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

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

  • 2. Berge-Seidl, Victoria
    et al.
    Pihlstrøm, Lasse
    Maple-Grødem, Jodi
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Larsen, Jan Petter
    Tysnes, Ole-Bjørn
    Toft, Mathias
    The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal2017In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 658, p. 48-52Article in journal (Refereed)
    Abstract [en]

    Objective: Coding variants in the GBA gene have been identified as the numerically most important genetic risk factors for Parkinson's disease (PD). In addition, genome-wide association studies (GWAS) have identified associations with PD in the SYT11-GBA region on chromosome 1q22, but the relationship to GBA coding variants have remained unclear. The aim of this study was to sequence the complete GBA gene in a clinical cohort and to investigate whether coding variants within the GBA gene may be driving reported association signals. Methods: We analyzed high-throughput sequencing data of all coding exons of GBA in 366 patients with PD. The identified low-frequency coding variants were genotyped in three Scandinavian case-controls series (786 patients and 713 controls). Previously reported risk variants from two independent association signals within the SYT11-GBA locus on chromosome 1 were also genotyped in the same samples. We performed association analyses and evaluated linkage disequilibrium (LD) between the variants. Results: We identified six rare mutations (1.6%) and two low-frequency coding variants in GBA. E326K (rs2230288) was significantly more frequent in PD patients compared to controls (OR 1.65, p = 0.03). There was no clear association of T369M (rs75548401) with disease (OR 1.43, p = 0.24). Genotyping the two GWAS hits rs35749011 and rs114138760 in the same sample set, we replicated the association between rs35749011 and disease status (OR 1.67, p = 0.03), while rs114138760 was found to have similar allele frequencies in patients and controls. Analyses revealed that E326K and rs35749011 are in very high LD (r(2) 0.95). Conclusions: Our results confirm that the GBA variant E326K is a susceptibility allele for PD. The results suggest that E326K may fully account for the primary association signal observed at chromosome 1q22 in previous GWAS of PD.

  • 3.
    Birzniece, Vita
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, I-M
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, MD
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, T
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Olsson, T
    Ovarian hormone effects on 5-hydroxytryptamine (2A) and 5-hydroxytryptamine (2C) receptor mRNA expression in the ventral hippocampus and frontal cortex of female rats.2002In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 319, no 3, p. 157-161Article in journal (Refereed)
    Abstract [en]

    Alterations in female gonadal hormones are associated with anxiety and mood changes. The aim of the present study was to determine influences of chronic gonadal hormone supplementation on 5-HT(2A) and 5-HT(2C) receptor mRNA levels in the ventral hippocampus and the frontal cerebral cortex. Ovariectomized adult female Sprague-Dawley rats (n=37) received implantation of subcutaneous pellets containing different dosages of 17beta-estradiol alone or in combination with progesterone, or placebo pellets, for 2 weeks. Serotonin receptor mRNA levels were analyzed by in situ hybridization in the ventral hippocampus and 5-HT(2A) receptor mRNA also in the frontal cortex. Estradiol treatment in combination with low-dose progesterone increased 5-HT(2A) receptor mRNA by 43% in the CA2 region of the ventral hippocampus, while estradiol combined with high-dose progesterone increased the expression of this gene by 84% in ventral CA1. 5-HT(2A) mRNA expression in the frontal cortex was not influenced by hormone manipulation. 5-HT(2C) receptor gene expression was in the ventral hippocampus decreased in the CA2, ventral CA1 and the subiculum subregions by high-dose estradiol treatment (8-20% decreases). Effects on mood by gonadal hormones can be mediated, at least partly, through influences on 5-HT(2A) and 5-HT(2C) receptor expression.

