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  • 501.
    Jones, Iwan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Novikova, Liudmila N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Renardy, Monika
    Ullrich, Andreas
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Regenerative effects of human embryonic stem cell-derived neural crest cells for treatment of peripheral nerve injury2018In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 12, no 4, p. E2099-E2109Article in journal (Refereed)
    Abstract [en]

    Surgical intervention is the current gold standard treatment following peripheral nerve injury. However, this approach has limitations, and full recovery of both motor and sensory modalities often remains incomplete. The development of artificial nerve grafts that either complement or replace current surgical procedures is therefore of paramount importance. An essential component of artificial grafts is biodegradable conduits and transplanted cells that provide trophic support during the regenerative process. Neural crest cells are promising support cell candidates because they are the parent population to many peripheral nervous system lineages. In this study, neural crest cells were differentiated from human embryonic stem cells. The differentiated cells exhibited typical stellate morphology and protein expression signatures that were comparable with native neural crest. Conditioned media harvested from the differentiated cells contained a range of biologically active trophic factors and was able to stimulate in vitro neurite outgrowth. Differentiated neural crest cells were seeded into a biodegradable nerve conduit, and their regeneration potential was assessed in a rat sciatic nerve injury model. A robust regeneration front was observed across the entire width of the conduit seeded with the differentiated neural crest cells. Moreover, the up-regulation of several regeneration-related genes was observed within the dorsal root ganglion and spinal cord segments harvested from transplanted animals. Our results demonstrate that the differentiated neural crest cells are biologically active and provide trophic support to stimulate peripheral nerve regeneration. Differentiated neural crest cells are therefore promising supporting cell candidates to aid in peripheral nerve repair.

  • 502.
    Jones, Iwan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Yelhekar, Tushar D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wiberg, Rebecca
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Johansson, Staffan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Development and validation of an in vitro model system to study peripheral sensory neuron development and injury2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 15961Article in journal (Refereed)
    Abstract [en]

    The ability to discriminate between diverse types of sensation is mediated by heterogeneous populations of peripheral sensory neurons. Human peripheral sensory neurons are inaccessible for research and efforts to study their development and disease have been hampered by the availability of relevant model systems. The in vitro differentiation of peripheral sensory neurons from human embryonic stem cells therefore provides an attractive alternative since an unlimited source of biological material can be generated for studies that specifically address development and injury. The work presented in this study describes the derivation of peripheral sensory neurons from human embryonic stem cells using small molecule inhibitors. The differentiated neurons express canonical- and modality-specific peripheral sensory neuron markers with subsets exhibiting functional properties of human nociceptive neurons that include tetrodotoxin-resistant sodium currents and repetitive action potentials. Moreover, the derived cells associate with human donor Schwann cells and can be used as a model system to investigate the molecular mechanisms underlying neuronal death following peripheral nerve injury. The quick and efficient derivation of genetically diverse peripheral sensory neurons from human embryonic stem cells offers unlimited access to these specialised cell types and provides an invaluable in vitro model system for future studies.

  • 503. Jones, Sari
    et al.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Sandblom, Johan
    Stigsdotter Neely, Anna
    Ingvar, Martin
    Magnus Petersson, Karl
    Bäckman, Lars
    Cognitive and neural plasticity in aging: general and task-specific limitations.2006In: Neuroscience Biobehavioral Reviews, ISSN 0149-7634, Vol. 30, no 6, p. 864-71Article in journal (Other academic)
    Abstract [en]

    There is evidence for cognitive as well as neural plasticity across the adult life span, although aging is associated with certain constraints on plasticity. In the current paper, we argue that the age-related reduction in cognitive plasticity may be due to (a) deficits in general processing resources, and (b) failure to engage in task-relevant cognitive operations. Memory-training research suggests that age-related processing deficits (e.g., executive functions, speed) hinder older adults from utilizing mnemonic techniques as efficiently as the young, and that this age difference is reflected by diminished frontal activity during mnemonic use. Additional constraints on memory plasticity in old age are related to difficulties that are specific to the task, such as creating visual images, as well as in binding together the information to be remembered. These deficiencies are paralleled by reduced activity in occipito-parietal and medial-temporal regions, respectively. Future attempts to optimize intervention-related gains in old age should consider targeting both general processing and task-specific origins of age-associated reductions in cognitive plasticity.

  • 504.
    Jonsson, Bert
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Karlsson, Linnea
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Lithner, Johan
    Umeå University, Faculty of Science and Technology, Umeå Mathematics Education Research Centre (UMERC). Umeå University, Faculty of Science and Technology, Department of Science and Mathematics Education.
    Liljekvist, Yvonne
    Karlstad University.
    Norqvist, Mathias
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Science and Technology, Department of Science and Mathematics Education.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Mathematical Teaching Method affects Performance and Brain Activity2012Conference paper (Refereed)
  • 505.
    Jonsson, Bert
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Stigsdotter Neely, Anna
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Working memory training in children with special education needs: A pilot study2008Conference paper (Other academic)
  • 506.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Byström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Davidson, Alice E.
    UCL Institute of Ophthalmology, London, UK.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kellgren, Therese
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Tuft, Stephen J.
    UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK.
    Koskela, Timo
    Koskelas Eye Clinic, Umeå, Sweden.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Hardcastle, Alison J.
    UCL Institute of Ophthalmology, London, UK.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED)2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 4, p. 463-473Article in journal (Refereed)
    Abstract [en]

    Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.

  • 507.
    Jonsson, Kent-Olov
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    Holt, Sandra
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Integrative Medical Biology. Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    The endocannabinoid system: current pharmacological research and therapeutic possibilities.2006In: Basic Clin Pharmacol Toxicol, ISSN 1742-7835, Vol. 98, no 2, p. 124-34Article in journal (Refereed)
  • 508.
    Jonsson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Linköping University.
    Norrgard, Orjan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Epithelial Expression of Vasoactive Intestinal Peptide in Ulcerative Colitis: Down-Regulation in Markedly Inflamed Colon2012In: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 57, no 2, p. 303-310Article in journal (Refereed)
    Abstract [en]

    Vasoactive intestinal peptide (VIP) has a number of important effects in intestinal physiology and pathology, including in ulcerative colitis (UC). The expression patterns of the predominant VIP receptor in the mucosa (the VPAC1 receptor) are unknown for the mucosa in UC. It is assumed that the sources of VIP in the intestine are the innervation and the inflammatory cells. The VIP and VPAC1 receptor expression patterns in the epithelial layer of UC and non-UC patients were examined in the present study. The influence of marked inflammation of the mucosa was evaluated. Specimens of the human colon, including the colon of UC patients, were examined concerning expressions of VIP and VPAC1 receptor, focusing on the epithelial layer. Immunohistochemistry and in situ hybridization were utilized. There were VIP mRNA reactions and also marked VPAC1 receptor immunoreactions in the normal and slightly/moderately affected epithelium. VIP mRNA reactions were not detected and VPAC1 immunoreactions were minimal in response to marked mucosal derangement. The findings suggest that there is a local production of VIP in the epithelial cells in normal and slightly/moderately inflamed mucosa but not in severely inflamed mucosa. Furthermore, a marked downregulation in VPAC1 receptor expressions occurs in the epithelium in severe UC. Based on the knowledge that VIP can have trophic, healing and anti-inflammatory effects, it is likely that the decrease in VIP mRNA and VPAC1 receptor reactions seen in severely affected mucosa in UC may be associated with adverse effects on intestinal function.

