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  • 101.
    Reid, Adam J
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. University of Manchester.
    Sun, M
    University of Manchester.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Downes, S
    University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. University of Manchester.
    Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis2011Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 199, s. 515-522Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Novel approaches are required in the clinical management of peripheral nerve injuries because current surgical techniques result in deficient sensory recovery. Microsurgery alone fails to address extensive cell death in the dorsal root ganglia (DRG), in addition to poor axonal regeneration. Incorporation of cultured cells into nerve conduits may offer a novel approach in which to combine nerve repair and enhance axonal regeneration with neuroprotective therapies. We examined apoptotic mediator expression in rat DRG neurons following repair of a 10-mm sciatic nerve gap using a novel synthetic conduit made of poly epsilon-caprolactone (PCL) and primed with adipose-derived stem cells (ADSC) differentiated towards a Schwann cell phenotype or with primary adult Schwann cells. Differentiated ADSC expressed a range of neurotrophic factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and neurotrophin-4 (NT4). Incorporation of either differentiated ADSC or Schwann cells significantly increased anti-apoptotic Bcl-2 mRNA expression (P<0.001) in the DRG, while significantly decreasing proapoptotic Bax (P<0.001) and caspase-3 mRNA (P<0.01) expression. Cleaved caspase-3 protein was observed in the DRG following nerve injury which was attenuated when nerve repair was performed using conduits seeded with cells. Cell incorporation into conduit repair of peripheral nerves demonstrates experimental promise as a novel intervention to prevent DRG neuronal loss. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  • 102.
    Reid, Adam J
    et al.
    Blond McIndoe Research Laboratories, Tissue Injury and Repair Group, University of Manchester, UK.
    Welin, Dag
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Terenghi, Giorgio
    Blond McIndoe Research Laboratories, Tissue Injury and Repair Group, University of Manchester, UK.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Peripherin and ATF3 genes are differentially regulated in regenerating and non-regenerating primary sensory neurons2010Inngår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1310, s. 1-7Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Peripheral nerve injury leads to deficient recovery of sensation and a causative factor may be that only 50-60% of primary sensory neurons succeed in regenerating axons after primary nerve repair. In this study, an in vivo rat sciatic nerve injury and regeneration model was combined with laser microdissection and quantitative real-time polymerase chain reaction with the aim of examining the gene expression of regenerative molecules in cutaneous and muscular sensory neurons. Recent studies have identified peripherin and ATF-3 molecules as crucial for neurite outgrowth propagation; our novel findings demonstrate a subpopulation of non-regenerating sensory neurons characterized by a failure to upregulate transcription of these molecules and that a greater peripherin mRNA expression in injured cutaneous neurons may potentiate this subpopulation to regenerate more axons than muscle afferent neurons following injury. The gene expression of the structural neurofilament NF-H is found to be significantly downregulated following injury in both sensory subpopulations.

  • 103.
    Schaakxs, Dominique
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Division of Plastic, Reconstructive and Aesthetic Surgery, CHUV, University Hospital of Lausanne, Switzerland.
    Kalbermatten, Daniel F
    Pralong, Etienne
    Raffoul, Wassim
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Poly-3-hydroxybutyrate strips seeded with regenerative cells are effective promoters of peripheral nerve repair2017Inngår i: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 11, nr 3, s. 812-821Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Peripheral nerve injuries are often associated with loss of nerve tissue and require a graft to bridge the gap. Autologous nerve grafts are still the 'gold standard' in reconstructive surgery but have several disadvantages, such as sacrifice of a functional nerve, neuroma formation and loss of sensation at the donor site. Bioengineered grafts represent a promising approach to address this problem. In this study, poly-3-hydroxybutyrate (PHB) strips were used to bridge a 10 mm rat sciatic nerve gap and their effects on long-term (12 weeks) nerve regeneration were compared. PHB strips were seeded with different cell types, either primary Schwann cells (SCs) or SC-like differentiated adipose-derived stem cells (dASCs) suspended in a fibrin glue matrix. The control group was PHB and fibrin matrix without cells. Functional and morphological properties of the regenerated nerve were assessed using walking track analysis, EMGs, muscle weight ratios and muscle and nerve histology. The animals treated with PHB strips seeded with SCs or dASCs showed significantly better functional ability than the control group. This correlated with less muscle atrophy and greater axon myelination in the cell groups. These findings suggest that the PHB strip seeded with cells provides a beneficial environment for nerve regeneration. Furthermore, dASCs, which are abundant and easily accessible, constitute an attractive cell source for future applications of cell therapy for the clinical repair of traumatic nerve injuries.

  • 104.
    Schaakxs, Dominique
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. University Hospital of Lausanne.
    Kalbermatten, Daniel F
    University Hospital of Basel.
    Raffoul, Wassim
    University Hospital of Lausanne.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Regenerative cell injection in denervated muscle reduces atrophy and enhances recovery following nerve repair2013Inngår i: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 47, nr 5, s. 691-701Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Functional muscle recovery after peripheral nerve injury is far from optimal, partly due to atrophy of the muscle arising from prolonged denervation. We hypothesized that injecting regenerative cells into denervated muscle would reduce this atrophy. Methods: A rat sciatic nerve lesion was performed, and Schwann cells or adipose-derived stem cells, untreated or induced to a Schwann-celllike phenotype (dASC), were injected into the gastrocnemius muscle. Nerves were either repaired immediately or capped to prevent muscle reinnervation. One month later, functionality was measured using a walking track test, and muscle atrophy was assessed by examining muscle weight and histology. Results: Schwann cells and dASC groups showed significantly better scores on functional tests when compared with injections of growth medium alone. Muscle weight and histology were also significantly improved in these groups. Conclusion: Cell injections may reduce muscle atrophy and could benefit nerve injury patients.

  • 105.
    Schenker, Michael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Burstedt, M K O
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Johansson, Roland S
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Precision grip function after hand replantation and digital nerve injury.2006Inngår i: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, Vol. 59, nr 7, s. 706-716Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Understanding how the loss of digital sensibility affects manual dexterity could have important implications for rehabilitation after hand injury. We investigated precision grip function during lifting tasks in seven patients after hand replantation, in five after single digital nerve injury and in four volunteers subjected to digital anaesthesia. Using their affected hand, all participants could successfully lift test objects with parallel and vertical grip surfaces and they all reliably increased the grip force with increasing object weight (0.11-0.55 kg). However, the grip forces used were frequently significantly higher than those applied by the unaffected hand. This was partly due to participants compensating for loss of sensibility with high grip force safety margins against slips, and partly related to misalignments of the fingertips on the grasp surfaces. The latter was most prominent after hand replantation. In a second series of lifting experiments we changed the shape of the grip surfaces in order to investigate the participants' ability to adapt grip forces based on tactile recognition of object shape. An important finding from this series was that in patients with poor clinical outcomes, the contralateral unaffected hand tended to mirror the abnormal grasp patterns of the injured hand. This suggests that control strategies developed for the impaired hand can influence the control of the contralateral uninjured hand.

  • 106. Schenker, Michael
    et al.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kay, Simon P
    Johansson, Roland S
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Precision grip function after free toe transfer in children with hypoplastic digits.2007Inngår i: J Plast Reconstr Aesthet Surg, ISSN 1748-6815, Vol. 60, nr 1, s. 13-23Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although toe-to-hand transfer has a defined role in the management of congenital hand deformities, it remains unclear how well children integrate the transferred digits into physiological grasping. We analysed fingertip forces in the precision grip of 13 patients when lifting a test object more than three years after free toe transfer for absent or hypoplastic digits. Clinically, most patients showed normal sensibility of transferred digits, but active motion and pinch strength were limited as compared to the normal hand. For the control of fingertip forces, two key features of the normal two-digit opposition grip were seen in all operated hands: adaptation of grip force to object weight and parallel coordination of lift and grip forces. These physiological grasping strategies developed independently of the patients' age at the time of operation, which ranged from one to 13 years. In four patients, we observed increased tangential load forces with the operated hand due to misalignments in the application of fingertips on the grasp surfaces. Such forces lead to increased grip force requirements on both fingers that may overload transferred digits with limited motor function. The need for optimal alignment of the grip axis during toe-transfer surgery is emphasised.