  • 4. Broom, Wendy J
    et al.
    Johnson, D V
    Auwarter, K E
    Iafrate, A J
    Russ, C
    Al-Chalabi, A
    Sapp, P C
    McKenna-Yasek, D
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brown, R H
    SOD1A4V-mediated ALS: absence of a closely linked modifier gene and origination in Asia2008In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 430, no 3, p. 241-245Article in journal (Refereed)
    Abstract [en]

    Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS. Approximately 20% of cases are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). In North America, SOD1(A4V) is the most common SOD1 mutation. Carriers of the SOD1(A4V) mutation share a common phenotype with rapid disease progression and death on average occurring at 1.4 years (versus 3-5 years with other dominant SOD1 mutations). Previous studies of SOD1(A4V) carriers identified a common haplotype around the SOD1 locus, suggesting a common founder for most SOD1(A4V) patients. In the current study we sequenced the entire common haplotypic region around SOD1 to test the hypothesis that polymorphisms in either previously undescribed coding regions or non-coding regions around SOD1 are responsible for the more aggressive phenotype in SOD1(A4V)-mediated ALS. We narrowed the conserved region around the SOD1 gene in SOD1(A4V) ALS to 2.8Kb and identified five novel SNPs therein. None of these variants was specifically found in all SOD1(A4V) patients. It therefore appears likely that the aggressive nature of the SOD1(A4V) mutation is not a result of a modifying factor within the region around the SOD1 gene. Founder analysis estimates that the A4V mutation occurred 540 generations (approximately 12,000 years) ago (95% CI 480-700). The conserved minimal haplotype is statistically more similar to Asian than European population DNA sets, suggesting that the A4V mutation arose in native Asian-Americans who reached the Americas through the Bering Strait.

  • 5. Broom, Wendy J
    et al.
    Johnson, Daniel V
    Garber, Manuel
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Lennon, Niall
    Landers, John
    Nusbaum, Chad
    Russ, Carsten
    Brown, Robert H
    DNA sequence analysis of the conserved region around the SOD1 gene locus in recessively inherited ALS2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 463, no 1, p. 64-69Article in journal (Refereed)
    Abstract [en]

    Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; 12-23% are associated with mutations in the Cu/Zn superoxide dismutase gene (SOD1). All ALS-linked SOD1 mutations present with a dominant pattern of inheritance apart from the aspartate to alanine mutation in exon 4 (D90A). This mutation has been observed in dominant, recessive and apparently sporadically cases. SOD1(D90A/D90A) ALS cases have a very slow disease progression (>10 years), raising the hypothesis that modifier genes linked to SOD1 ameliorate the phenotype of recessively inherited SOD1(D90A/D90A) mutations. Previous sequence analysis of a conserved haplotype region around the SOD1 gene did not reveal any functional polymorphisms within known coding or putative regulatory regions. In the current study we expanded the previous analyses by sequencing the entire SOD1 conserved haplotypic region. Although many polymorphisms were identified, none of these variants explain the slowly progressive phenotype observed in patients with recessive SOD1(D90A) mutations. This study disproves the hypothesis that there is a tightly linked genetic protective factor specifically located close to the SOD1 gene in SOD1(D90A) mediated ALS.

  • 6.
    di Summa, Pietro G.
    et al.
    Department of Plastic, Reconstructive Surgery, University Hospital of Lausanne (CHUV), Rue du Bugnon 46, 1011 Lausanne, Switzerland. Electronic address: Pietro.Di-Summa@chuv.ch..
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Campisi, Corrado C.
    Department of Plastic, Reconstructive Surgery, University Hospital of Genova, Ospedale S. Martino, Largo Rossana Benzi 10, 16132 Genova, Italy.
    Raffoul, Wassim
    Department of Plastic, Reconstructive Surgery, University Hospital of Lausanne (CHUV), Rue du Bugnon 46, 1011 Lausanne, Switzerland.
    Kalbermatten, Daniel F.
    Department of Plastic, Reconstructive Surgery, University Hospital of Basel, Spitalstrasse 21, CH-4031 Basel, Switzerland.
    Collagen (NeuraGen(®)) nerve conduits and stem cells for peripheral nerve gap repair2014In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 572, p. 26-31Article in journal (Refereed)
    Abstract [en]