  • 509.
    Jonsson, Samuel
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Rebecca
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    McGrath, Aleksandra M
    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.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Effect of delayed peripheral nerve repair on nerve regeneration, Schwann cell function and target muscle recovery2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, article id e56484Article in journal (Refereed)
    Abstract [en]

    Despite advances in surgical techniques for peripheral nerve repair, functional restitution remains incomplete. The timing of surgery is one factor influencing the extent of recovery but it is not yet clearly defined how long a delay may be tolerated before repair becomes futile. In this study, rats underwent sciatic nerve transection before immediate (0) or 1, 3, or 6 months delayed repair with a nerve graft. Regeneration of spinal motoneurons, 13 weeks after nerve repair, was assessed using retrograde labeling. Nerve tissue was also collected from the proximal and distal stumps and from the nerve graft, together with the medial gastrocnemius (MG) muscles. A dramatic decline in the number of regenerating motoneurons and myelinated axons in the distal nerve stump was observed in the 3- and 6-months delayed groups. After 3 months delay, the axonal number in the proximal stump increased 2-3 folds, accompanied by a smaller axonal area. RT-PCR of distal nerve segments revealed a decline in Schwann cells (SC) markers, most notably in the 3 and 6 month delayed repair samples. There was also a progressive increase in fibrosis and proteoglycan scar markers in the distal nerve with increased delayed repair time. The yield of SC isolated from the distal nerve segments progressively fell with increased delay in repair time but cultured SC from all groups proliferated at similar rates. MG muscle at 3- and 6-months delay repair showed a significant decline in weight (61% and 27% compared with contra-lateral side). Muscle fiber atrophy and changes to neuromuscular junctions were observed with increased delayed repair time suggestive of progressively impaired reinnervation. This study demonstrates that one of the main limiting factors for nerve regeneration after delayed repair is the distal stump. The critical time point after which the outcome of regeneration becomes too poor appears to be 3-months.

  • 510.
    Josefsson, Maria
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Daniels, Michael
    University of Texas at Austin.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Causal inference with longitudinal outcomes and non-ignorable drop-out: Estimating the effect of living alone on cognitive decline2016In: Journal of the Royal Statistic Society, Series C: Applied Statistics, ISSN 0035-9254, E-ISSN 1467-9876, Vol. 65, no 1, p. 131-144Article in journal (Refereed)
    Abstract [en]

    We develop a model to estimate the causal effect of living arrangement (living alone versus living with someone) on cognitive decline based on a 15-year prospective cohort study, where episodic memory function is measured every 5 years. One key feature of the model is the combination of propensity score matching to balance confounding variables between the two living arrangement groups—to reduce bias due to unbalanced covariates at baseline, with a pattern–mixture model for longitudinal data—to deal with non-ignorable dropout. A fully Bayesian approach allows us to convey the uncertainty in the estimation of the propensity score and subsequent matching in the inference of the causal effect of interest. The analysis conducted adds to previous studies in the literature concerning the protective effect of living with someone, by proposing a modelling approach treating living arrangement as an exposure.

  • 511.
    Josefsson, Maria
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Department of Statistics.
    Pudas, Sara
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nilsson, Lars-Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Centre for Population Studies (CPS). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Genetic and lifestyle predictors of 15-Year longitudinal change in episodic memory2012In: Journal of The American Geriatrics Society, ISSN 0002-8614, E-ISSN 1532-5415, Vol. 60, no 12, p. 2308-2312Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To reveal distinct longitudinal trajectories in episodic memory over 15 years and to identify demographic, lifestyle, health-related, and genetic predictors of stability or decline. DESIGN: Prospective cohort study. SETTING: The Betula Project, Umeå, Sweden. PARTICIPANTS: One thousand nine hundred fifty-four healthy participants aged 35 to 85 at baseline. MEASUREMENTS: Memory was assessed according to validated episodic memory tasks in participants from a large population-based sample. Data were analyzed using a random-effects pattern-mixture model that considered the effect of attrition over two to four longitudinal sessions. Logistic regression was used to determine significant predictors of stability or decline relative to average change in episodic memory. RESULTS: Of 1,558 participants with two or more test sessions, 18% were classified as maintainers and 13% as decliners, and 68% showed age-typical average change. More educated and more physically active participants, women, and those living with someone were more likely to be classified as maintainers, as were carriers of the met allele of the catechol-O-methyltransferase gene. Less educated participants, those not active in the labor force, and men were more likely to be classified as decliners, and the apolipoprotein E ɛ4 allele was more frequent in decliners. CONCLUSION: Quantitative, attrition-corrected assessment of longitudinal changes in memory can reveal substantial heterogeneity in aging trajectories, and genetic and lifestyle factors predict such heterogeneity.

  • 512.
    Josefsson, Maria
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Imputation of missing longitudinal fMRI dataManuscript (preprint) (Other academic)
  • 513.
    Jönsson, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    The neuronal and non-neuronal substance P, VIP and cholinergic systems in the colon in ulcerative colitis2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease. Neuropeptides, especially vasoactive intestinal peptide (VIP) and substance P (SP), have long been considered to play key roles in UC. Among other effects, these neuropeptides have trophic and growth-modulating as well as wound-healing effects. Furthermore, whilst VIP has anti-inflammatory properties, SP has pro-inflammatory effects. It is generally assumed that the main source of SP and VIP in the intestine is the tissue innervation. It is not known whether or not they are produced in the epithelial layer. The details concerning the expressions of their receptors in UC are also, to a great extent, unclear. Apart from the occurrence of peptidergic systems in the intestine, there are also neuronal as well as non-neuronal cholinergic systems. The pattern concerning the latter is unknown with respect to UC.

    The studies in this thesis aimed to investigate the expression of SP and VIP and their major receptors (NK-1R and VPAC1) in UC colon, compared to non-UC colon. The main emphasis was devoted to the epithelium. A second aim was to examine for levels of these neuropeptides in blood plasma in UC. Another aim was to examine for the non-neuronal cholinergic system in UC, thus, to investigate whether there is acetylcholine production outside nerves in the UC colon. Methods used in the thesis were immunohistochemistry, in situ hybridization, enzyme immunosorbent assay, and in vitro receptor autoradiography.

    For the first time, mRNA for VIP and SP has here been found in the colonic epithelium. That was especially noted in UC mucosa showing a rather normal morphology, and in non-UC mucosa. Marked derangement of the mucosa was found to lead to a distinct decrease in VIP binding, and also a decrease in the expression level of VIP receptor VPAC1 in the epithelium. In general, there was an upregulation of the SP receptor NK-1R in the epithelium when the mucosa was deranged. The plasma levels of SP and VIP were higher for UC patients compared to healthy controls. There were marked correlations between the levels of the peptides in plasma, their levels in the mucosa and the degree of mucosal derangement/inflammation. A pronounced nonneuronal cholinergic system was found in both UC and non-UC colon. Certain changes occurred in this system in response to inflammation/derangement in UC. The present study shows unexpectedly that expressions for VIP and SP are not only related to the nerve structures and the inflammatory cells. The downregulation of VPAC1 expression, and the tendencies of upregulation of NK-1R expression levels when there is marked tissue derangement, may be a drawback for the intestinal function. The study also shows that there is a marked release of neuropeptides to the bloodstream in parallel with a marked derangement of the mucosa in UC. The cholinergic effects in the UC colon appear not only to be associated with nerverelated effects, but also effects of acetylcholine produced in local non-neuronal cells. The thesis shows that local productions for not only acetylcholine, but also SP and VIP, occur to a larger extent than previously considered.

  • 514.
    Jönsson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Norrgård, Orjan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Presence of a marked nonneuronal cholinergic system in human colon: study of normal colon and colon in ulcerative colitis2007In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 13, no 11, p. 1347-1356Article in journal (Other academic)
    Abstract [en]

    BACKGROUND: The body has not only a neuronal but also a nonneuronal cholinergic system. Both systems are likely to be very important, particularly in inflammatory conditions. The patterns and importance of the nonneuronal cholinergic system in patients with ulcerative colitis (UC) are largely unknown.

    METHODS: The colons of UC and non-UC patients were examined for expression patterns of choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and the muscarinic receptor of the M(2) subtype.

    RESULTS: ChAT and VAChT immunoreactions and mRNA reactions for ChAT were detected in epithelial and endocrine cells, in cells in the lamina propria, and in blood vessel walls. Furthermore, a marked M(2) immunoreaction was noted for epithelium, blood vessel walls, and smooth musculature. ChAT and VAChT immunoreactions were significantly higher in endocrine and epithelial cells, respectively, in non-UC mucosa than in UC mucosa. On the other hand, there was a tendency toward higher M(2) levels in epithelium of UC patients.