  • 107.
    Song, Yafeng
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Stål, Per S
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Yu, Ji-Guo
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Lorentzon, Ronny
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Backman, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Forsgren, Sture
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Inhibitors of endopeptidase and angiotensin-converting enzyme lead to an amplification of the morphological changes and an upregulation of the substance P system in a muscle overuse model2014Inngår i: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 15, s. 126-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: We have previously observed, in studies on an experimental overuse model, that the tachykinin system may be involved in the processes of muscle inflammation (myositis) and other muscle tissue alterations. To further evaluate the significance of tachykinins in these processes, we have used inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), substances which are known to terminate the activity of various endogenously produced substances, including tachykinins.

    METHODS: Injections of inhibitors of NEP and ACE, as well as the tachykinin substance P (SP), were given locally outside the tendon of the triceps surae muscle of rabbits subjected to marked overuse of this muscle. A control group was given NaCl injections. Evaluations were made at 1 week, a timepoint of overuse when only mild inflammation and limited changes in the muscle structure are noted in animals not treated with inhibitors. Both the soleus and gastrocnemius muscles were examined morphologically and with immunohistochemistry and enzyme immunoassay (EIA).

    RESULTS: A pronounced inflammation (myositis) and changes in the muscle fiber morphology, including muscle fiber necrosis, occurred in the overused muscles of animals given NEP and ACE inhibitors. The morphological changes were clearly more prominent than for animals subjected to overuse and NaCl injections (NaCl group). A marked SP-like expression, as well as a marked expression of the neurokinin-1 receptor (NK-1R) was found in the affected muscle tissue in response to injections of NEP and ACE inhibitors. The concentration of SP in the muscles was also higher than that for the NaCl group.

    CONCLUSIONS: The observations show that the local injections of NEP and ACE inhibitors led to marked SP-like and NK-1R immunoreactions, increased SP concentrations, and an amplification of the morphological changes in the tissue. The injections of the inhibitors thus led to a more marked myositis process and an upregulation of the SP system. Endogenously produced substances, out of which the tachykinins conform to one substance family, may play a role in mediating effects in the tissue in a muscle that is subjected to pronounced overuse.

  • 108.
    Spang, Christoph
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Idrottsmedicin. Pure Sports Med Clin, Cabot Pl West, London E14 4QS, England and Univ Coll London Hosp, Inst Sports Exercise & Hlth, 170 Tottenham Court Rd, London W1T 7HA, England.
    Docking, S. I.
    Masci, L.
    Andersson, Gustav
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    The plantaris tendon: a narrative review focusing on anatomical features and clinical importance2016Inngår i: The Bone & Joint Journal, ISSN 2049-4394, E-ISSN 2049-4408, Vol. 98B, nr 10, s. 1312-1319Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    In recent years, the plantaris tendon has been implicated in the development of chronic painful mid-portion Achilles tendinopathy. In some cases, a thickened plantaris tendon is closely associated with the Achilles tendon, and surgical excision of the plantaris tendon has been reported to be curative in patients who have not derived benefit following conservative treatment and surgical interventions. The aim of this review is to outline the basic aspects of, and the recent research findings, related to the plantaris tendon, covering anatomical and clinical studies including those dealing with histology, imaging and treatment.

  • 109.
    Suhr, Ole B
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Anan, Intissar
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Backman, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Karlsson, A
    Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden.
    Lindqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Mörner, Stellan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Waldenström, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Do troponin and B-natriuretic peptide detect cardiomyopathy in transthyretin amyloidosis?2008Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 263, nr 3, s. 294-301Artikkel i tidsskrift (Fagfellevurdert)
  • 110.
    Svala, Gabriella
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Long time follow up of scaphoid fracture treatment: Internal screw fixation vs. plaster cast immobilization2015Independent thesis Basic level (professional degree), 20 poäng / 30 hpOppgave
  • 111.
    Terenghi, Giorgio
    et al.
    University of Manchester.
    Hart, Andrew
    University of Manchester.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    The nerve injury and the dying neurons: diagnosis and prevention2011Inngår i: Journal of hand surgery. European volume, ISSN 1753-1934, Vol. 36E, nr 9, s. 730-734Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Following distal nerve injury significant sensory neuronal cell death occurs in the dorsal root ganglia, while after a more proximal injury, such as brachial plexus injury, a sizeable proportion of spinal motoneurons also undergo cell death. This phenomenon has been undervalued for a long time, but it has a significant role in the lack of functional recuperation, as neuronal cells cannot divide and be replaced, hence the resulting nerve regeneration is usually suboptimal. It is now accepted that this cell death is due to apoptosis, as indicated by analysis of specific genes involved in the apoptotic signalling cascade. Immediate nerve repair, either by direct suturing or nerve grafting, gives a degree of neuroprotection, but this approach does not fully prevent neuronal cell death and importantly it is not always possible. Our work has shown that pharmacological intervention using either acetyl-L-carnitine (ALCAR) or N-acetyl-cysteine (NAC) give complete neuroprotection in different types of peripheral nerve injury. Both compounds are clinically safe and experimental work has defined the best dose, timing after injury and duration of administration. The efficacy of neuroprotection of ALCAR and NAC can be monitored non-invasively using MRI, as demonstrated experimentally and more recently by clinical studies of the volume of dorsal root ganglia. Translation to patients of this pharmacological intervention requires further work, but the available results indicate that this approach will help to secure a better functional outcome following peripheral nerve injury and repair.

  • 112. Terenghi, Giorgio
    et al.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Chapter 21: Use of stem cells for improving nerve regeneration2009Inngår i: International review of neurobiology, ISSN 0074-7742, E-ISSN 2162-5514, Vol. 87, s. 393-403Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    A clear need exists for new surgical approaches to enhance the recuperation of functions after peripheral nerve injury and repair. At present, advances in the regenerative medicine fields of biomaterials, cellular engineering, and molecular biology are all contributing to the development of a bioengineered nerve implant, which could be used clinically as an alternative to nerve autograft. In this review we examine the recent progress in this field, looking in particular at the applicability of Schwann cells and stem cell transplantation to enhance nerve regeneration.

  • 113.
    Tse, Kai-Hei
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Mechanisms and improvements of cell transplantation for nerve repair2011Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Trauma to the nervous system is a frequent clinical problem and new approaches to nerve repair are required. Autologous cell transplantation together with a suitable scaffold material could be used to create a bio-active artificial nerve graft to enhance regeneration. The work presented in this licentiate thesis attempts to improve both the biomaterial and cellular components of this repair strategy.

    In the first study, by using common biodegradable polyesters, namely poly-ε-caprolactone (PCL) and poly -L,D- lactic acid (PLA), a thin film scaffold prototype was fabricated by using a solvent-evaporation method. These scaffolds, with thicknesses of approximately 10-20 µm, exhibited a heterogenous but continuous surface topography decorated with pore/pits of regulated sizes. The sizes of the pore/pits ranged from 0.5 to 30 µm2and could be modulated by varying the ratios of PLA and PCL. Biocompatibility of these scaffolds was demonstrated by using adipose derived stem cells (ADSC) differentiated into a Schwann cell-like phenotype (dADSC), which showed attachment and proliferation on the films, maintenance of glial cell markers expression and enhancement of neurite outgrowth in co-culture with dorsal root ganglia (DRG) neurons.

