described with varying results. We describe a new simplified lateral hinge approach that splits the collateral ligament to provide adequate exposure of the joint. Following insertion of the prosthesis the collateral ligament is simply repaired, side-to-side, which stabilizes the joint. As the central slip, opposite collateral ligament, flexor and extensor tendons have not been violated, early active mobilization without splinting is possible, and the risk of instability, swan-neck, and boutonniere deformity are reduced. The indications, contraindications, surgical technique, and rehabilitation protocol are described.

  • 44.
    Bjur, Dennis
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    The human Achilles tendon: innervation and intratendinous production of nerve signal substances - of importance in understanding the processes of Achilles tendinosis2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tendinopathies are painful tendon conditions of presumably multifactorial genesis. In tendinosis, as in Achilles tendinosis, there is apart from pain also morphological changes which are described as degenerative with no signs of inflammation. The exact mechanisms behind these conditions are still, to a large extent, unknown. Pain, being the foremost impairing symptom, leads us to the hypothesis that nerves are deeply involved in the symptoms and processes of Achilles tendinosis. Locally produced nerve signal substances may also be involved in the processes. Knowledge of the innervation patterns within the tendon and knowledge on a possible local nerve signal substance production are therefore of utmost importance. There is a lack of information on these aspects.

    The specific aims of this thesis were 1) to investigate the innervation patterns regarding general, sensory, cholinergic and sympathetic innervations, and 2) to examine for the possible occurrence of a production of nerve signal substances and a presence of receptors related to these in the tendon cells, the tenocytes. Painfree normal and tendinosis Achilles tendons were examined.

    Immunohistochemistry, using antibodies against the general nerve marker PGP9.5, the synthesizing enzymes for acetylcholine (choline acetyltransferase; ChAT), and catecholamines (tyrosine hydroxylase; TH), the vesicular acetylcholine transporter (VAChT), neuropeptide Y (NPY), substance P and calcitonin gene-related peptide, was applied. Immunohistochemistry was also used for the delineation of muscarinic (M2R), adrenergic (α1-AR) and NPY-ergic (Y1 and Y2) receptors. To detect mRNA for TH and ChAT, in situ hybridization was used.

    In normal Achilles tendons, as well as in the tendinosis tendons, there was a very scanty innervation within the tendon tissue proper, the main general, sensory and sympathetic innervations being found in the paratendinous loose connective tissue. Interestingly, the tenocytes showed immunoreactions for ChAT, VAChT, TH, M2R, α1-AR and Y1R. The reactions were clearly more observable in tendons of tendinosis patients than in those of controls. The tenocytes of tendinosis patients also displayed mRNA reactions for ChAT and TH. Nevertheless, all tenocytes in the tendinosis specimens did not show these reactions. Immunoreactions for α1-AR, M2R and Y1R were also seen for blood vessel walls.

    The present thesis shows that there is a very limited innervation within tendon tissue proper, whilst there is a substantial innervation in the paratendinous loose connective tissue. It also gives evidence for an occurrence of production of catecholamines and acetylcholine in tenocytes, especially for tendinosis tendons. Furthermore, that ACh, catecholamines and NPY can have effects on these, as well as on blood vessels, via the receptors observed.

    The observations suggest that Achilles tendon tissue, whilst containing a very scarce innervation, exhibits autocrine/paracrine cholinergic/catecholaminergic/NPY-ergic effects that are upregulated in tendinosis. These findings are of great importance as the results of such effects may mimic processes that are known to occur in tendinosis. That includes effects related to proliferation and angiogenesis, and blood vessel and collagen regulating effects.

    In conclusion, within the Achilles tendon there is a very scarce innervation, whilst there appears to be a marked local production of nerve signal substances in Achilles tendinosis, namely in the tenocytes, the cells also harbouring receptors for these substances. The observations give a new insight into how the tendon tissue of the Achilles tendon is influenced by signal substances and may give options for new treatments of Achilles tendinosis.

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  • 45.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of the neuropeptide Y 1 receptor in tenocytes and blood vessel walls in the human Achilles tendon2009In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 43, no 13, p. 1136-1142Article in journal (Refereed)
    Abstract [en]

    Background: There are still questions concerning the mechanisms of development of chronic pain and impaired function of tendons (tendinosis). Aspects that are known to occur are cell proliferation, angiogenesis and altered blood flow regulation. Neuropeptide NPY (NPY) is widely distributed in the body and has powerful effects in relation to these processes. NPY has its effects via the G-protein-coupled Y receptors. There is no information concerning the presence or absence of NPY receptors in Achilles tendons or other tendons.

    Objective: To clarify the expression patterns of the NPY receptors Y1 and Y2 in normal and tendinosis Achilles tendons of man.

    Methods: Immunohistochemical methods were used. Examination on NPY was carried out in parallel.