    CONCLUSIONS: There is a pronounced nonneuronal cholinergic system in the colon, which has previously been ignored when discussing cholinergic influences in UC. Furthermore, it is evident that certain changes in the nonneuronal cholinergic system occur in response to inflammation/derangement in UC. Cholinergic effects in the colon can be considered to be related not only to nerve-related effects but also to effects of acetylcholine from nonneuronal local cells. Thus, the recently discussed phenomenon of a "cholinergic antiinflammatory pathway" in the intestine may have a pronounced nonneuronal component.

  • 515.
    Jönsson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Norrgård, Orjan
    Hansson, Magnus
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Decrease in binding for the neuropeptide VIP in response to marked inflammation of the mucosa in ulcerative colitis2007In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1107, p. 280-289Article in journal (Other academic)
    Abstract [en]

    The neuropeptide vasoactive intestinal peptide (VIP) is involved in the neuroimmunomodulation of the intestine. In the present study, specimens from the sigmoid colon of ulcerative colitis (UC) and non-UC patients were examined for immunohistochemistry and in vitro receptor autoradiography. Marked occurrence of VIP binding was observed in the mucosa. However, there were very low levels of binding in areas showing pronounced inflammation/derangement. The study shows that marked derangement of the mucosa leads to a distinct decrease in VIP binding. Thus, it is possible that a decrease in trophic and anti-inflammatory VIP effects occurs in areas exhibiting a very marked inflammation.

  • 516.
    Jönsson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Norrgård, Örjan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of mRNA for VIP and Substance P and presence of VPAC1 and NK-1 receptor expressions in the colonic epithelium of man: changed pattern in ulcerative colitisManuscript (Other academic)
    Abstract [en]

     

    The neuropeptides vasoactive intestinal peptide (VIP) and substance P (SP) are considered to be important in ulcerative colitis (UC). It is generally assumed that the main source of VIP and SP in the intestine is the innervation. There is no information concerning whether or not they are produced by cells in the epithelial layer. Concerning UC, there is also a lack of information concerning the VIP-receptor VPAC1 in the epithelium. In the present study, UC and non-UC colon was examined concerning expressions of VIP, SP, VPAC1 and the SP-preferred receptor, neurokinin-1 (NK-1R). Both immunohistochemistry and in situ hybridization were applied. mRNA expression for both VIP and SP were observed in the epithelium. The mRNA reactions were seen in normal and little/moderately affected mucosa. There were very marked VPAC1 immunoreactions in the epithelium, in non-UC mucosa and in little affected UC mucosa. A decrease in VPAC1 immunoreactions was noted in the epithelium in markedly affected UC mucosa. Existence of VIP immunoreaction, VIP mRNA, VPAC1 immunoreaction, SP mRNA, NK-1R immunoreaction and Substance P receptor (TACR1) mRNA was shown for cells in lamina propria and submucosa. The present study shows unexpectedly that mRNA for both VIP and SP are not only expressed in neuronal perikarya and lamina propria and submucosal cells but also in the colonic epithelium, and that marked changes in VPAC1 receptor expressions occur for this layer in severe UC. It is tentative to speculate that autocrine/paracrine VIP and SP effects may occur within the epithelium. The decrease in VPAC1 receptor reactions seen in severely UC affected mucosa may be a drawback for the intestinal function.

     

  • 517.
    Jönsson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Norrgård, Örjan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Kirurgi.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Substance P and the neurokinin-1 receptor in relation to eosinophilia in ulcerative colitis2005In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 26, no 5, p. 799-814Article in journal (Refereed)
    Abstract [en]

    Substance P (SP) has been implicated in the pathophysiology of ulcerative colitis (UC) and it has been suggested that blocking of its effect would be advantageous in this disease. Eosinophils have also been implicated in the pathophysiology of UC. In the present study, specimens from the sigmoid colon of UC patients were investigated by the use of antisera against SP and the neurokinin-1 receptor (NK-1R) and staining for demonstration of eosinophils. The degrees of SP innervation and NK-1R immunoreaction, as well as the levels of eosinophil infiltration, varied between different patients. Interestingly, NK-1R immunoreaction in the epithelium was often seen to be the most marked where there were numerous eosinophils in the underlying mucosa and where the mucosa showed a marked morphologic derangement. The observations suggest that there are marked fluctuations in effects of SP and eosinophils during the disease. The infiltrating eosinophils may be involved in the destruction of the mucosal tissue. Furthermore, for the majority of cases where there is marked derangement of the mucosa, it is apparent that there is an upregulation of the NK-1 receptor in the epithelium in parallel with the infiltration of the eosinophils.

  • 518.
    Kaboodvand, Neda
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
    Bäckman, Lars
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
    The retrosplenial cortex: a memory gateway between the cortical default mode network and the medial temporal lobe2018In: Human Brain Mapping, ISSN 1065-9471, E-ISSN 1097-0193, Vol. 39, no 5, p. 2020-2034Article in journal (Refereed)
    Abstract [en]

    The default mode network (DMN) involves interacting cortical areas, including the posterior cingulate cortex (PCC) and the retrosplenial cortex (RSC), and subcortical areas, including the medial temporal lobe (MTL). The degree of functional connectivity (FC) within the DMN, particularly between MTL and medial-parietal subsystems, relates to episodic memory (EM) processes. However, past resting-state studies investigating the link between posterior DMN-MTL FC and EM performance yielded inconsistent results, possibly reflecting heterogeneity in the degree of connectivity between MTL and specific cortical DMN regions. Animal work suggests that RSC has structural connections to both cortical DMN regions and MTL, and may thus serve as an intermediate layer that facilitates information transfer between cortical and subcortical DMNs. We studied 180 healthy old adults (aged 64-68 years), who underwent comprehensive assessment of EM, along with resting-state fMRI. We found greater FC between MTL and RSC than between MTL and the other cortical DMN regions (e.g., PCC), with the only significant association with EM observed for MTL-RSC FC. Mediational analysis showed that MTL-cortical DMN connectivity increased with RSC as a mediator. Further analysis using a graph-theoretical approach on DMN nodes revealed the highest betweenness centrality for RSC, confirming that a high proportion of short paths among DMN regions pass through RSC. Importantly, the degree of RSC mediation was associated with EM performance, suggesting that individuals with greater mediation have an EM advantage. These findings suggest that RSC forms a critical gateway between MTL and cortical DMN to support EM in older adults.

  • 519.
    Kadi, F
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ahlgren, Christina
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Waling, Kerstin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Sundelin, Gunnevi
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The effects of different training programs on the trapezius muscle of women with work-related neck and shoulder myalgia2000In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 100, no 3, p. 253-8Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to examine the effects of training on the structural characteristics of the trapezius muscle in women with work-related trapezius myalgia. Muscle biopsies were taken before and after 10 weeks of three different training programs (strength, endurance and coordination). Enzyme-immunohistochemical analysis was performed to assess muscle fibre types, fibre area, capillary supply and cytochrome c oxidase (COX) activity. There was an increase in the proportion of type IIA fibres in strength trained group (P < 0.05). Strength training elicited a preferential increase in the area of type II fibres (P < 0.05); both strength and endurance programs induced an increase in the number of capillaries around type I and IIA muscle fibres. Finally, all training programs induced a decrease in the proportion of COX-negative fibres. In conclusion, the trapezius muscle of women with neck and shoulder myalgia is characterised by a great potential of adaptation to physical exercise over a period of 10 weeks. The significant changes in the number of capillaries and the specific changes induced by training at the level of muscle fibres might well explain the improvement of muscle function.

  • 520.
    Kadi, F
    et al.
    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.
    Concomitant increases in myonuclear and satellite cell content in female trapezius muscle following strength training.2000In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 113, no 2, p. 99-103Article in journal (Refereed)
    Abstract [en]

    A skeletal muscle fibre maintains its cytoplasmic volume by means of hundreds of myonuclei distributed along its entire length. Therefore it is hypothesised that changes in fibre size would involve modifications in myonuclear number. In this study, we have examined whether 10 weeks of strength training can induce changes in the number of myonuclei and satellite cells in female trapezius muscles. Biopsies were taken pre- and posttraining from the upper part of the descending trapezius muscle of nine subjects. Muscle samples were analysed for fibre area and myonuclear and satellite cell number using immunohistochemistry. There was a 36% increase in the cross-sectional area of muscle fibres. The hypertrophy of muscle fibres was accompanied by an approximately 70% increase in myonuclear number and a 46% increase in the number of satellite cells. Myonuclei number was positively correlated to satellite cell number indicating that a muscle with an increased concentration of myonuclei will contain a correspondingly higher number of satellite cells. The acquisition of additional myonuclei appears to be required to support the enlargement of multinucleated muscle cells following 10 weeks of strength training. Increased satellite cell content suggests that mitotic divisions of satellite cells produced daughter cells that became satellite cells.