    Collagen nerve guides are used clinically for peripheral nerve defects, but their use is generally limited to lesions up to 3cm. In this study we combined collagen conduits with cells as an alternative strategy to support nerve regeneration over longer gaps. In vitro cell adherence to collagen conduits (NeuraGen(®) nerve guides) was assessed by scanning electron microscopy. For in vivo experiments, conduits were seeded with either Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC) or left empty (control group), conduits were used to bridge a 1cm gap in the rat sciatic nerve and after 2-weeks immunohistochemical analysis was performed to assess axonal regeneration and SC infiltration. The regenerative cells showed good adherence to the collagen walls. Primary SC showed significant improvement in distal stump sprouting. No significant differences in proximal regeneration distances were noticed among experimental groups. dMSC and dASC-loaded conduits showed a diffuse sprouting pattern, while SC-loaded showed an enhanced cone pattern and a typical sprouting along the conduits walls, suggesting an increased affinity for the collagen type I fibrillar structure. NeuraGen(®) guides showed high affinity of regenerative cells and could be used as efficient vehicle for cell delivery. However, surface modifications (e.g. with extracellular matrix molecule peptides) of NeuraGen(®) guides could be used in future tissue-engineering applications to better exploit the cell potential.

  • 7.
    Eriksson, Johan
    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).
    Kalpouzos, Grégoria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. 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).
    Rewiring the brain with repeated retrieval: A parametric fMRI study of the testing effect2011In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 505, no 1, p. 36-40Article in journal (Refereed)
    Abstract [en]

    The "testing effect" refers to the beneficial effects on memory performance from being tested, a phenomenon of potentially substantial implications in educational settings. While the effect itself is firmly established in previous research, little is known of related brain changes. Here we used fMRI and a parametric design to show that repeated successful retrieval during a memory acquisition phase leads to higher brain activity in the anterior cingulate cortex (ACC) at a subsequent test phase. The extent of ACC activity increase correlated across individuals with memory performance 5 months later. In relation to recent research that associates the ACC with memory consolidation processes, the present results suggest that the testing effect may operate at the systems level by enhancing consolidation of memory representations.

  • 8.
    Grimsholm, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Dalén, Tore
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Unexpected finding of a marked non-neuronal cholinergic system in human knee joint synovial tissue.2008In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 442, no 2, p. 128-33Article in journal (Refereed)
    Abstract [en]

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

  • 9.
    Hart, Andrew McKay
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Blond-McIndoe Centre, Royal Free and University College Medical School, University Department of Surgery, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
    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
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pharmacological enhancement of peripheral nerve regeneration in the rat by systemic acetyl-L-carnitine treatment2002In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 334, no 3, p. 181-185Article in journal (Refereed)
    Abstract [en]

    Peripheral nerve trauma remains a major cause of morbidity, largely due to the death of similar to40% of innervating sensory neurons, and to slow regeneration after repair. Acetyl-L-carnitine (ALCAR) is a physiological peptide that virtually eliminates sensory neuronal death, and may improve regeneration after primary nerve repair. This study determines the effect of ALCAR upon regeneration after secondary nerve repair, thereby isolating its effect upon neuronal regenerative capacity. Two months after unilateral sciatic nerve division 1 cm nerve graft repairs were performed (n = 5), and treatment with 50 mg/kg/day ALCAR was commenced for 6 weeks until harvest. Regeneration area and distance were determined by quantitative immunohistochemistry. ALCAR treatment significant increased immunostaining for both nerve fibres (total area 264% increase, P < 0.001; percentage area 229% increase, P < 0.001), and Schwann cells (total area 264% increase, P < 0.05; percentage area 86% increase, P < 0.05), when compared to no treatment. Regeneration into the distal stump was greatly enhanced (total area 2242% increase, P = 0.008; percentage area 3034% increase, P = 0.008). ALCAR significantly enhances the regenerative capacity of neurons that survive peripheral nerve trauma, in addition to its known neuroprotective effects.

  • 10.
    Hu, Xiao-Lei
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Bergström, Sven-Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rönnbäck, Annica
    Karolinska Institute, Dept NVS, KI-Alzheimer Disease Research Center, KASPAC, Novum, SE-141 57 Huddinge, Sweden.
    Dahlqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Enriched environment increases spinophilin mRNA expression and spinophilin immunoreactive dendritic spines in hippocampus and cortex2010In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 476, no 2, p. 79-83Article in journal (Refereed)
    Abstract [en]