    Transplantation of cells for nerve injuries remains sub-optimal due to their limited survival rates. In the second study, a chemical ischemia model (metabolically induced by sodium azide and 2-deoxyglucose) was established to investigate the differential effects of ischemia and serum deprivation on mesenchymal stem cells (MSCs). MSCs were more suseptible to combined than individual blockade of glycolysis and oxidative phosphorylation. Apoptotic and autophagy pathways were activated in the MSCs. Chemical ischemia or serum withdrawal alone induced a similar amount of cell death with significantly different intracellular ATP maintenance; but their effects were additive. The levels of various neurotrophin extracellular matrix and angiogenic factors expressed by the cells were shown to be differentially affected by ischemia but unaffected by changes in serum level. Stem cells isolated from both adipose tissue (ADSC) and bone marrow (BMSC) reacted similarly under these conditions. This chemical ischemia model will enable future screening of pharmacological agents to enhance the survival of MSCs under stress conditions.

    The mechanism underlying the neurotrophic potential of MSCs is unknown. In the third study in this thesis it is hypothesised that MSCs, upon stimulation with different growth factors, could produce brain derived neurotrophic factor (BNDF) with a similar molecular mechanism to that described in the nervous system. Within 24 hours of stimulation, ADSC and BMSC showed high secretion levels of BDNF, and these cells were able to enhance axonal outgrowth in DRG neurons at levels similar to long-term differentiated MSCs. Both the neuronal activity dependent promoterBDNFexon IV, along with full length protein encodingBDNFexon IX, were up-regulated upon stimulation.BDNFgating transcription factor, cyclic cAMP responsive element binding (CREB) protein, was also found to be activated but blocking of CREB phosphorylation with the small molecule inhibitor H89 did not suppress expression of BDNF protein suggesting compensatory pathways are involved.

    In summary, these studies indicate that MSCs are compatible with polyester based microporous scaffolds but the cells are highly susceptible to the stress conditions mimicking the hostile milieu at a nerve injury site. Preliminary studies hint at the molecular mechanism regulation BDNF expression in MSC and imply the interactions between MSCs and axons may play a role in the neurotrophic activity of the stem cells.

  • 114.
    Tse, Kai-Hei
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    The reactions of adipose tissue and bone marrow-derived stem cells in an ischaemia-like microenvironment2012Inngår i: Journal of tissue engineering and regenerative medicine, ISSN 1932-7005, Vol. 6, nr 6, s. 473-485Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mesenchymal stem cells (MSCs) from adipose tissue and bone marrow are promising cell sources for autologous cell therapy of nerve injuries, as demonstrated by their intrinsic neurotrophic potential. However, extensive death of transplanted cells limits their full benefits. This study investigated the effects of ischaemia (metabolically induced by sodium azide and 2-deoxyglucose) and serum-derived mitogens on the viability and functional profile of MSCs in vitro. MSCs were more susceptible to combined, rather than individual, blockade of glycolysis and oxidative phosphorylation. Apoptosis and autophagy were involved in ischaemia-induced cell death. Chemical ischaemia alone and serum withdrawal alone induced a similar amount of cell death, with significantly different intracellular ATP maintenance. Combined ischaemia and serum deprivation had additive effects on cell death. Expression of the extracellular matrix (ECM) molecules laminin and fibronectin was attenuated under ischaemia and independent of serum level; however, BDNF and NGF levels remained relatively constant. Strong upregulation of VEGF and to a lesser extent angiopoietin-1 was observed under ischaemia but not in serum withdrawal conditions. Importantly, this study demonstrated similar reactions of MSCs derived from adipose and bone marrow tissue, in ischaemia-like and mitogen-deprived microenvironments in terms of viability, cellular energetics, cell death mechanisms and expression levels of various growth-promoting molecules. Also, the results suggest that ischaemia has a larger impact on the ability of MSCs to survive transplantation than withdrawal of mitogens. Copyright © 2011 John Wiley & Sons, Ltd.

  • 115.
    Tse, Kai-Hei
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Intrinsic mechanisms underlying the de novo BDNF expression of mesenchymal stem cellsManuskript (preprint) (Annet vitenskapelig)
  • 116.
    Tse, Kai-Hei
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Intrinsic mechanisms underlying the neurotrophic activity of adipose derived stem cells2015Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 331, nr 1, s. 142-151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adipose derived stem cells (ADSC) can be differentiated into Schwann cell-like cells which enhance nerve function and regeneration. However, the signalling mechanisms underlying the neurotrophic potential of ADSC remain largely unknown. In this study, we hypothesised that ADSC, upon stimulation with a combination of growth factors, could rapidly produce brain derived neurotrophic factor (BDNF) with a similar molecular mechanism to that functioning in the nervous system. Within 48h of stimulation, ADSC demonstrated potent neurotrophic effects on dorsal root ganglion neurons, at a magnitude equivalent to that of the longer term differentiated Schwann cell-like cells. Stimulated ADSC showed rapid up-regulation of the neuronal activity dependent promoter BDNF exon IV along with an augmented expression of full length protein encoding BDNF exon IX. BDNF protein was secreted at a concentration similar to that produced by differentiated Schwann cell-like cells. Stimulation also activated the BDNF expression gating transcription factor, cAMP responsive element binding (CREB) protein. However, blocking phosphorylation of CREB with the protein kinase A small molecule inhibitor H89 did not suppress secretion of BDNF protein. These results suggest rapid BDNF production in ADSC is mediated through multiple compensatory pathways independent of, or in addition to, the CREB neuronal activation cascade.

  • 117. Ward, Ella Rose
    et al.
    Andersson, Gustav
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Gaida, Jamie E.
    Fat pads adjacent to tendinopathy: more than a coincidence?2016Inngår i: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 50, nr 24, s. 1491-1492Artikkel i tidsskrift (Fagfellevurdert)
  • 118.
    Welin, Dag
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi, Anatomi. Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Handkirurgi.
    Neuroprotection and axonal regeneration after peripheral nerve injury2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Following microsurgical reconstruction of injured peripheral nerves, severed axons are able to undergo spontaneous regeneration. However, the functional result is always unsatisfactory with poor sensory recovery and reduced motor function. One contributing factor is the retrograde neuronal death, which occurs in the dorsal root ganglia (DRG) and in the spinal cord. An additional clinical problem is the loss of nerve tissue that often occurs in the trauma zone and which requires “bridges” to reconnect separated nerve ends. The present thesis investigates the extent of retrograde degeneration in spinal motoneurons and cutaneous and muscular afferent DRG neurons after permanent axotomy and following treatment with N-acetyl-cysteine (NAC). In addition, it examines the survival and growth-promoting effects of nerve reconstructions performed by primary repair and peripheral nerve grafting in combination with NAC treatment.

    In adult rats, cutaneous sural and muscular medial gastrocnemius DRG neurons and spinal motoneurons were retrogradely labeled with fluorescent tracers from the homonymous transected nerves. Survival of labeled neurons was assessed at different time points after nerve transection, ventral root avulsion and ventral rhizotomy. Axonal regeneration was evaluated using fluorescent tracers after sciatic axotomy and immediate nerve repair. Intraperitoneal or intrathecal treatment with NAC was initiated immediately after nerve injury or was delayed for 1-2 weeks.