  • 521.
    Kadi, Fawzi
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bonnerud, P
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Eriksson, A
    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.
    The expression of androgen receptors in human neck and limb muscles: effects of training and self-administration of androgenic-anabolic steroids2000In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 113, no 1, p. 25-29Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the immunohistochemical expression of androgen receptors (AR) in human vastus lateralis and trapezius muscles and to determine whether long-term strength training and self-administration of androgenic-anabolic steroids are accompanied by changes in AR content. Biopsy samples were taken from eight high-level power-lifters (P), nine high-level power-lifters who used anabolic steroids (PAS) and six untrained subjects (U). Myonuclei and AR were visualised in cross-sections stained with the monoclonal antibody against AR and 4',6-diamidino-2-phenylindole. The proportion of AR-containing myonuclei per fibre cross-section was higher in the trapezius than in the vastus lateralis (P<0.05). In the trapezius, the proportion of AR-containing myonuclei was higher in P compared to U and in PAS compared to both P and U (P<0. 05). On the contrary, in the vastus lateralis, there were no differences in AR content between the three groups. Myonuclear number in both muscles was higher in P compared to U and in PAS compared to both P and U (P<0.05). In conclusion, AR content differs greatly between human neck and limb muscles. Moreover, the regulation of AR-containing myonuclei following training and self-administration of androgenic-anabolic steroids is muscle dependent.

  • 522.
    Kadi, Fawzi
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Eriksson, Anders
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Butler-Browne, GS
    Thornell, L-E
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Cellular adaptation of the trapezius muscle in strength-trained athletes1999In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 111, no 3, p. 189-195Article in journal (Refereed)
  • 523.
    Kadi, Fawzi
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Eriksson, Anders
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Holmner, S
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Effects of anabolic steroids on the muscle cells of strength trained athletes1999In: Medicine & Science in Sports & Exercise, ISSN 0195-9131, E-ISSN 1530-0315, Vol. 31, no 11, p. 1528-1534Article in journal (Refereed)
  • 524.
    Kalbermatten, Daniel
    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.
    Nerve gap repair by the use of artificial conduits and cultured cells2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Peripheral nerve injuries are often associated with loss of nerve tissue and require autologous nerve grafts to provide a physical substrate for axonal growth. This thesis investigates the use of fibrin as both a tubular conduit to guide nerve regeneration and also as a matrix material to suspend various regenerative cell types within/on poly-3-hydroxybutyrate (PHB) nerve conduits. Adipose derived stem cells (ASC) are found in abundant quantities. In this thesis the ability of rat ASC to differentiate into Schwann cells was determined and a preliminary study of the neurotrophic potential of human ASC was also investigated.

    Rat sciatic nerve axotomy was performed proximally in the thigh to create a 10-mm gap between the nerve stumps and the gap was bridged using the various conduits.  At early time points the nerve grafts were harvested and investigated for axonal and Schwann cell markers.  After 16 weeks the regenerative response from sensory and motor neurons was also evaluated following retrograde labelling with Fast Blue fluorescent tracer. Stem cells were treated with a mixture of glial growth factors and after 2 weeks in vitro the expression of Schwann cell markers was analysed by immunocytochemistry and Western blotting.  ASC were cocultured with the NG108-15 neuronal cell line to determine their ability to promote neurite outgrowth.  Human ASC were isolated from the deep and superficial layers of abdominal fat tissue obtained during abdominoplasty procedures.  RT-PCR was used to investigate the expression of neurotrophic factors.

    Immunohistochemistry showed a superior nerve regeneration distance in the fibrin conduit compared with PHB. The fibrin conduit promoted regeneration of 60% of sensory neurones and 52% of motor neurones when compared with an autograft group at 16 weeks. The total number of myelinated axons in the distal nerve stump in the fibrin-conduit group reached 86% of the graft and the weight of gastrocnemius and soleus muscles recovered to 82% and 89% of the controls, respectively. In vitro studies showed that rat ASC could be differentiated to a Schwann cell phenotype. These treated cells enhanced both the number of NG108-15 cells expressing neurites and neurite length. In the same coculture model system, human superficial fat layer ASC induced significantly enhanced neurite outgrowth when compared with the deep layer fat cells. RT-PCR analysis showed ASC isolated from both layers expressed neurotrophic factors.

    These results indicate that a tubular fibrin conduit can be used to promote neuronal regeneration following peripheral nerve injury. There was also a beneficial effect of using a fibrin matrix to seed cells within/on PHB conduits which should ultimately lead to improved functional recovery following nerve injury.  There might also be an advantage to use a simple strip of PHB rather than a conventional tube-like structure implying that single fascicle nerve grafting could be advantageous for nerve repair.  The results of in vitro experiments indicate adipose tissue contains a pool of regenerative stem cells which can be differentiated to a Schwann cell phenotype and given that human ASC express a range of neurotrophic factors they are likely to be of clinical benefit for treatment of peripheral nerve injuries.

  • 525.
    Kalbermatten, Daniel F
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Erba, P
    Mahay, Daljeet
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Pierer, Gerhard
    Terenghi, Giorgio
    Schwann cell strip for peripheral nerve repair2008In: Journal of Hand Surgery - British and European Volume, ISSN 0266-7681, E-ISSN 1532-2211, Vol. 33, no 5, p. 587-594Article in journal (Refereed)
    Abstract [en]

    Many strategies have been investigated to provide an ideal substitute to treat a nerve gap injury. Initially, silicone conduits were used and more recently conduits fabricated from natural materials such as poly-3-hydroxybutyrate (PHB) showed good results but still have their limitations. Surgically, a new concept optimising harvested autologous nerve graft has been introduced as the single fascicle method. It has been shown that a single fascicle repair of nerve grafting is successful. We investigated a new approach using a PHB strip seeded with Schwann cells to mimic a small nerve fascicle. Schwann cells were attached to the PHB strip using diluted fibrin glue and used to bridge a 10-mm sciatic nerve gap in rats. Comparison was made with a group using conventional PHB conduit tubes filled with Schwann cells and fibrin glue. After 2 weeks, the nerve samples were harvested and investigated for axonal and Schwann cell markers. PGP9.5 immunohistochemistry showed a superior nerve regeneration distance in the PHB strip group versus the PHB tube group (> 10 mm, crossed versus 3.17+/- 0.32 mm respectively, P<0.05) as well as superior Schwann cell intrusion (S100 staining) from proximal (> 10 mm, crossed versus 3.40+/- 0.36 mm, P<0.01) and distal (> 10 mm, crossed versus 2.91+/- 0.31 mm, P<0.001) ends. These findings suggest a significant advantage of a strip in rapidly connecting a nerve gap lesion and imply that single fascicle nerve grafting is advantageous for nerve repair in rats.