    Housing rodents in an enriched environment (EE) induces structural and functional plasticity in the adult brain, including increased dendritic sprouting and number of dendritic spines. However, the molecular mechanisms behind EE-induced brain plasticity remain largely unknown. Circadian rhythm plays an important role in memory processing but the neurobiological mechanisms of how circadian rhythm affects memory and brain plasticity remain controversial. In the current study, we studied the expression of spinophilin, a protein highly enriched in dendritic spines and involved in spine morphology and synaptic plasticity, to examine the effects of EE and circadian rhythm in rats housed in EE for different periods of time. Spinophilin mRNA expression was studied by in situ hybridization and the density of spinophilin immunoreactive puncta was quantified after immunohistochemical staining. Compared to rats living in a deprived environment (DE), we found a transient increase in the density of spinophilin immunoreactive puncta in hippocampus and cortex after 1 week of EE housing and persistent elevations of spinophilin mRNA expression during 1-4 weeks of environmental enrichment. Increased spinophilin expression was found during the light phase of the diurnal cycle, but not the dark phase. Thus, enriched housing altered the diurnal variation in spinophilin mRNA expression, suggesting that circadian modulation is likely to be important for experience dependent plasticity. The current results suggest a possible role for spinophilin in neuronal plasticity induced by environmental enrichment, but further studies are needed to establish a cause-effect relation.

  • 11.
    Kaarniranta, Kai
    et al.
    Department of Ophthalmology, University of Kuopio, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
    Ryhänen, Tuomas
    Department of Ophthalmology, University of Kuopio, Kuopio, Finland.
    Karjalainen, Hannu
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Suuronen, Tiina
    Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland.
    Huhtala, Anne
    University of Tampere Medical School, Tampere, Finland.
    Kontkanen, Matti
    Department of Ophthalmology, North Karelia Central Hospital, Joensuu, Finland.
    Teräsvirta, Markku
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
    Uusitalo, Hannu
    Department of Ophthalmology, University of Kuopio, Kuopio, Finland.
    Salminen, Antero
    Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
    Geldanamycin increases 4-hydroxynonenal (HNE)-induced cell death in human retinal pigment epithelial cells.2005In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 382, no 1-2, p. 185-190, article id 15911146Article in journal (Refereed)
    Abstract [en]

    Development of age-related macular degeneration (AMD) is associated with functional abnormalities and cell death in retinal pigment epithelial (RPE) cells attributable to oxidative stress. To minimize the adverse effects of oxidative stress, cells activate their defence systems, e.g., via increased expression of heat shock protein (Hsp), activation of stress sensitive AP-1 and NF-kappaB transcription factors. In this study, we examined the accumulation of Hsp70 protein, activation of AP-1 and NF-kappaB transcription factors in human ARPE-19 cells subjected to a 4-hydroxynonenal (HNE)-induced oxidative stress. In addition, the influence of Hsp90 inhibitor geldanamycin (GA) was studied in HNE-treated cells. Mitochondrial metabolic activity and apoptosis were determined to evaluate cell death in the ARPE-19 cells. The ARPE-19 cells showed increased accumulation of Hsp70 protein before of the cytotoxic hallmarks appearing in response to HNE. In contrast, increased DNA-binding activities of AP-1 or NF-kappaB transcription factors were not seen under HNE insults. Interestingly, GA significantly increased cell death in the HNE-treated cells, which was involved in caspase-3 independent apoptosis. This study reveals that the Hsps have an important role in the cytoprotection of RPE cells subjected to HNE-derived oxidative stress.

  • 12.
    Kalezic, Ivana
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Pilyavskii, AI
    Maisky, VA
    Kostyukov, AI
    Windhorst, U
    Johansson, H
    Distinctive pattern of c-fos expression in the feline cervico-lumbar spinal cord after stimulation of vanilloid receptors in dorsal neck muscles2004In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 364, no 2, p. 94-97Article in journal (Refereed)
    Abstract [en]

    In the present study, c-fos expression in the spinal cord has been used as a marker of neuronal activation induced by capsaicin-sensitive sensory afferents from the dorsal neck muscles in cats (n = 6). The number of Fos-immunoreactive neurons, which were revealed using the avidin-biotin-peroxidase method, was significantly increased in the cervical and lumbar spinal cord. In contrast to the control group (n = 3), 2 h after intramuscular capsaicin injection, c-fos expression was more extensive ipsilaterally to the injected side in the C3-C6 segments, and bilaterally in the L4-L6 segments. Most labeled neurons in the cervical spinal cord were small and giant cells, predominantly located in the middle and lateral parts of lamina I and, additionally, at the neck of the dorsal horn (lamina V), i.e., within the zones of termination of high-threshold muscle afferents. The widespread distribution of labeled cells throughout the cervical cord within the intermediate zone (lamina VII) coincided with the sites of last-order premotor interneurons and cells of origin of long crossed and uncrossed descending propriospinal pathways to the lumbar spinal cord. These findings suggest possible mechanisms for spreading of nociceptive signals between cervical and lumbar regions.