    Counts of labeled gastrocnemius DRG neurons did not reveal any significant retrograde cell death after nerve transection. Sural axotomy induced a delayed loss of DRG cells, which amounted to 43- 48% at 8-24 weeks postoperatively. Proximal transection of the sciatic nerve at 1 week after initial axonal injury did not further increase retrograde DRG degeneration, nor did it affect survival of corresponding motoneurons. In contrast, rhizotomy and ventral root avulsion induced marked 26- 53% cell loss among spinal motoneurons. Primary repair or peripheral nerve grafting supported regeneration of 53-60% of the motoneurons and 47-49% of the muscular gastrocnemius DRG neurons at 13 weeks postoperatively. For the cutaneous sural DRG neurons, primary repair or peripheral nerve grafting increased survival by 19-30% and promoted regeneration of 46-66% of the cells. Regenerating sural and medial gastrocnemius DRG neurons upregulate transcription of peripherin and activating transcription factor 3. The gene expression of the structural neurofilament proteins of high molecular weight was significantly downregulated following injury in both regenerating and non-regenerating sensory neurons. Treatment with NAC was neuroprotective for spinal motoneurons after ventral rhizotomy and avulsion, and sural DRG neurons after sciatic nerve injury. However, combined treatment with nerve graft and NAC had significant additive effect on neuronal survival and also increased the number of sensory neurons regenerating across the graft. In contrast, NAC treatment neither affected the number of regenerating motoneurons nor the number of myelinated axons in the nerve graft and in the distal nerve stump.

    In summary, the present results demonstrate that cutaneous sural sensory neurons are more sensitive to peripheral nerve injury than muscular gastrocnemius DRG cells. Moreover, the retrograde loss of cutaneous DRG cells taking place despite immediate nerve repair would still limit recovery of cutaneous sensory functions. Experimental data also show that NAC provides a highly significant degree of neuroprotection in animal models of adult nerve injury and could be combined with nerve grafting to further attenuate retrograde neuronal death and to promote functional regeneration.

  • 119.
    Welin, Dag
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikova, Liudmila N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kellerth, Jan-Olof
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Effects of N-acetyl-cysteine on the survival and regeneration of sural sensory neurons in adult rats2009Inngår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1287, nr 1, s. 58-66Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Microsurgical reconstruction of injured peripheral nerves often results in limited functional recovery. One contributing factor is the retrograde neuronal degeneration of sensory neurons in the dorsal root ganglia (DRG) and of motor neurons in the spinal cord. The present study investigates the neuroprotective and growth-promoting effects of N-acetyl-cysteine (NAC) on sensory DRG neurons and spinal motoneurons after sciatic axotomy and nerve grafting in adult rats. Sciatic axotomy and nerve grafting were performed at 1 week after sural DRG neurons and motoneurons were retrogradely labeled with the fluorescent tracer Fast Blue. To assess the efficacy of axonal regeneration, a second fluorescent dye Fluoro-Ruby was applied distal to the graft at 12 weeks after nerve repair. At 8-13 weeks after axotomy, only 52-56% of the sural sensory neurons remained in the lumbar DRG, while the majority of motoneurons survived the sciatic nerve injury. Nerve grafting alone or continuous intrathecal NAC treatment (2.4 mg/day) improved survival of sural DRG neurons. Combined treatment with nerve graft and NAC had significant additive effect on neuronal survival and also increased the number of sensory neurons regenerating across the graft. However, NAC treatment neither affected the number of regenerating motoneurons nor the number of myelinated axons in the nerve graft or in the distal nerve stump. The present results demonstrate that NAC provides a highly significant effect of neuroprotection in an animal nerve injury model and that combination with nerve grafting further attenuates retrograde cell death and promotes regeneration of sensory neurons.

  • 120.
    Welin, Dag
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Novikova, Liudmila
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kellerth, Jan-Olof
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Novikov, Lev
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Survival and regeneration of cutaneous and muscular afferent neurons after peripheral nerve injury in adult rats2008Inngår i: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 186, s. 315-323Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Peripheral nerve injury induces the retrograde degeneration of dorsal root ganglion (DRG) cells, which affects predominantly the small-diameter cutaneous afferent neurons. This study compares the time-course of retrograde cell death in cutaneous and muscular DRG cells after peripheral nerve transection as well as neuronal survival and axonal regeneration after primary repair or nerve grafting. For comparison, spinal motoneurons were also included in the study. Sural and medial gastrocnemius DRG neurons were retrogradely labeled with the fluorescent tracers Fast Blue (FB) or Fluoro-Gold (FG) from the homonymous transected nerves. Survival of labeled sural and gastrocnemius DRG cells was assessed at 3 days and 1-24 weeks after axotomy. To evaluate axonal regeneration, the sciatic nerve was transected proximally at 1 week after FB-labeling of the sural and medial gastrocnemius nerves and immediately reconstructed using primary repair or autologous nerve grafting. Twelve weeks later, the fluorescent tracer Fluoro-Ruby (FR) was applied 10 mm distal to the sciatic lesion in order to double-label sural and gastrocnemius neurons that had regenerated across the repair site. Counts of labeled gastrocnemius DRG neurons did not reveal any significant retrograde cell death after nerve transection. In contrast, sural axotomy induced a delayed loss of sural DRG cells, which amounted to 22% at 4 weeks and 43-48% at 8-24 weeks postoperatively. Proximal transection of the sciatic nerve at 1 week after injury to the sural or gastrocnemius nerves neither further increased retrograde DRG degeneration, nor did it affect survival of sural or gastrocnemius motoneurons. Primary repair or peripheral nerve grafting supported regeneration of 53-60% of the spinal motoneurons and 47-49% of the muscular DRG neurons at 13 weeks postoperatively. In the cutaneous DRG neurons, primary repair or peripheral nerve grafting increased survival by 19-30% and promoted regeneration of 46-66% of the cells. The present results suggest that cutaneous DRG neurons are more sensitive to peripheral nerve injury than muscular DRG cells, but that their regenerative capacity does not differ from that of the latter cells. However, the retrograde loss of cutaneous DRG cells taking place despite immediate nerve repair would still limit the recovery of cutaneous sensory functions.

  • 121.
    West, Christian A
    et al.
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi, Anatomi. Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Handkirurgi.
    Davies, Karen A
    Hart, Andrew M
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi, Anatomi. Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Handkirurgi.
    Wiberg, Mikael
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi, Anatomi. Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Handkirurgi.
    Williams, Steve R
    Terenghi, Giorgio
    Volumetric magnetic resonance imaging of dorsal root ganglia for the objective quantitative assessment of neuron death after peripheral nerve injury.2007Inngår i: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 203, nr 1, s. 22-33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prevention of neuron death after peripheral nerve injury is vital to regaining adequate cutaneous innervation density and quality of sensation, and while experimentally proven neuroprotective therapies exist, there lacks suitable clinical outcome measures for translational research. Axotomized dorsal root ganglia (DRG) histologically exhibit volume reduction in proportion to the amount of neuronal death within them. Hence, this study evaluated the validity of using magnetic resonance imaging (MRI) to quantify DRG volume as a proxy measure of cell death. A high-resolution 3D MRI sequence was developed for volumetric quantification of the L4 DRG in the rat sciatic nerve model. An unoperated "control" group (n=4), and a "nerve transection" group (n=6), 4 weeks after axotomy, were scanned. Accuracy and validity of the technique were evaluated by comparison with morphological quantification of DRG volume and stereological counts of surviving neurons (optical fractionator). The technique was precise (coefficient of variation=4.3%), highly repeatable (9% variability), and sensitive (mean 15.0% volume reduction in axotomized ganglia detected with statistical significance: p<0.01). MRI showed strong and highly significant correlation with morphological measures of DRG volume loss (r=0.90, p<0.001), which in turn correlated well with neuron loss (r=0.75, p<0.05). MRI similarly exhibited direct correlation with neuron loss (r=0.67, p<0.05) with consistent agreement. MRI volumetric quantification of DRG is therefore a valid in vivo measure of neuron loss. As a non-invasive, objective measure of neuronal death after nerve trauma this technique has potential as a diagnostic modality and a quantitative tool for clinical studies of neuroprotective agents.