  • 526.
    Kalbermatten, Daniel F
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Mahay, Daljeet
    Mantovani, Cristina
    Pettersson, Jonas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Raffoul, W
    Balcin, H
    Pierer, G
    Terenghi, Giorgio
    Fibrin matrix for suspension of regenerative cells in an artificial nerve conduit2008In: Journal of plastic, reconstructive and aesthetic surgery, ISSN 1878-0539, Vol. 61, no 6, p. 669-675Article in journal (Refereed)
    Abstract [en]

    Peripheral nerve injury presents with specific problems of neuronal reconstructions, and from a clinical viewpoint a tissue engineering approach would facilitate the process of repair and regeneration. We have previously used artificial nerve conduits made from bioresorbable poly-3-hydroxybutyrate (PHB) in order to refine the ways in which peripheral nerves are repaired and reconnected to the target muscles and skin. The addition of Schwann cells (SC) or differentiated mesenchymal stem cells (dMSC) to the conduits enhances regeneration. In this study, we have used a matrix based on fibrin (Tisseel) to fill optimally the nerve-conduits with cells. In vitro analysis showed that both SC and MSC adhered significantly better to PHB in the presence of fibrin and cells continued to maintain their differentiated state. Cells were more optimally distributed throughout the conduit when seeded in fibrin than by delivery in growth medium alone. Transplantation of the nerve conduits in vivo showed that cells in combination with fibrin matrix significantly increased nerve regeneration distance (using PGP9.5 and S100 distal and proximal immunohistochemistry) when compared with empty PHB conduits. This study shows the beneficial combinatory effect of an optimised matrix, cells and conduit material as a step towards bridging nerve gaps which should ultimately lead to improved functional recovery following nerve injury.

  • 527.
    Kalbermatten, Daniel F
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pettersson, Jonas
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pierer, Gerhard
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Terenghi, Giorgio
    New fibrin conduit for peripheral nerve repair2009In: Journal of reconstructive microsurgery, ISSN 0743-684X, E-ISSN 1098-8947, Vol. 25, no 1, p. 27-33Article in journal (Refereed)
    Abstract [en]

    An ideal substitute to treat a nerve gap has not been found. Initially, silicone conduits were employed. Later, conduits were fabricated from collagen or polyesters carbonates. More recently, it has been shown that a bioresorbable material, poly-3-hydroxybutyrate (PHB), can enhance nerve repair. The present investigation shows the use of fibrin as a conduit to guide nerve regeneration and bridge nerve defects. In this study we prepared and investigated a novel nerve conduit made from fibrin glue. Using a rodent sciatic nerve injury model (10-mm gap), we compared the extent of nerve regeneration through the new fibrin conduits versus established PHB conduits. After 2 and 4 weeks, conduits containing proximal and distal stumps were harvested. We evaluated the initial axon and Schwann cell stimulation using immunohistochemistry. The conduits presented full tissue integration and were completely intact. Axons crossed the gap after 1 month. Immunohistochemistry using the axonal marker PGP 9.5 showed a superior nerve regeneration distance in the fibrin conduit compared with PHB (4.1 mm versus 1.9 mm). Schwann cell intrusion (S100 staining) was similarly enhanced in the fibrin conduits, both from the proximal (4.2 mm versus 2.1 mm) and distal ends (3.2 mm versus 1.7 mm). These findings suggest an advantage of the new fibrin conduit for the important initial phase of peripheral nerve regeneration. The use of fibrin glue as a conduit is a step toward a usable graft to bridge peripheral nerve lesions. This might be clinically interesting, given the widespread acceptance of fibrin glue among the surgical community.

  • 528.
    Kalbermatten, Daniel F
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Schaakxs, Dominique
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fat2011In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 344, no 2, p. 251-260Article in journal (Refereed)
    Abstract [en]

    New approaches to the clinical treatment of traumatic nerve injuries may one day utilize stem cells to enhance nerve regeneration. Adipose-derived stem cells (ASC) are found in abundant quantities and can be harvested by minimally invasive procedures that should facilitate their use in such regenerative applications. We have analyzed the properties of human ASC isolated from the deep and superficial layers of abdominal fat tissue obtained during abdominoplasty procedures. Cells from the superficial layer proliferate significantly faster than those from the deep layer. In both the deep and superficial layers, ASC express the pluripotent stem cell markers oct4 and nanog and also the stro-1 cell surface antigen. Superficial layer ASC induce the significantly enhanced outgrowth of neurite-like processes from neuronal cell lines when compared with that of deep layer cells. However, analysis by reverse transcription with the polymerase chain reaction and by enzyme-linked immunosorbent assay has revealed that ASC isolated from both layers express similar levels of the following neurotrophic factors: nerve growth factor, brain-derived neurotrophic factor and glial-derived neurotrophic factor. Thus, human ASC show promising potential for the treatment of traumatic nerve injuries. In particular, superficial layer ASC warrant further analysis of their neurotrophic molecules.

  • 529.
    Kalbermatten, Daniel F
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wettstein, Reto
    vonKanel, Oliver
    Erba, Paolo
    Pierer, Gerhard
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Haug, Martin
    Sensate lateral arm flap for defects of the lower leg.2008In: Annals of plastic surgery, ISSN 1536-3708, Vol. 61, no 1, p. 40-6Article in journal (Refereed)
    Abstract [en]

    Ideally, reconstruction of lower extremity soft tissue defects includes not only an esthetically pleasing 3-dimensional shape and solid anchoring to the underlying structures to resist shear forces, but should also address the restoration of sensation. Therefore, we present a prospective study on defect reconstruction of the lower leg and ankle to evaluate the role of sensate free fasciocutaneous lateral arm flap and the impact of sensory nerve reconstruction. Thirty patients were allocated randomly to the study group (n = 15) that obtained end-to-side sensate coaptation using the lower lateral cutaneous brachial nerve to the tibial nerve using the epineural window technique, or to the control group reconstructed without nerve coaptation. At 1-year follow-up the patients were evaluated for pain sensation, thermal sensibility, static and moving 2-point discrimination, and Semmes-Weinstein monofilament tests. Data from both groups were compared and statistically analyzed with the Mann-Whitney U test and the Fisher exact test. Flaps of the study group reached a static and moving 2-point discrimination and Semmes-Weinstein monofilament tests nearly equal to the contralateral leg area and significantly better than flaps of the control group. Donor damage morbidity of the tibial nerve did not occur. To our point of view resensation should be carried out by end-to-side neurorrhaphy to the tibial nerve because of the superior restoration of sensibility.

  • 530.
    Kalbermatten, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Schaakxs, Dominique
    Kingham, Paul
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fatManuscript (preprint) (Other academic)
    Abstract [en]

    New approaches to the clinical treatment of traumatic nerve injuries may one day utilize stem cells to enhance nerve regeneration.  Adipose derived stem cells (ASC) are found in abundant quantities and can be harvested by minimally invasive procedures which should facilitate their use in such regenerative applications.  In this study, we have analyzed the properties of human ASC isolated from the deep and superficial layers of abdominal fat tissue obtained during abdominoplasty procedures.  Cells from the superficial layer proliferated significantly faster than those from the deep layer. Both in the deep and superficial layers, ASC expressed the pluripotent stem cell markers oct4 and nanog and also the stro-1 cell surface antigen.  Superficial layer ASC induced significantly enhanced neurite outgrowth from NG108-15 motor neuron like cells when compared with the deep layer cells.  However, RT-PCR analysis showed that ASC isolated from both layers expressed similar levels of the neurotrophic factors NGF, BDNF, GDNF and NT-3.  These results indicate that human ASC have promising potential for the treatment of traumatic nerve injuries and that superficial layer ASC might represent the more optimal cell type for such applications.

  • 531.
    Kalpouzos, Gregoria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Memory Self-Efficacy Beliefs Modulate Brain Activity when Encoding Real-World Future Intentions2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e73850-Article in journal (Refereed)
    Abstract [en]

    Background: While the use of different cognitive strategies when encoding episodic memory information has been extensively investigated, modulation of brain activity by memory self-efficacy beliefs has not been studied yet.

    Methodology/Principal Findings: Sixteen young adults completed the prospective and retrospective metamemory questionnaire, providing individual subjective judgments of everyday memory function. The day after, using functional magnetic resonance imaging, the participants had to memorize real-world intentions (e. g., return a book to the library), which were performed later on in a virtual environment. Participants also performed offline cognitive tasks evaluating executive functions, working memory, and attention. During encoding, activity was found in medial temporal lobe, left prefrontal cortex, medial parietal regions, occipital areas, and regions involved in (pre) motor processes. Based on results from the questionnaire, the group was split into low and high memory self-efficacy believers. Comparison of encoding-related brain activity between the 2 groups revealed that the low memory self-efficacy believers activated more the hippocampus bilaterally, right posterior parahippocampal cortex, precuneus, and left lateral temporal cortex. By contrast, more activity was found in dorsal anterior cingulate gyrus for the high-memory believers. In addition, the low-memory believers performed more poorly at feature binding and (at trend) manipulating visuospatial information in working memory.