  • 13. Kautto, Mervi
    et al.
    Kampman, Olli
    Mononen, Nina
    Lehtimaki, Terho
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Koivisto, Pasi A.
    Leinonen, Esa
    Serotonin transporter (5-HTTLPR) and norepinephrine transporter (NET) gene polymorphisms: Susceptibility and treatment response of electroconvulsive therapy in treatment resistant depression2015In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 590, p. 116-120Article in journal (Refereed)
    Abstract [en]

    Serotonin transporter (5-HTTLPR) and norepinephrine transporter (NET182C) polymorphisms are associated with susceptibility and treatment response in major depressive disorder (MDD). Thus, we examined association between these polymorphisms and susceptibility to treatment resistant depression, and treatment response in severe MDD patients treated with electroconvulsive therapy (ECT).

    In total, 119 Finnish patients with treatment resistant depression and 395 healthy volunteer blood donors were genotyped. Depression severity was assessed using the Montgomery-Asberg Depression Scale (MADRS), with MADRS score change during ECT the treatment response indicator.

    Underrepresentation of the 5-HTTLPR 1/1 genotype in the NET TT subgroup was observed in patients compared with controls. There were no genotype or allele frequency differences between patients and control groups separately. Patients with combined 5-HTTLPR 1/1 and NET TT genotypes also had poorer treatment responses than other patients. No differences in ECT response were observed when the polymorphisms were examined separately.

    Our results suggest that a NET 182C and 5-HTTLPR polymorphism interaction is associated with susceptibility to treatment resistant depression and ECT treatment response in antidepressant resistant depression patients. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

  • 14.
    Kingham, Paul J
    et al.
    Blond McIndoe Laboratories, Tissue Injury & Repair Research Group, School of Clinical and Laboratory Sciences, The University of Manchester, Manchester, UK.
    Mantovani, Maria Cristina
    Blond McIndoe Laboratories, Tissue Injury & Repair Research Group, School of Clinical and Laboratory Sciences, The University of Manchester, Manchester, UK.
    Terenghi, Giorgio
    Blond McIndoe Laboratories, Tissue Injury & Repair Research Group, School of Clinical and Laboratory Sciences, The University of Manchester, Manchester, UK.
    Notch independent signalling mediates Schwann cell-like differentiation of adipose derived stem cells2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 467, no 2, p. 164-168Article in journal (Refereed)
    Abstract [en]

    Adipose derived stem cells (ASC) differentiate into a Schwann cell (SC)-like phenotype but the signalling pathways mediating this are unknown. We hypothesised that notch might be involved, given its important role in regulating SC development. Rat ASC were differentiated using bFGF, PDGF, GGF-2 and forskolin. RT-PCR analysis showed that mRNA for notch-1 and notch-2 receptors and the notch responsive gene, hes-1, were expressed throughout the differentiation process whereas jagged-1 a notch ligand, and the hey-1 gene were markedly down-regulated. In contrast delta-1 was up-regulated with differentiation and was strongly expressed by rat primary SC. Treatment of ASC with N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor which blocks notch signalling, had no effect on up-regulation of SC proteins S100 or GFAP during differentiation. Furthermore, when co-cultured with NG108-15 neurons, differentiated ASC cultures treated in the absence or presence of DAPT enhanced neurite outgrowth to similar levels. Differentiated ASC expressed PMP-22 but P0 was only present when co-cultured with dorsal root ganglia neurons. DAPT did not affect the expression of these myelin proteins. Thus, ASC express components of the notch signalling pathway but our studies suggest notch is unlikely to play a role in the neurotrophic activity and myelination capability of ASC differentiated into SC-like cells.