  • 122.
    West, Christian A
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Blond McIndoe Research Laboratories, University of Manchester, Manchester, UK.
    Hart, Adrew M
    Terenghi, Giorgio
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Analysis of the dose-response of N-acetylcysteine in the prevention of sensory neuronal loss after peripheral nerve injury2007Inngår i: How to Improve the Results of Peripheral Nerve Surgery / [ed] H. Millesi, R. Schmidhammer, Springer, 2007, Vol. 100, s. 29-31Kapittel i bok, del av antologi (Annet vitenskapelig)
    Abstract [en]

    BACKGROUND: N-Acetylcysteine (NAC) is a safe pharmaceutical agent known to protect cells from oxidative damage. Following peripheral nerve transection, NAC has been found to eliminate sensory neuronal loss. This study examines the dose-response relationship of NAC in preventing neuronal death. METHODS AND FINDINGS: The rat sciatic nerve transection model was used, and stereological quantification of sensory neuron survival carried out at two weeks post-axotomy. NAC was administered systemically as an intraperitoneal injection to five groups of rats at a range of doses (1-300 mg/kg/day). Significant neuronal loss was observed in the 1 mg/kg/day dosage group (18.5% loss, p = 0.067 vs. sham treatment). A degree of neuroprotection occurred with 10 mg/kg/day (9.1% loss, p &lt; 0.005 vs. control), whilst there was no significant loss with either 150 or 300 mg/kg/day. CONCLUSIONS: The prevention of sensory neuronal loss with NAC is dose dependent and effective over a wide therapeutic range. This analysis confirms the efficacy of systemic administration and provides a dose framework with which NAC has clinical potential to improve outcome after peripheral nerve trauma.

  • 123.
    West, Christian Alexander
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Ljungberg, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Hart, Andrew
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Plastic Surgery Research, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom, Canniesburn Plastic Surgery Unit, Scottish National Brachial Plexus Service, Glasgow Royal Infirmary, Glasgow, United Kingdom.
    Sensory neuron death after upper limb nerve injury and protective effect of repair: clinical evaluation using volumetric magnetic resonance imaging of dorsal root Ganglia.2013Inngår i: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 73, nr 4, s. 632-640Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Extensive death of sensory neurons after nerve trauma depletes the number of regenerating neurons, contributing to inadequate cutaneous innervation density and poor sensory recovery. Experimentally proven neuroprotective neoadjuvant drugs require noninvasive in vivo measures of neuron death to permit clinical trials. In animal models of nerve transection, magnetic resonance imaging (MRI) proved a valid tool for quantifying sensory neuron loss within dorsal root ganglia (DRG) by measuring consequent proportional shrinkage of respective ganglia.

    OBJECTIVE: This system is investigated for clinical application after upper limb nerve injury and microsurgical nerve repair.

    METHODS: A 3-T clinical magnet was used to image and measure volume (Cavalieri principle) of C7-T1 DRG in uninjured volunteers (controls, n = 14), hand amputees (unrepaired nerve injury, n = 5), and early nerve repair patients (median and ulnar nerves transected, microsurgical nerve repair within 24 hours, n = 4).

    RESULTS: MRI was well tolerated. Volumetric analysis was feasible in 74% of patients. A mean 14% volume reduction was found in amputees' C7 and C8 DRG (P < .001 vs controls). Volume loss was lower in median and ulnar nerve repair patients (mean 3% volume loss, P < .01 vs amputees), and varied among patients. T1 DRG volume remained unaffected.

    CONCLUSION: MRI provides noninvasive in vivo assessment of DRG volume as a proxy clinical measure of sensory neuron death. The significant decrease found after unrepaired nerve injury provides indirect clinical evidence of axotomy-induced neuronal death. This loss was less after nerve repair, indicating a neuroprotective benefit of early repair. Volumetric MRI has potential diagnostic applications and is a quantitative tool for clinical trials of neuroprotective therapies.

  • 124.
    West, Christian Alexander
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    McKay Hart, Andrew
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Terenghi, Giorgio
    Manchester University.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Sensory Neurons of the Human Brachial Plexus: A Quantitative Study Employing Optical Fractionation and In-Vivo Volumetric Magnetic Resonance Imaging.2012Inngår i: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 70, nr 5, s. 1183-1194Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Extensive neuron death following peripheral nerve trauma is implicated in poor sensory recovery. Translational research for experimentally proven neuroprotective drugs requires knowledge of the numbers and distribution of sensory neurons in the human upper limb, and a novel non-invasive clinical measure of neuron loss. OBJECTIVE: To compare optical fractionation and volumetric MRI of dorsal root ganglia (DRG) in histological quantification and objective clinical assessment of human brachial plexus sensory neurons. METHODS: Bilateral C5-T1 DRG were harvested from 5 human cadavers for stereological volume measurement and sensory neuron counts (optical fractionator). MRI scans were obtained from 14 normal volunteers for volumetric analysis of C5-T1 DRG. RESULTS: 425,409 (SD 15,596) sensory neurons innervate the brachial plexus with a significant difference in neuron counts and DRG volume between segmental levels (p<0.0001), with C7 ganglion containing the most. DRG volume correlated with neuron counts (r=0.75, p<.001). Vertebral artery pulsation hindered C5&6 imaging, yet high resolution MRI of C7, C8 and T1 DRG permitted unbiased volume measurement. In accord with histological analysis, MRI confirmed a significant difference between C7, C8 and T1 DRG volume (p<.001), inter-individual variability (COV 15.3%), and sex differences (p=.04). Slight right-left (R/L) sided disparity in neuron counts (2.5%, p=.04) was possibly related to hand dominance, but no significant volume disparity existed. CONCLUSION: Neuron counts for the human brachial plexus are presented. These correlate with histological DRG volumes and concur with volumetric MRI results in human volunteers. Volumetric MRI of C7-T1 DRG is a legitimate non-invasive proxy measure of sensory neurons for clinical study.

  • 125.
    Wiberg, Mikael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Backman, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Wahlström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Dahlin, Lars B
    Plexus brachialis-skador hos vuxna: Tidig nervreparation ger bättre kliniskt slutresultat2009Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, nr 9, s. 586-590Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [sv]

    Unga personer kan drabbas av skador på plexus brachialis – armens nervfläta – vid högenergitrauma.

    Medicinsk prioritering av patientens samtliga skador för adekvata åtgärder ska alltid göras vid stort trauma.

    Noggrann och tidig, eventuellt upprepad, klinisk neurologisk diagnostik kompletterad med tex MRI, DT-myelografi och neurofysiologiska undersökningar ska göras för att kartlägga plexusskadan.

    Neurobiologisk forskning visar att celldöd kan minskas och nervutväxt förbättras vid tidig nervreparation.

    Olika reparations- och rekonstruktionstekniker används beroende på plexusskadans omfattning och lokalisation.

    Tidig kirurgi och rekonstruktion vid plexusskador förbättrar det kliniska slutresultatet.

    Rehabiliteringen är omfattande och inkluderar ett adekvat omhändertagande av smärtproblematik.