    Conclusion/Significance: Overall, these findings indicate that memory self-efficacy beliefs modulate brain activity during intentional encoding. Low memory self-efficacy believers activated more brain areas involved in visuospatial operations such as the hippocampus. Possibly, this increase reflects attempts to compensate for poor performance of certain neurocognitive processes, such as feature binding. By contrast, high-memory believers seemed to rely more on executive-like processes involved in cognitive control.

  • 532. Kalpouzos, Gregoria
    et al.
    Garzon, Benjamin
    Sitnikov, Rouslan
    Heiland, Carmel
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Stockholm, Sweden; .
    Persson, Jonas
    Backman, Lars
    Higher Striatal Iron Concentration is Linked to Frontostriatal Underactivation and Poorer Memory in Normal Aging2017In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 27, no 6, p. 3427-3436Article in journal (Refereed)
    Abstract [en]

    In the brain, intracellular iron is essential for cellular metabolism. However, an overload of free iron is toxic, inducing oxidative stress and cell death. Although an increase of striatal iron has been related to atrophy and impaired cognitive performance, the link between elevated iron and altered brain activity in aging remains unexplored. In a sample of 37 younger and older adults, we examined whether higher striatal iron concentration could underlie age-related differences in frontostriatal activity induced by mental imagery of motor and non-motor scenes, and poorer recall of the scenes. Higher striatal iron concentration was linked to underrecruitment of frontostriatal regions regardless of age and striatal volume, the iron-activity association in right putamen being primarily driven by the older adults. In older age, higher striatal iron was related to poorer memory. Altered astrocytic functions could account for the link between brain iron and brain activity, as astrocytes are involved in iron buffering, neurovascular coupling, and synaptic activity. Our preliminary findings, which need to be replicated in a larger sample, suggest a potential frontostriatal target for intervention to counteract negative effects of iron accumulation on brain function and cognition.

  • 533.
    Kalpouzos, Grégoria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Sjölie, Daniel
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Molin, Jonas
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Neurocognitive systems related to real-world prospective memory2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 10, p. e13304-Article in journal (Refereed)
    Abstract [en]

    Taken together, these findings show how brain systems complementary interact during real-world PM, and support a more complete model of PM that can be applied to naturalistic PM tasks and that we named PROspective MEmory DYnamic (PROMEDY) model because of its dynamics on both multi-phase iteration and the interactions of distinct neurocognitive networks.

  • 534.
    Kalpouzos, Grégoria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Persson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Local brain atrophy accounts for functional activity differences in normal aging.2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 3, p. 623.e1-623.e13Article in journal (Refereed)
    Abstract [en]

    Functional brain imaging studies of normal aging typically show age-related under- and overactivations during episodic memory tasks. Older individuals also undergo nonuniform gray matter volume (GMv) loss. Thus, age differences in functional brain activity could at least in part result from local atrophy. We conducted a series of voxel-based blood oxygen level-dependent (BOLD)-GMv analyses to highlight whether age-related under- and overrecruitment was accounted for by GMv changes. Occipital GMv loss accounted for underrecruitment at encoding. Efficiency reduction of sensory-perceptual mechanisms underpinned by these areas may partly be due to local atrophy. At retrieval, local GMv loss accounted for age-related overactivation of left dorsolateral prefrontal cortex, but not of left dorsomedial prefrontal cortex. Local atrophy also accounted for age-related overactivation in left lateral parietal cortex. Activity in these frontoparietal regions correlated with performance in the older group. Atrophy in the overrecruited regions was modest in comparison with other regions as shown by a between-group voxel-based morphometry comparison. Collectively, these findings link age-related structural differences to age-related functional under- as well as overrecruitment.

  • 535. Kanitz, Gunter
    et al.
    Cipriani, Christian
    Edin, Benoni B.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Classification of Transient Myoelectric Signals for the Control of Multi-Grasp Hand Prostheses2018In: IEEE transactions on neural systems and rehabilitation engineering, ISSN 1534-4320, E-ISSN 1558-0210, Vol. 26, no 9, p. 1756-1764Article in journal (Refereed)
    Abstract [en]

    Understanding the neurophysiological signals underlying voluntary motor control and decoding them for controlling limb prostheses is one of the major challenges in applied neuroscience and rehabilitation engineering. While pattern recognition of continuous myoelectric (EMG) signals is arguably the most investigated approach for hand prosthesis control, its underlying assumption is poorly supported, i.e., that repeated muscular contractions produce consistent patterns of steady-state EMGs. In fact, it still remains to be shown that pattern recognition-based controllers allow natural control over multiple grasps in hand prosthesis outside well-controlled laboratory settings. Here, we propose an approach that relies on decoding the intended grasp from forearm EMG recordings associated with the onset of muscle contraction as opposed to the steady-state signals. Eight unimpaired individuals and two hand amputees performed four grasping movements with a variety of arm postures while EMG recordings subsequently processed to mimic signals picked up by conventional myoelectric sensors were obtained from their forearms and residual limbs, respectively. Off-line data analyses demonstrated the feasibility of the approach also with respect to the limb position effect. The sampling frequency and length of the classified EMG window that off-line resulted in optimal performance were applied to a controller of a research prosthesis worn by one hand amputee and proved functional in real-time when operated under realistic working conditions.

  • 536.
    Karalija, Amar
    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.
    Diagnostic and therapeutic strategies following spinal cord and brachial plexus injuries2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Traumatic injuries to the spinal cord and brachial plexus induce a significant inflammatory response in the nervous tissue with progressive degeneration of neurons and glial cells, and cause considerable physical and mental suffering in affected patients. This thesis investigates the effects of the antioxidants N-acetyl-cysteine (NAC) and acetyl-L- carnitine (ALC) on the survival of motoneurons in the brainstem and spinal cord, the expression of pro-apoptotic and pro-inflammatory cell markers, axonal sprouting and glial cell reactions after spinal hemisection in adult rats. In addition, a novel MRI protocol has been developed to analyse the extent of neuronal degeneration in the spinal cord. Rubrospinal neurons and tibial motoneurons were pre-labelled with the fluorescent tracer Fast Blue one week before cervical C3 or lumbar L5 spinal cord hemisection. The intrathecal treatment with the antioxidants NAC (2.4mg/day) or ALC (0.9 mg/day) was initiated immediately after injury using Alzet2002 osmotic mini pumps. Spinal cord injury increased the expression of apoptotic cell markers BAX and caspase 3, induced significant degeneration of rubrospinal neurons and spinal motoneurons with associated decrease in immunoreactivity for microtubule-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker glial fibrillary acidic protein and microglial markers OX42 and ED1 was markedly increased. Treatment with NAC and ALC attenuated levels of BAX, caspase 3, OX42 and ED1 expression after 2 weeks postoperatively. After 4-8 weeks of continuous intratheca ltreatment, NAC and ALC rescued approximately half of the rubrospinal neurons and spinal motoneurons destined to die, promoted axonal sprouting, restored the density of MAP2 and synaptophysin immunoreactivity and reduced the microglial reaction. However, antioxidant therapy did not affect the reactive astrocytes in the trauma zone. The inflammation modulating properties of ALC were also studied using cultures of human microglial cells. ALC increased the microglial production of interleukin IL-6 and BDNF, thereby possibly mediating the anti-inflammatory and pro-regenerative effects shown in vivo. To study degeneration in the spinal cord following pre-ganglionic and post-ganglionic brachial plexus injuries, adult rat models of ventral root avulsion and peripheral nerve injury were used. A novel MRI protocol was employed and the images were compared to morphological changes found in histological preparations. Ventral root avulsion caused degeneration of dendritic branches and axonal terminals in the spinal cord, followed by significant shrinkage of the ventral horn. Extensive astroglial and microglial reactions were detected in the histological preparations. Peripheral nerve injury reduced the density of dendritic branches but did not cause shrinkage of the ventral horn. Quantitative analysis of MRI images demonstrated changes in the ventral horn following ventral root avulsion only, thus validating the developed MRI technique as a possible tool for the differentiation of pre-ganglionic and post-ganglionic nerve injuries.