    Results: The tenocytes showed strong immunoreactions for the Y1 receptor. The immunoreactions were more intense in the tenocytes of the tendinosis tendons than in those of the non-tendinosis tendons. The rounded/oval tenocytes typically seen in tendinosis tendons exhibited marked Y1 receptor reactions on their exterior. Pronounced Y1 reactions were seen in the smooth muscle of the arterioles of both tendinosis and non-tendinosis tendons. No reactions for the Y2 receptor were noted. NPY was detected in nerve fascicles and in the perivascular innervation.

    Conclusions: The present study shows that there is a morphologic correlate for the occurrence of pronounced NPY effects via the Y1 receptor in both tenocytes, this especially being a fact for tendinosis tendons, and blood vessel walls in the Achilles tendon. The findings are of particular interest as NPY is known to have proliferative, angiogenic and blood vessel regulating effects. The effects of targeting the Y1 receptor in tendinosis is an interesting task to be further evaluated.

  • 46.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The innervation pattern of the human Achilles tendon: studies of the normal and tendinosis tendon with markers for general and sensory innervation2005In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 320, no 1, p. 201-206Article in journal (Refereed)
    Abstract [en]

    Pain-free normal Achilles tendons and chronic painful Achilles tendons were examined by the use of antibodies against a general nerve marker (protein gene-product 9.5, PGP9.5), sensory markers (substance P, SP; calcitonin gene-related peptide, CGRP), and immunohistochemistry. In the normal tendons, immunoreactions against PGP9.5 and against SP/CGRP were encountered in the paratendinous loose connective tissue, being confined to nerve fascicles and to nerve fibers located in the vicinity of blood vessels. To some extent, these immunoreactions also occurred in the tendon tissue proper. Immunoreaction against PGP9.5 and against SP/CGRP was also observed in the tendinosis samples and included immunoreactive nerve fibers that were intimately associated with small blood vessels. In conclusion, Mechanoreceptors (sensory corpuscles) were occasionally observed, nerve-related components are present in association with blood vessels in both the normal and the tendinosis tendon.

  • 47.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Immunohistochemical and in situ hybridization observations favor a local catecholamine production in the human Achilles tendon2008In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 23, no 2, p. 197-208Article in journal (Refereed)
    Abstract [en]

    Results of recent studies using immunohistochemistry show evidence of an occurrence of catecholamine production in the cells (tenocytes) of patellar tendons exhibiting tendinopathy (tendinosis). In the present study, antibodies against the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) and alpha1-adrenoreceptors were applied to sections of specimens of normal and tendinosis Achilles tendons. In situ hybridization using a probe detecting human TH mRNA was also utilized. It was found that sympathetic innervation was very scarce. On the other hand, there were distinct alpha1-adrenoreceptor immunoreactions in blood vessel walls. Interestingly, tenocytes, particularly from tendinosis samples in which the tenocytes showed an abnormal shape (not the typical slender appearance), displayed TH immunoreactions and reactions for TH mRNA. Of further interest was the finding of alpha1-adrenoreceptor immunoreactions in tenocytes. The observations show not only evidence of local catecholamine production at the protein level, which was the case in recent studies for the patellar tendon, but also at the mRNA level. The observations suggest that the tenocytes, especially those with disfigured appearances in tendinosis, can produce catecholamines and also that they can respond to sympathetic transmitters. This is of interest as adrenergic stimulation in other parts of the body is known to induce degenerative/apoptotic and proliferative events, features which are seen in Achilles tendinosis. These observations are completely new findings concerning the human Achilles tendon. It is likely that locally produced catecholamines and the occurrence of autocrine/paracrine effects of these substances are of great relevance during the process of tendinosis.

  • 48.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Observations in favor of a presence of local catecholamine production in the human Achilles tendon - of importance when understanding potential adrenergic effects in Achilles tendinosis.2006Conference paper (Refereed)
    Abstract [en]