  • 126.
    Wiberg, Rebecca
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    An exploration of the mechanisms behind peripheral nerve injury2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Despite surgical innovation, the sensory and motor outcome after peripheral nerve injury is incomplete. In this thesis, the biological pathways potentially responsible for the poor functional recoveries were investigated in both the distal nerve stump/target organ, spinal motoneurons and dorsal root ganglia (DRG). The effect of delayed nerve repair was determined in a rat sciatic nerve transection model. There was a dramatic decline in the number of regenerating motoneurons and myelinated axons found in the distal nerve stumps of animals undergoing nerve repair after a delay of 3 and 6 months. RT-PCR of the distal nerve stumps showed a decline in expression of Schwann cells (SC) markers, with a progressive increase in fibrotic and proteoglycan scar markers, with increased delayed repair time. Furthermore, the yield of SC which could be isolated from the distal nerve segments progressively fell with increased delay in repair time. Consistent with the impaired distal nerve stumps the target medial gastrocnemius (MG) muscles at 3- and 6-months delayed repair were atrophied with significant declines in wet weights (61% and 27% compared with contralateral sides). The role of myogenic transcription factors, muscle specific microRNAs and musclespecific E3 ubiquitin ligases in the muscle atrophy was investigated in both gastrocnemius and soleus muscles following either crush or nerve transection injury. In the crush injury model, the soleus muscle showed significantly increased recovery in wet weight at days 14 and 28 (compared with day 7) which was not the case for the gastrocnemius muscle which continued to atrophy. There was a significantly more pronounced up-regulation of MyoD expression in the denervated soleus muscle compared with the gastrocnemius muscle. Conversely, myogenin was more markedly elevated in the gastrocnemius versus soleus muscles. The muscles also showed significantly contrasting transcriptional regulation of the microRNAs miR-1 and miR-206. MuRF1 and Atrogin-1 showed the highest levels of expression in the denervated gastrocnemius muscle. Morphological and molecular changes in spinal motoneurons were compared after L4-L5 ventral root avulsion (VRA) and distal peripheral nerve axotomy (PNA). Neuronal degeneration was indicated by decreased immunostaining for microtubule-associated protein-2 in dendrites and synaptophysin in presynaptic boutons after both VRA and PNA. Immunostaining for ED1-reactive microglia and GFAPpositive astrocytes was significantly elevated in all experimental groups. qRT-PCR analysis and Western blotting of the ventral horn from L4-L5 spinal cord segments revealed a significant upregulation of apoptotic cell death mediators including caspases-3 and -8 and a range of related death receptors following VRA. In contrast, following PNA, only caspase-8 was moderately upregulated. The mechanisms of primary sensory neuron degeneration were also investigated in the DRG following peripheral nerve axotomy, where several apoptotic pathways including those involving the endoplasmic reticulum were shown to be upregulated. In summary, these results show that the critical time point after which the outcome of regeneration becomes too poor appears to be 3-months. Both proximal and distal injury affect spinal motoneurons morphologically, but VRA induces motoneuron degeneration mediated through both intrinsic and extrinsic apoptotic pathways. Primary sensory neuron degeneration involves several different apoptotic pathways, including the endoplasmic reticulum.

  • 127.
    Wiberg, Rebecca
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Jonsson, Samuel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikova, Liudmila N.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Investigation of the Expression of Myogenic Transcription Factors, microRNAs and Muscle-Specific E3 Ubiquitin Ligases in the Medial Gastrocnemius and Soleus Muscles following Peripheral Nerve Injury2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 12, artikkel-id e0142699Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite surgical innovation, the sensory and motor outcome after a peripheral nerve injury remains incomplete. One contributing factor to the poor outcome is prolonged denervation of the target organ, leading to apoptosis of both mature myofibres and satellite cells with subsequent replacement of the muscle tissue with fibrotic scar and adipose tissue. In this study, we investigated the expression of myogenic transcription factors, muscle specific microRNAs and muscle-specific E3 ubiquitin ligases at several time points following denervation in two different muscles, the gastrocnemius (containing predominantly fast type fibres) and soleus (slow type) muscles, since these molecules may influence the degree of atrophy following denervation. Both muscles exhibited significant atrophy (compared with the contra-lateral sides) at 7 days following either a nerve transection or crush injury. In the crush model, the soleus muscle showed significantly increased muscle weights at days 14 and 28 which was not the case for the gastrocnemius muscle which continued to atrophy. There was a significantly more pronounced up-regulation of MyoD expression in the denervated soleus muscle compared with the gastrocnemius muscle. Conversely, myogenin was more markedly elevated in the gastrocnemius versus soleus muscles. The muscles also showed significantly contrasting transcriptional regulation of the microRNAs miR-1 and miR-206. MuRF1 and Atrogin-1 showed the highest levels of expression in the denervated gastrocnemius muscle. This study provides further insights regarding the intracellular regulatory molecules that generate and maintain distinct patterns of gene expression in different fibre types following peripheral nerve injury.

  • 128.
    Wiberg, Rebecca
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikova, Liudmila
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    A Morphological and Molecular Characterization of the Spinal Cord after Ventral Root Avulsion or Distal Peripheral Nerve Axotomy Injuries in Adult Rats2017Inngår i: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 34, nr 3, s. 652-660Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Retrograde cell death in sensory dorsal root ganglion cells following peripheral nerve injury is well established. However, available data regarding the underlying mechanism behind injury induced motoneuron death are conflicting. By comparing morphological and molecular changes in spinal motoneurons after L4-L5 ventral root avulsion (VRA) and distal peripheral nerve axotomy (PNA) 7 and 14 days postoperatively, we aimed to gain more insight about the mechanism behind injury-induced motoneuron degeneration. Morphological changes in spinal cord were assessed by using quantitative immunohistochemistry. Neuronal degeneration was revealed by decreased immunostaining for microtubuleassociated protein-2 in dendrites and synaptophysin in presynaptic boutons after both VRA and PNA. Significant motoneuron atrophy was already observed at 7 days post-injury, independently of injury type. Immunostaining for ED1 reactive microglia was significantly elevated in all experimental groups, as well as the astroglial marker glial fibrillary acidic protein (GFAP). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of the ventral horn from L4-L5 spinal cord segments revealed a significant upregulation of genes involved in programmed cell death including caspase-3, caspase-8, and related death receptors TRAIL-R, tumor necrosis factor (TNF)-R, and Fas following VRA. In contrast, following PNA, caspase-3 and the death receptor gene expression levels did not differ from the control, and there was only a modest increased expression of caspase-8. Moreover, the altered gene expression correlated with protein changes. These results show that the spinal motoneurons reacted in a similar fashion with respect to morphological changes after both proximal and distal injury. However, the increased expression of caspase-3, caspase-8, and related death receptors after VRA suggest that injury- induced motoneuron degeneration is mediated through an apoptotic mechanism, which might involve both the intrinsic and the extrinsic pathways.