  • 537.
    Karalija, Amar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Andersson, Magnus N.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    The surgical treatment of familial cylindromatosis through subgaleal scalp excision2015In: Case reports in plastic surgery & hand surgery, ISSN 2332-0885, Vol. 2, no 3-4, p. 57-59Article in journal (Refereed)
    Abstract [en]

    We treated a 65-year-old woman with familial cylindromatosis, with cylindromas covering the entire scalp. Subgaleal tumor excision and split skin grafting was performed. The graft take was deemed to be excellent, with almost 100% coverage 2.5 weeks after operation, no complications and a satisfying esthetic result.

  • 538.
    Karalija, Amar
    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.
    Kelk, Peyman
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The effects of acetyl-­L-­carnitine treatment on neuroinflammation: An in vitro studyManuscript (preprint) (Other academic)
  • 539.
    Karalija, Amar
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Neuroprotective Effects of N-Acetyl-Cysteine and Acetyl-L-Carnitine after Spinal Cord Injury in Adult Rats2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41086-Article in journal (Refereed)
    Abstract [en]

    Following the initial acute stage of spinal cord injury, a cascade of cellular and inflammatory responses will lead to progressive secondary damage of the nerve tissue surrounding the primary injury site. The degeneration is manifested by loss of neurons and glial cells, demyelination and cyst formation. Injury to the mammalian spinal cord results in nearly complete failure of the severed axons to regenerate. We have previously demonstrated that the antioxidants N-acetyl-cysteine (NAC) and acetyl-L-carnitine (ALC) can attenuate retrograde neuronal degeneration after peripheral nerve and ventral root injury. The present study evaluates the effects of NAC and ALC on neuronal survival, axonal sprouting and glial cell reactions after spinal cord injury in adult rats. Tibial motoneurons in the spinal cord were pre-labeled with fluorescent tracer Fast Blue one week before lumbar L5 hemisection. Continuous intrathecal infusion of NAC (2.4 mg/day) or ALC (0.9 mg/day) was initiated immediately after spinal injury using Alzet 2002 osmotic minipumps. Neuroprotective effects of treatment were assessed by counting surviving motoneurons and by using quantitative immunohistochemistry and Western blotting for neuronal and glial cell markers 4 weeks after hemisection. Spinal cord injury induced significant loss of tibial motoneurons in L4-L6 segments. Neuronal degeneration was associated with decreased immunostaining for microtubular-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker GFAP and microglial marker OX42 was increased. Treatment with NAC and ALC rescued approximately half of the motoneurons destined to die. In addition, antioxidants restored MAP2 and synaptophysin immunoreactivity. However, the perineuronal synaptophysin labeling was not recovered. Although both treatments promoted axonal sprouting, there was no effect on reactive astrocytes. In contrast, the microglial reaction was significantly attenuated. The results indicate a therapeutic potential for NAC and ALC in the early treatment of traumatic spinal cord injury.

  • 540.
    Karalija, Amar
    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.
    Novikova, Liudmila N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Differentiation of pre- and postganglionic nerve injury using MRI of the spinal cord2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0168807Article in journal (Refereed)
    Abstract [en]

    Brachial plexus injury (BPI) is a devastating type of nerve injury, potentially causing loss of motor and sensory function. Principally, BPI is either categorized as preganglionic or post- ganglionic, with the early establishment of injury level being crucial for choosing the correct treatment strategy. Despite diagnostic advances, the need for a reliable, non-invasive method for establishing the injury level remains. We studied the usefulness of in vivo mag- netic resonance imaging (MRI) of the spinal cord for determination of injury level. The find- ings were related to neuronal and glial changes. Rats underwent unilateral L4 & L5 ventral roots avulsion or sciatic nerve axotomy. The injuries served as models for pre- and postgan- glionic BPI, respectively. MRI of the L4/L5 spinal cord segments 4 weeks after avulsion showed ventral horn (VH) shrinkage on the injured side compared to the uninjured side. Axotomy induced no change in the VH size on MRI. Following avulsion, histological sections of L4/L5 revealed shrinkage in the VH grey matter area occupied by NeuN-positive neurons, loss of microtubular-associated protein-2 positive dendritic branches (MAP2), pan-neurofila- ment positive axons (PanNF), synaptophysin-positive synapses (SYN) and increase in immunoreactivity for the microglial OX42 and astroglial GFAP markers. Axotomy induced no changes in NeuN-reactivity, modest decrease of MAP2 immunoreactivity, no changes in SYN and PanNF labelling, and a modest increase in OX42 and SYN labeling. Histological and radiological findings were congruent when assessing changes after axotomy, while MRI somewhat underestimated the shrinkage. This study indicates a potential diagnostic value of structural spinal cord MRI following BPI. 

  • 541.
    Karalija, Amar
    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.
    Novikova, Ludmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The effects of N-acetyl-cysteine and acetyl-l-carnitine on neural survival, neuroinflammation and regeneration following spinal cord injury2014In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 269, p. 143-151Article in journal (Refereed)
    Abstract [en]

    Traumatic spinal cord injury induces a long-standing inflammatory response in the spinal cord tissue, leading to a progressive apoptotic death of spinal cord neurons and glial cells. We have recently demonstrated that immediate treatment with the antioxidants N-acetyl-cysteine (NAC) and acetyl-l-carnitine (ALC) attenuates neuroinflammation, induces axonal sprouting, and reduces the death of motoneurons in the vicinity of the trauma zone 4weeks after initial trauma. The objective of the current study was to investigate the effects of long-term antioxidant treatment on the survival of descending rubrospinal neurons after spinal cord injury in rats. It also examines the short- and long-term effects of treatment on apoptosis, inflammation, and regeneration in the spinal cord trauma zone. Spinal cord hemisection performed at the level C3 induced a significant loss of rubrospinal neurons 8weeks after injury. At 2weeks, an increase in the expression of the apoptosis-associated markers BCL-2-associated X protein (BAX) and caspase 3, as well as the microglial cell markers OX42 and ectodermal dysplasia 1 (ED1), was seen in the trauma zone. After 8weeks, an increase in immunostaining for OX42 and the serotonin marker 5HT was detected in the same area. Antioxidant therapy reduced the loss of rubrospinal neurons by approximately 50%. Treatment also decreased the expression of BAX, caspase 3, OX42 and ED1 after 2weeks. After 8weeks, treatment decreased immunoreactivity for OX42, whereas it was increased for 5HT. In conclusion, this study provides further insight in the effects of treatment with NAC and ALC on descending pathways, as well as short- and long-term effects on the spinal cord trauma zone.

  • 542. Karhula, Sakari
    et al.
    Finnilä, Mikko
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, P. R. China.
    Ylärinne, Janne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Kauppinen, Sami
    Rieppo, Lassi
    Pritzker, Kenneth P H
    Nieminen, Heikki
    Saarakkala, Simo
    Effects of articular cartilage constituents on phosphotungstic acid enhanced micro-computed tomography2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0171075Article in journal (Refereed)
    Abstract [en]

    Contrast-enhanced micro-computed tomography (CEμCT) with phosphotungstic acid (PTA) has shown potential for detecting collagen distribution of articular cartilage. However, the selectivity of the PTA staining to articular cartilage constituents remains to be elucidated. The aim of this study was to investigate the dependence of PTA for the collagen content in bovine articular cartilage. Adjacent bovine articular cartilage samples were treated with chondroitinase ABC and collagenase to degrade the proteoglycan and the collagen constituents in articular cartilage, respectively. Enzymatically degraded samples were compared to the untreated samples using CEμCT and reference methods, such as Fourier-transform infrared imaging. Decrease in the X-ray attenuation of PTA in articular cartilage and collagen content was observed in cartilage depth of 0-13% and deeper in tissue after collagen degradation. Increase in the X-ray attenuation of PTA was observed in the cartilage depth of 13-39% after proteoglycan degradation. The X-ray attenuation of PTA-labelled articular cartilage in CEμCT is associated mainly with collagen content but the proteoglycans have a minor effect on the X-ray attenuation of the PTA-labelled articular cartilage. In conclusion, the PTA labeling provides a feasible CEμCT method for 3D characterization of articular cartilage.