    The mid-portion of the Achilles tendon is a frequently injured and pathologically affected tendon region. Achilles tendinosis presents with chronic tendon pain and impaired function, and most often occurs in the mid-portion of the tendon. Nerve-related effects are likely to be of great significance in the pathogenesis of this condition, and information on innervation patterns is therefore of importance. However, the available information on these aspects is limited for the human Achilles tendon. Via staining for a general nerve marker it has previously been shown that there is a presence of innervation in the loose paratendinous connective tissue and to some extent also within the tendon tissue proper. This innervation has been found to partly conform to sensory innervation. There is no information at all on the patterns of sympathetic innervation in the human Achilles tendon. This is a drawback as it is crucial to know the basis for adrenergic effects on blood vessel regulation in tendinosis and as efferent sympathetic nerve activities may be related to pain symptoms. In the present study, therefore, specimens of tendon tissue from the human Achilles tendon of both tendinosis patients and normal controls were immunohistochemically examined concerning expression of the rate limiting enzyme in catecholamine production, tyrosine hydroxylase (TH), and of neuropeptide Y (NPY). In normal tendons, TH- and NPY-immunoreactive nerve fibers were occasionally detected in nerve fascicles and in arterial walls in the paratendinous tissue, but were not detected with certainty within the tendon tissue proper. In the specimens of tendinosis affected tendons, TH-and NPY-immunoreactive nerve fibers were almost non-existent. Surprisingly, however, TH-immunoreactions could be seen in the tendon cells (tenocytes) themselves. Sections were also processed for demonstration of α1-, α2a-, and β1- adrenoreceptors. It was hereby seen that there were immunoreactions for adrenergic receptors in the walls of some of the blood vessels, as well as in some of the tenocytes. The observations show that there is a limited sympathetic innervation at the level of the paratendinous tissue and in principle a non-existent such innervation within the tendon tissue proper. On the other hand, as evidenced by findings of TH-immunoreaction in tenocytes, it appears as if there is a local production of catecholamines within the tendon tissue proper itself. Thus, the tenocytes might be an important source of mediators that bind to the adrenergic receptors in the tissue. The observations of adrenergic receptors on tenocytes are furthermore of interest as adrenergic stimulation in other situations can lead to degenerative/apoptotic events and an affection on cell growth. These facts are thus highly interesting when trying to understand how such events can occur in Achilles tendinosis. Similarly, cartilage and menisci have in recent studies been found to harbor cells that express adrenergic receptors, but nevertheless to be very scarcely equipped with nerves. Although there is a very limited sympathetic innervation in the Achilles tendon, our observations show that there is a morphologic correlate for the occurrence of adrenergic actions in the tendon, via effects of locally produced catecholamines.

  • 49.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Presence of a non-neuronal cholinergic system and occurrence of up- and down-regulation in expression of M2 muscarinic acetylcholine receptors: new aspects of importance regarding Achilles tendon tendinosis (tendinopathy)2008In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 331, no 2, p. 385-400Article in journal (Refereed)
    Abstract [en]

    Limited information is available concerning the existence of a cholinergic system in the human Achilles tendon. We have studied pain-free normal Achilles tendons and chronically painful Achilles tendinosis tendons with regard to immunohistochemical expression patterns of the M(2) muscarinic acetylcholine receptor (M(2)R), choline acetyltransferase (ChAT), and vesicular acetylcholine transporter (VAChT). M(2)R immunoreactivity was detected in the walls of blood vessels. As evidenced via parallel staining for CD31 and alpha-smooth muscle actin, most M(2)R immunoreactivity was present in the endothelium. M(2)R immunoreactivity also occured in tenocytes, which regularly immunoreact for vimentin. The degree of M(2)R immunoreactivity was highly variable, tendinosis tendons that exhibit hypercellularity and hypervascularity showing the highest levels of immunostaining. Immunoreaction for ChAT and VAChT was detected in tenocytes in tendinosis specimens, particularly in aberrant cells. In situ hybridization revealed that mRNA for ChAT is present in tenocytes in tendinosis specimens. Our results suggest that autocrine/paracrine effects occur concerning the tenocytes in tendinosis. Up-regulation/down-regulation in the levels of M(2)R immunoreactivity possibly take place in tenocytes and blood vessel cells during the various stages of tendinosis. The presumed local production of acetylcholine (ACh), as evidenced by immunoreactivity for ChAT and VAChT and the detection of ChAT mRNA, appears to evolve in response to tendinosis. These observations are of importance because of the well-known vasoactive, trophic, and pain-modulating effects that ACh is known to have and do unexpectedly establish the presence of a non-neuronal cholinergic system in the Achilles tendon.

  • 50.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Increased expression of cannabinoid CB(1) receptors in achilles tendinosis2011In: PLOS ONE, E-ISSN 1932-6203, Vol. 6, no 9, p. e24731-Article in journal (Refereed)
    Abstract [en]

    Background: The endogenous cannabinoid system is involved in the control of pain. However, little is known as to the integrity of the cannabinoid system in human pain syndromes. Here we investigate the expression of the cannabinoid receptor 1 (CB(1)) in human Achilles tendons from healthy volunteers and from patients with Achilles tendinosis.

    Methodology: Cannabinoid CB(1) receptor immunoreactivity (CB(1)IR) was evaluated in formalin-fixed biopsies from individuals suffering from painful Achilles tendinosis in comparison with healthy human Achilles tendons.

    Principal Findings: CB(1)IR was seen as a granular pattern in the tenocytes. CB(1)IR was also observed in the blood vessel wall and in the perineurium of the nerve. Quantification of the immunoreactivity in tenocytes showed an increase of CB(1) receptor expression in tendinosis tissue compared to control tissue.

    Conclusion: Expression of cannabinoid receptor 1 is increased in human Achilles tendinosis suggesting that the cannabinoid system may be dysregulated in this disorder.

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