  • 129.
    Wilson, Andrew D H
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Hart, Andrew
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Terenghi, Giorgio
    Blond McIndoe Research Laboratory, Plastic and Reconstructive Surgery Research, University of Manchester, Manchester, UK.
    Delayed acetyl-L-carnitine administration and its effect on sensory neuronal rescue after peripheral nerve injury.2008Inngår i: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1532-1959, Vol. 60, nr 2, s. 114-118Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Protection of sensory neurons after peripheral nerve injury is clinically crucial since inadequate sensory recovery is seriously affected by the death of up to 40% of sensory neurons. Immediate acetyl-L-carnitine (ALCAR) treatment eliminates this cell loss, but may not always be clinically feasible, hence we studied the effect of delaying the initiation of ALCAR treatment. Five groups of rats (n=5 per group) underwent unilateral sciatic nerve axotomy. ALCAR treatment (50 mg/kg/day) was initiated immediately, or after delays of 6 h, 24 h or 7 days after injury. A sham-treated group served as control. L4 and L5 dorsal root ganglia were harvested bilaterally 2 weeks after injury and stereological sensory neuron counts were obtained. Immediate sham treatment provided no neuroprotection (25% loss). Cell loss was eliminated when ALCAR was commenced within

  • 130.
    Wilson, Andrew D H
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. University Department of Surgery, Blond McIndoe Centre, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
    Hart, Andrew
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi. University Department of Surgery, Blond McIndoe Centre, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Terenghi, Giorgio
    University Department of Surgery, Blond McIndoe Centre, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
    Primary sensory neuronal rescue with systemic acetyl-L-carnitine following peripheral axotomy. A dose-response analysis2003Inngår i: British Journal of Plastic Surgery, ISSN 0007-1226, E-ISSN 1465-3087, Vol. 56, nr 8, s. 732-739Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The loss of a large proportion of primary sensory neurons after peripheral nerve axotomy is well documented. As a consequence of this loss, the innervation density attained on completion of regeneration will never be normal, regardless of how well the individual surviving neurons regenerate. Acetyl-L-carnitine (ALCAR), an endogenous peptide in man, has been demonstrated to protect sensory neurons, thereby avoiding loss after peripheral nerve injury. In this study we examined the dose-response effect of ALCAR on the primary sensory neurons in the rat dorsal root ganglia (DRG) 2 weeks after sciatic nerve axotomy. Six groups of adult rats (n=5) underwent unilateral sciatic nerve axotomy, without repair, followed by 2 weeks systemic treatment with one of five doses of ALCAR (range 0.5-50 mg/kg/day), or normal saline. L4 and L5 dorsal root ganglia were then harvested bilaterally and sensory neuronal cell counts obtained using the optical disector technique. ALCAR eliminated neuronal loss at higher doses (50 and 10 mg/kg/day), while lower doses did result in loss (12% at 5 mg/kg/day, p<0.05; 19% at 1 mg/kg/day, p<0.001; 23% at 0.5 mg/kg/day, p<0.001) compared to contralateral control ganglia. Treatment with normal saline resulted in a 25% (p<0.001) loss, demonstrating no protective effect in accordance with previous studies.ALCAR preserves the sensory neuronal cell population after axotomy in a dose-responsive manner and as such, has potential for improving the clinical outcome following peripheral nerve trauma when doses in excess of 10 mg/kg/day are employed.

  • 131.
    Wilson, Andrew D H
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Hart, Andrew
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Terenghi, Giorgio
    Blond McIndoe Research Laboratories, Tissue Injury and Repair Group, University of Manchester, Room 3.106 Stopford Building, Oxford Road, Manchester M13 9PT, UK.
    Acetyl-l-carnitine increases nerve regeneration and target organ reinnervation: A morphological study2010Inngår i: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1532-1959, Journal of plastic, reconstructive & aesthetic surgery : JPRAS, ISSN 1878-0539, Vol. 63, nr 7, s. 1186-1195Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Peripheral nerve injury frequently results in functional morbidity since standard management fails to adequately address many of the neurobiological hurdles to optimal regeneration. Neuronal survival and regeneration are neurotrophin dependent and require increased aerobic capacity. Acetyl-l-carnitine (ALCAR) facilitates this need and prevents neuronal loss. ALCAR is clinically safe and is shown here to significantly improve nerve regeneration and target organ reinnervation. Two groups of five rats underwent sciatic nerve division followed by immediate repair. One group received parenteral ALCAR (50mg/kg/day) from time of operation until termination at 12 weeks. A 'sham treatment' group received normal saline. A third group was left unoperated and did not receive any treatment. A segment of nerve was harvested between 5mm proximal and 10mm distal to the repair in operated groups, and at the corresponding level in the unoperated group. Mean axonal count in normal, non-axotomised nerve was 14,720 (SD 2378). That of the saline group (17,217 SD 1808) was not significantly different from normal nerve (P=0.0985). Mean number of myelinated axons in the ALCAR group (24,460 SD 3750) was significantly greater than both sham group (P<0.01) and normal nerve (P=0.0012). Mean myelin thickness in the saline treated group (0.408mum SD 0.067mum) was less than normal nerve (0.770mum SD 0.143mum) (P<0.001). Mean myelin thickness in the ALCAR group (0.627mum SD 0.052mum) was greater than the sham (saline) group (P<0.01) and not statistically different from normal nerve (P=0.07). ALCAR increased dermal PGP9.5 staining by 210% compared to sham treatment (P<0.0001) and significantly reduced the mean percentage weight loss in gastrocnemius muscle (ALCAR group 0.203% vs. 0.312% in sham group P=0.015). ALCAR not only increases the number of regenerating nerve fibres but also morphologically improves the quality of regeneration and target organ reinnervation. Adjuvant ALCAR treatment may improve both sensory and motor outcomes and merits further investigation.

  • 132.
    Wåglin, Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Radiological and clinical outcome of scaphoid fractures fixated with the Herbert screw at Östersund county hospital. A case control study of Herbert screw fixations at Östersund county hospital during the years 1985-20132015Independent thesis Basic level (professional degree), 20 poäng / 30 hpOppgave
  • 133.
    Wåglin, Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Radiological and clinical outcome of scaphoid fractures fixated with the Herbert screw at Östersund county hospital.: A case control study of Herbert screw fixations at Östersund county hospital during the years 1985-20132015Independent thesis Basic level (professional degree), 20 poäng / 30 hpOppgave
  • 134.
    Yasa, Kawwa
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Per- och postoperativsmärta vid handkirurgiska ingrepp. Hur mycket smärta upplever patienter under ett handkirurgiskt ingrepp och de tre första postoperativa dagarna?2014Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
  • 135. Zetlitz, Elisabeth
    et al.
    Wearing, Scott Cameron
    Nicol, Alexander
    Mackay Hart, Andrew
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Objective Assessment of Surgical Training in Flexor Tendon Repair: The Utility of a Low-Cost Porcine Model as Demonstrated by a Single-Subject Research Design2012Inngår i: Journal of Surgical Education, ISSN 1931-7204, Vol. 69, nr 4, s. 504-510Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: This study evaluated the utility of a porcine flexor tendon model and standard biomechanical testing procedures to quantify the acquisition of surgical skills associated with Zone II flexor tendon repair in a trainee by benchmarking task performance outcomes relative to evidence-based standards. STUDY DESIGN: Single-subject repeated measures research design. Bench-top set-up of apparatus undertaken in a University Research laboratory. After initial directed learning, a trainee repaired 70 fresh flexor digitorum profundus tendons within the flexor sheath using either a Pennington or ventral-locking-loop modification of a two-strand Kessler core repair. Tendon repairs were then preconditioned and distracted to failure. Key biomechanical parameters of the repair, including the ultimate tensile strength (UTS), yield strength, 3 mm gap force and stiffness, were calculated. Repairs were divided into 3 categories, early (first 10 days), intermediate (ensuing 10 days), and late repairs (final 10 days), and potential changes in repair properties over the training period were evaluated using a general linear modeling approach. RESULTS: There was a significant change in the mechanical characteristics of the repairs over the training period, evidencing a clear learning effect (p < 0.05). Irrespective of the repair technique employed, early and intermediate repairs were characterized by a significantly lower UTS (29% and 20%, respectively), 3 mm gap (21% and 16%, respectively), and yield force (18% and 23%, respectively), but had a higher stiffness (33% and 38%, respectively) than late repairs (p < 0.05). The UTS of late repairs (47-48 N) were comparable to those published within the literature (45-51 N), suggesting surgical competence of the trainee. CONCLUSIONS: This simple, low-cost porcine model appears to be useful for providing preclinical training in flexor tendon repair techniques and has the potential to provide a quantitative index to evaluate the competency of surgical trainees. Further research is now required to identify optimal training parameters for flexor tendon repair and to develop procedure-specific standards for adequate benchmarking.