  • 15.
    Kompus, Kristiina
    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.
    Default mode network gates the retrieval of task-irrelevant incidental memories2011In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 487, no 3, p. 318-321Article in journal (Refereed)
    Abstract [en]

    Episodic memories can be retrieved by an intentional search for certain information. Alternatively, a past episode may enter our consciousness without any intention to retrieve it, prompted by a stimulus in our surroundings. Incidental retrieval does not occur upon each encounter with a familiar stimulus, suggesting that a gating mechanism exists which regulates incidental retrieval activity. We analyzed data from a functional magnetic resonance imaging study on incidental retrieval in healthy young adults and found that failure to incidentally retrieve was selectively associated with reduced activation of lateral and medial parietal regions as well as ventromedial frontal cortex, areas implicated in default mode network. This is the first demonstration that relative deactivation of the brain regions associated with the default mode gates the consciousness from currently irrelevant memories.

  • 16.
    Kompus, Kristiina
    et al.
    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).
    Hugdahl, Kenneth
    Öhman, Arne
    Marklund, Petter
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Distinct control networks for cognition and emotion in the prefrontal cortex2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 467, no 2, p. 76-80Article in journal (Refereed)
    Abstract [en]

    The activation of dorsolateral prefrontal cortex (dlPFC) has been suggested to reflect the engagement of a control mechanism for top-down biasing of context processing in resource-demanding memory tasks. Here we tested the hypothesis that the dlPFC subserves a similar function also in attention and emotion tasks. 18 healthy young adults were tested in a functional magnetic resonance imaging (fMRI) study where the demands for context processing were manipulated in three different cognitive domains: auditory attention, episodic retrieval, and emotion regulation. We found that the right dlPFC was jointly sensitive to increased cognitive demands in the attention and memory tasks. By contrast, increased demands in the emotion task (reappraisal) were associated with increased activity in ventromedial PFC along with decreased amygdala activity. Our findings of divergent prefrontal control networks for cognitive and emotional control extend previous separations of cognition and emotion in the anterior cingulate cortex.

  • 17.
    Korotkov, A.
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Ljubisavljevic, M.
    Thunberg, J.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Kataeva, G.
    Roudas, M.
    Pakhomov, S.
    Radovanovic, S.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Lyskov, E.
    Medvedev, S.
    Johansson, H.
    Changes in human regional cerebral blood flow following hypertonic saline induced experimental muscle pain: a positron emission tomography study2002In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 335, no 2, p. 119-123Article in journal (Refereed)
    Abstract [en]

    A positron emission tomography imaging study was performed on 16 healthy volunteers to reveal changes in cortical activation during acute muscle pain induced by intra-muscular injection of hypertonic saline into the left triceps brachii muscle. Changes in regional cerebral blood flow (rCBF) were measured with the use of [(15)O] labelled water during 'Rest1', 'Needle' (insertion of a needle without injection), 'Rest2' and 'Pain' conditions. Differences in rCBF were found in the comparison of Pain and Needle, and Pain and Rest2 conditions, revealing activation of the contralateral insula and putamen. The results are discussed with respect to possible differences in brain processing of muscle and cutaneous noxious inputs.

  • 18.
    Lind, Johanna
    et al.
    Department of Clinical Neuroscience, MR Research Center, Karolinska Hospital N-8, S-171 76 Stockholm, Sweden.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Persson, Jonas
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Ingvar, Martin
    Department of Clinical Neuroscience, MR Research Center, Karolinska Hospital N-8, S-171 76 Stockholm, Sweden.
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University, S-106 91 Stockholm, Sweden.
    Bäckman, Lars
    National Centre of Aging, Box 6401, S-113 82 Stockholm, Sweden.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Cruts, Marc
    Department of Molecular Genetics, Flanders Interuniversity, Institute of Biotechnology, University of Antwerp, B-2610 Antwerpen, Belgium.
    Sleegers, Kristel
    Department of Molecular Genetics VIB8, University of Antwerp, Campus CDE, Universiteitsplein 1, B-2610 Antwerp, Belgium.
    Van Broeckhoven, Christine
    Department of Molecular Genetics, Flanders Interuniversity, Institute of Biotechnology, University of Antwerp, B-2610 Antwerpen, Belgium.
    Nyberg, Lars
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Reduced hippocampal volume in non-demented carriers fo the apolipoprotein E ε4: Relation to chronological age and recognition memory2006In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 396, no 1, p. 23-27Article in journal (Refereed)
    Abstract [en]