  • 543.
    Karlsson, Linnea
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Juslin, Peter
    Olsson, Henrik
    Different neural systems underlie multiple-cue judgment depending on the cue-combination ruleIn: Psychological Science, ISSN 0956-7976, E-ISSN 1467-9280Article in journal (Refereed)
  • 544.
    Karlsson, Linnea
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Wiklund-Hornqvist, Carola
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Jonsson, Bert
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Retrieval practice is characterized by reduced fronto-striatal activity2013In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 25, no Suppl., p. S82-S83Article in journal (Other academic)
  • 545.
    Karlsson, Sari
    et al.
    Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Karlsson, Per
    Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, Stockholm, Sweden.
    Fischer, Håkan
    Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
    Thilers, Petra
    Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
    MacDonald, Stuart
    Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
    Brehmer, Yvonne
    Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
    Rieckmann, Anna
    Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
    Halldin, Christer
    Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, Stockholm, Sweden.
    Farde, Lars
    Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, Stockholm, Sweden.
    Bäckman, Lars
    Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
    Modulation of striatal dopamine D1 binding by cognitive processing2009In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 48, no 2, p. 398-404Article in journal (Refereed)
    Abstract [en]

    There is strong evidence that dopamine (DA) is implicated in higher-order cognitive functioning, but it remains controversial whether D1 receptor binding can be modified by cognitive activity. We examined striatal D1 binding potential (BP) in 20 younger (22-30 years) and 20 older (65-75 years) persons who underwent two [(11)C] SCH 23390 PET measurements, one while resting and one while performing a cognitive task taxing inhibitory functioning. The younger persons showed significant task-related BP reductions in sensorimotor, limbic, and associative striatum during cognitive activity compared to rest. Older persons showed no reliable BP reductions in any striatal subregion. These findings demonstrate that D1 receptor binding can be modified by cognitive activity in younger persons, but also provide novel evidence for the notion that human aging is associated not only with lower DA receptor density but also with altered modifiability of the DA system.

  • 546.
    Karlsson, Sari
    et al.
    Karolinska Institute.
    Rieckmann, Anna
    Karolinska Institute.
    Karlsson, Per
    Karolinska Hospital.
    Farde, Lars
    Karolinska Hospital.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Bäckman, Lars
    Karolinska Institute.
    Relationship of dopamine D1 receptor binding in striatal and extrastriatal regions to cognitive functioning in healthy humans2011In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 57, no 2, p. 346-351Article in journal (Refereed)
    Abstract [en]

    Dopamine (DA) availability in both striatal and extrastriatal brain regions has been implicated in cognitive performance. Given that different brain regions are neuroanatomically and functionally different, DA receptor binding in different brain regions may be selectively important to specific cognitive functions. Using PET and the radioligand SCH23390, we measured D1 receptor binding potential (BP(ND)) in dorsolateral prefrontal cortex (DLPFC), hippocampus (HC), as well as in sensorimotor (SMST), associative (AST), and limbic (LST) striatum in 20 healthy younger persons. Subjects completed tasks assessing executive functioning, episodic memory, speed, and general knowledge. Unlike previous reports, we found no linear or curvilinear relationships between D1 receptor binding in DLPFC and performance in any cognitive task. However, BP(ND) in HC was positively linked to executive performance as well as to speed and knowledge. With regard to the striatal subregions, D1 BP(ND) in SMST was more strongly related to speed compared to the other striatal subregions, whereas D1 BP(ND) in AST was more strongly linked to general knowledge. These findings provide support for the notion that D1 receptors in separate brain regions are differentially related to performance in tasks tapping various cognitive domains.

  • 547.
    Karlsson, Urban
    Umeå University, Faculty of Medicine, Integrative Medical Biology.
    GABA-, glycine- and glutamate-induced currents in rat medial preoptic neurons: functional interactions and modulation by capsaicin2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The medial preoptic nucleus (MPN) of the hypothalamus plays a major role in many functions involved in maintaining bodily homeostasis, such as thermoregulation and osmoregulation, as well as in the control of complex behaviours, e.g. sexual behaviour. A fundamental basis for the control and execution of these functions is the synaptic communication between neurons of the MPN. However, the functional properties of the synapses involved are largely unknown. The present thesis is a study of ligand-gated ion channels involved in the pre- and post-synaptic aspects of neuronal communication in the MPN of rat. The aim was to clarify synaptic properties in the MPN, to identify the major channel types involved and to obtain a better understanding of their functional properties.

    By fast application of agonists to isolated neurons, it was first demonstrated that all neurons responded to glutamate with currents mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and a majority of neurons also with currents mediated by N-Methyl-D-aspartate (NMDA) receptors. All neurons also responded to γ-aminobutyric acid (GABA) and glycine with currents mediated by GABAA receptors and glycine receptors, respectively. These findings show that fast-acting excitatory and inhibitory amino-acid transmitters are most likely important for communication between hypothalamic neurons.

    Application of agonists to isolated neurons revealed cross-talk, detected as an apparent cross-desensitization, between the responses to GABA and those to glycine. Parallel analysis of current and conductance, using gramicidin-perforated patches to avoid perturbing intracellular chloride concentration, showed that the cross-talk was not dependent on a direct interaction between the receptors as previously suggested, but was a consequence of the change in the intracellular chloride concentration during receptor activation. Strengthened by a computer model, the analysis also showed that the current decay in the presence of GABA or glycine was mainly due to a change in the chloride driving force and that receptor desensitization played a minor role only.

    The role of thermo-sensitive transient receptor potential TRPV1 channels in the regulation of glutamate- and GABA-mediated transmission was studied in the slice preparation, where much of the synaptic connections between neurons are preserved. It was shown that application of the TRPV1 agonist capsaicin increased the frequency of excitatory AMPA receptor- mediated as well as inhibitory GABAA receptor-mediated postsynaptic currents. This effect was partly presynaptic and demonstrates that TRP channels play a role in regulating synaptic transmission in the MPN. The results imply that such mechanisms may possibly contribute to the thermoregulation by MPN neurons.

  • 548.
    Karlsson, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Druzin, Michael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Johansson, Staffan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Cl concentration changes and desensitization of GABAA and glycine receptors2011In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 138, no 6, p. 609-626Article in journal (Refereed)
    Abstract [en]

    Desensitization of ligand-gated ion channels plays a critical role for the information transfer between neurons. The current view on γ-aminobutyric acid (GABA)A and glycine receptors includes significant rapid components of desensitization as well as cross-desensitization between the two receptor types. Here, we analyze the mechanism of apparent cross-desensitization between native GABAA and glycine receptors in rat central neurons and quantify to what extent the current decay in the presence of ligand is a result of desensitization versus changes in intracellular Cl concentration ([Cl]i). We show that apparent cross-desensitization of currents evoked by GABA and by glycine is caused by changes in [Cl]i. We also show that changes in [Cl]i are critical for the decay of current in the presence of either GABA or glycine, whereas changes in conductance often play a minor role only. Thus, the currents decayed significantly quicker than the conductances, which decayed with time constants of several seconds and in some cells did not decay below the value at peak current during 20-s agonist application. By taking the cytosolic volume into account and numerically computing the membrane currents and expected changes in [Cl]i, we provide a theoretical framework for the observed effects. Modeling diffusional exchange of Cl between cytosol and patch pipettes, we also show that considerable changes in [Cl]i may be expected and cause rapidly decaying current components in conventional whole cell or outside-out patch recordings. The findings imply that a reevaluation of the desensitization properties of GABAA and glycine receptors is needed.

  • 549.
    Karlsson, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Haage, David
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Staffan
    Currents evoked by GABA and glycine in acutely dissociated neurons from the rat medial preoptic nucleus1997In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 770, no 1-2, p. 256-260Article in journal (Refereed)
  • 550.
    Karlsson, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Sundgren, Anna
    Näsström, Jacques
    Johansson, Staffan
    Glutamate-evoked currents in acutely dissociated neurons from the rat medial preoptic nucleus1997In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 759, no 2, p. 270-276Article in journal (Refereed)
891011121314 501 - 550 of 1307
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