  • 136.
    Zhang, Cheng-Gang
    et al.
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi, Anatomi.
    Ma, Jian-Jun
    Terenghi, Giorgio
    Mantovani, Cristina
    Wiberg, Mikael
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi, Anatomi. Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Handkirurgi.
    Phrenic nerve transfer in the treatment of brachial plexus avulsion: an experimental study of nerve regeneration and muscle morphology in rats.2004Inngår i: Microsurgery, ISSN 0738-1085, E-ISSN 1098-2752, Vol. 24, nr 3, s. 232-240Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The regeneration of motor and sensory neurons and the morphological changes of the target muscle after phrenic nerve transfer were investigated in adult rats. Six months following nerve transfer, 326.0 +/- 16.31 phrenic motoneurons regenerated into musculocutaneous nerve, which is not different from the normal number of phrenic motoneurons. The regenerated motoneurons exhibited a 14% nonsignificant hypertrophy. Of the dorsal root ganglia (DRG) neurons, 255.8 +/- 45.26 regenerated, which was significantly lower than the number of normal phrenic DRG neurons. The regenerated phrenic DRG neurons showed a 24% close-to-significant atrophy. The target muscle fiber morphology changed considerably after reinnervation. The present results suggest that the phrenic nerve has very good regenerative ability in terms of its motoneurons and a relatively insufficient sensory neuronal regeneration.

  • 137. Zhang, Cheng-Gang
    et al.
    Welin, Dag
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikov, Lev
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kellerth, Jan-Olof
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Hart, Andrew McKay
    Motorneuron protection by N-acetyl-cysteine after ventral root avulsion and ventral rhizotomy2005Inngår i: British Journal of Plastic Surgery, ISSN 0007-1226, E-ISSN 1465-3087, Vol. 58, nr 6, s. 765-773Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Motor recovery after proximal nerve injury remains extremely poor, despite advances in surgical care. Several neurobiological hurdles are implicated, the most fundamental being extensive cell death within the motorneuron pool. N-acetyl-cysteine almost completely protects sensory neurons after peripheral axotomy, hence its efficacy in protecting motorneurons after ventral root avulsion/rhizotomy was investigated. In adult rats, the motorneurons supplying medial gastrocnemius were unilaterally pre-labelled with retrograde tracer (true-blue/fluoro-gold), prior to L5 and 6 ventral root avulsion, or rhizotomy. Groups received either intraperitoneal N-acetyl-cysteine (ip, 150 or 750 mg/kg/day), immediate or delayed intrathecal N-acetyl-cysteine treatment (it, 2.4 mg/day), or saline; untreated animals served as controls. Either 4 (avulsion model) or 8 (rhizotomy model) weeks later, the pre-labelled motorneurons' mean soma area and survival were quantified. Untreated controls possessed markedly fewer motorneurons than normal due to cell death (avulsion 53% death; rhizotomy 26% death, P<0.01 vs. normal). Motorneurons were significantly protected by N-acetyl-cysteine after avulsion (ip 150 mg/kg/day 40% death; it 30% death, P<0.01 vs. no treatment), but particularly after rhizotomy (ip 150 mg/kg/day 17% death; ip 750 mg/kg/day 7% death; it 5% death, P<0.05 vs. no treatment). Delaying intrathecal treatment for 1 week after avulsion did not impair neuroprotection, but a 2-week delay was deleterious (42% death, P<0.05 vs. 1-week delay, 32% death). Treatment prevented the decrease in soma area usually found after both types of injury. N-acetyl-cysteine has considerable clinical potential for adjuvant treatment of major proximal nerve injuries, including brachial plexus injury, in order that motorneurons may survive until surgical repair facilitates regeneration.

  • 138.
    Åberg, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Ljungberg, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Edin, E
    Jenmalm, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Millqvist, H
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Nordh, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurofysiologi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Considerations in evaluating new treatment alternatives following peripheral nerve injuries: a prospective clinical study of methods used to investigate sensory, motor and functional recovery.2007Inngår i: J Plast Reconstr Aesthet Surg, ISSN 1748-6815, Vol. 60, nr 2, s. 103-13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The current problem finding reliable and objective methods for evaluating results after peripheral nerve repair is a challenge when introducing new clinical techniques. The aim of this study was to obtain reference material and to evaluate the applicability of different tests used for clinical assessment after peripheral nerve injuries. Fifteen patients with a history of complete median nerve transsection and repair, and 15 healthy volunteers were included. Each subject was investigated using a battery of conventional and new tests for functional, sensory and motor recovery including questionnaires, clinical evaluations, neurophysiological and physiological findings. The results were statistically analysed and comparisons were made within the patient group and between patients and healthy volunteers using a 'per protocol' and an 'intention to treat' approach. Criteria for success were stipulated in order to be able to judge the usefulness of each method. The results showed that 19 of 34 variables, representing six of 16 methods, were not able to fulfil the criteria and were thus questionable for the evaluations of nerve repair in a clinical trial setting. However, 2pd, sensory recovery according to the non-modified British Medical Research Council, sensory neurography, manual muscle test, electromyography, questionnaires (i.e. DASH and the 4 question form) and performance tests (i.e. AMPS and Sollerman's subtests 4 and 8) did fulfil the criteria defined for being useful.

  • 139.
    Åberg, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Ljungberg, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Edin, Ellenor
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Millqvist, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Nordh, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurofysiologi.
    Theorin, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Terenghi, Giorgio
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Clinical evaluation of a resorbable wrap-around implant as an alternative to nerve repair: A prospective, assessor-blinded, randomised clinical study of sensory, motor and functional recovery after peripheral nerve repair.2009Inngår i: Journal of plastic, reconstructive & aesthetic surgery : JPRAS, ISSN 1748-6815, Vol. 62, nr 11, s. 1503-1509Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Peripheral nerve injures are common and often result in impaired functional recovery. The majority of injuries involve the arm and/or the hand. The traditional treatment for peripheral nerve injuries is repair by using microsurgical techniques, either by primary nerve suture or nerve graft, but research to find more successful methods that could improve recovery is ongoing. Tubulisation has been investigated by several authors and is suggested as an alternative to microsurgical techniques. The resorbable poly[(R)-3-hydroxybutyrate] (PHB) is one of the materials that has been previously tested experimentally. In this prospective, randomised, assessor-blinded clinical study, PHB was investigated as an alternative to epineural suturing in the treatment of peripheral nerve injuries at the wrist/forearm level of the arm. Twelve patients, with a complete, common, sharp injury of the median and/or ulnar nerve at the wrist/forearm level, were treated by either using PHB or microsurgical epineural end-to-end suturing. All patients were assessed using a battery of tests, including evaluation of functional, sensory and motor recovery by means of clinical, neurophysiological, morphological and physiological evaluations at 2 weeks and 3, 6, 9, 12 and 18 months after surgery. No adverse events or complications considered as product related were reported, and thus PHB can be regarded as a safe alternative for microsurgical epineural suturing. The majority of the methods in the test battery showed no significant differences between the treatment groups, but one should consider that the study involved a limited number of patients and a high variability was reported for the evaluating techniques. However, sensory recovery, according to the British Medical Research Council score and parts of the manual muscle test, suggested that treating with PHB may be advantageous as compared to epineural suturing. This, however, should be confirmed by large-scale efficacy studies.

123 101 - 139 of 139
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