    Apolipoprotein E ε4 (APOE ε4) is the main known genetic risk factor for Alzheimer's disease (AD). Some previous studies have reported structural brain changes as well as cognitive deficits in non-demented APOE ε4 carriers, but the pattern of results is inconsistent and studies with larger sample sizes have been called for. Here we compared hippocampal volume and recognition–memory performance between AD-symptom-free carriers (N = 30) and non-carriers (N = 30) of the APOE ε4 (age range: 49–79 years). We observed reduced right hippocampal volume in APOE ε4 carriers, and found that the difference was most pronounced before the age of 65. Further, the APOE ε4 carriers made significantly more false alarms in the recognition–memory test, and the number of false alarms correlated significantly with right hippocampus volume. These results indicate that relatively young individuals at genetic risk for AD have smaller hippocampal volume and lower performance on hippocampal-dependent cognitive tasks. A question for the future is whether smaller hippocampal volume represents early-onset hippocampal volume reduction or an inherent trait.

  • 19.
    Luisa Rojo Antuna, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rodriguez-Gaztelumendi, Antonio
    Pazos, Angel
    Diaz, Alvaro
    Differential adaptive changes on serotonin and noradrenaline transporters in a rat model of peripheral neuropathic pain2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 515, no 2, p. 181-186Article in journal (Refereed)
    Abstract [en]

    Serotonin and noradrenaline reuptake inhibitors have shown to produce antinociceptive effects in several animal models of neuropathic pain. In the present work, we have analyzed the density of brain and spinal serotonin and noradrenaline transporters (5-HIT and NAT) in a rat model of neuropathic pain, the spinal nerve ligation (SNL). Quantitative autoradiography revealed a significant decrease in the density of 5-HIT ([H-3]citalopram binding) at the level of the lumbar spinal cord following 2 weeks of neuropathic surgery (lamina V. -40%: 6.01 +/- 0.64 nCi/mg tissue in sham-animals vs 3.59 +/- 1.56 in SNL-animals; lamina X, -30%: 9.10 +/- 2.00 vs 6.40 +/- 1.93 and lamina IX, -22%: 12.01 +/- 2.41 vs 9.42 +/- 1.58). By contrast, NAT density ([H-3]nisoxetine binding) was significantly increased (lamina I-II, +34%: 2.20 +/- 0.45 vs 2.96 +/- 0.65; lamina V. +57%: 1.34 +/- 0.28 vs 2.11 +/- 0.66; and lamina IX, +58%: 2.39 0.71 vs 3.78 +/- 1.10). At supraspinal structures, SNL induced adaptive changes only in the density of 5-HIT (septal nuclei, +33%: 10.18 +/- 2.03 vs 13.53 +/- 1.14: CA3 field of hippocampus, +18%: 6.94 +/- 1.01 vs 8.21 +/- 0.81: paraventricular thalamic nucleus, +21%: 15.18 +/- 1.88 vs 18.35 +/- 2.08: lateral hypothalamic area, +40%: 12.68 +/- 1.90 vs 17.8 +/- 2.55: ventromedial hypothalamic nuclei, +19%: 7.16 +/- 0.92 vs 8.55 +/- 0.40; and dorsal raphe nucleus, +15%: 35.22 +/- 3.88 vs 40.68 +/- 13.11). Thus, we demonstrate, in the SNL model of neuropathic pain, the existence of opposite changes in the spinal expression of 5-WIT (down-regulation) and NAT(up-regulation), and the presence of supraspinal adaptive changes (up-regulation) only on 5-HIT density. These findings may help understanding the pathogeny of neuropathic pain and the differential analgesic action of antidepressants targeting 5-HIT and/or NAT transporters. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

  • 20.
    McGrath, Aleksandra M
    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.
    Brohlin, Maria
    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.
    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.
    Fibrin conduit supplemented with human mesenchymal stem cells and immunosuppressive treatment enhances regeneration after peripheral nerve injury2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 516, no 2, p. 171-176Article in journal (Refereed)
    Abstract [en]

    To address the need for the development of bioengineered replacement of a nerve graft, a novel two component fibrin glue conduit was combined with human mesenchymal stem cells (MSC) and immunosupressive treatment with cyclosporine A. The effects of MSC on axonal regeneration in the conduit and reaction of activated macrophages were investigated using sciatic nerve injury model. A 10mm gap in the sciatic nerve of a rat was created and repaired either with fibrin glue conduit containing diluted fibrin matrix or fibrin glue conduit containing fibrin matrix with MSC at concentration of 80×10(6)cells/ml. Cells were labeled with PKH26 prior to transplantation. The animals received daily injections of cyclosporine A. After 3 weeks the distance of regeneration and area occupied by regenerating axons and ED1 positives macrophages was measured. MSC survived in the conduit and enhanced axonal regeneration only when transplantation was combined with cyclosporine A treatment. Moreover, addition of cyclosporine A to the conduits with transplanted MSC significantly reduced the ED1 macrophage reaction.

  • 21.
    Naghavi, Hamid Reza
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. 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.
    Cortical regions underlying successful encoding of semantically congruent and incongruent associations between common auditory and visual objects.2011In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 505, no 2, p. 191-195Article in journal (Refereed)
    Abstract [en]

    Recent studies implicate regions in the frontal, temporal and occipital cortices of the brain in audio-visual (AV) integration of familiar objects. It remains unclear, however, which brain regions contribute to the creation of object-related AV memories, and whether activation of these regions is affected by crossmodal congruency. Here we used event-related functional MRI in a subsequent memory paradigm to investigate the neural substrates of successful encoding of semantically congruent and incongruent AV memories. Creation of both types of memories activated a region in the left inferior frontal gyrus (IFG). In addition, successful encoding of semantically related and unrelated AV pairs was correlated with increased activity in regions within the right lateral occipital cortex and bilateral lateral temporal cortex, respectively. These results may highlight a common role of IFG in retrieval of semantic information during encoding and suggest that the occipital and temporal cortices differentially process perceptual versus conceptual associations of AV memories.

  • 22.
    Naghavi, Hamid Reza
    et al.
    Tehran University of Medical Sciences, Institute for Cognitive Science Studies, Tehran, Iran.
    Eriksson, Johan
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. 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.
    The claustrum/insula region integrates conceptually related sounds and pictures2007In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 422, no 1, p. 77-80Article in journal (Refereed)
    Abstract [en]

    The brain is able to create coherent percepts from multisensory input. This phenomenon, known as multisensory integration (MSI), is a ubiquitous feature of everyday life and has been found to be essential for a reliable interaction with the environment. Recent functional neuroimaging studies suggest that several different networks are engaged in various forms of MSI depending on the nature of information being integrated. However, little is known about the neural basis of a fundamental form of MSI in natural conditions; integration of common auditory and visual objects which are conceptually related, such as when we look at a cat and hear a meowing sound. Here we used event-related fMRI to compare the brain response to conceptually related and unrelated pairs of audio-visual stimuli denoting common objects. Our protocol was designed to preclude contamination of the results by cognitive processes additional to those needed for MSI. The results indicate that higher-order temporal and occipital areas respond to coincident sounds and pictures regardless of their semantic relationship; whereas, the right claustrum/insula region is differentially activated in association with multisensory integration of conceptually related common objects. This observation has important implications for understanding how multimodal information about common objects is represented in the brain.

  • 23.
    Norberg, Anna
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Exclusion of the juvenile myoclonic epilepsy gene EFHC1 as the cause of migraine on chromosome 6, but association to two rare polymorphisms in MEP1A and RHAG.2006In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 396, no 2, p. 137-142Article in journal (Refereed)
  • 24. Norlén, M
    et al.
    Allard, Per
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Reduction in number of dopamine uptake sites but unchanged number of piperazine-acceptor/CYP450IID6 binding sites in the human caudate nucleus in aging.1996In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 209, no 3, p. 161-4Article in journal (Refereed)
    Abstract [en]

    A substantial decrease in number of striatal dopamine uptake sites is a characteristic finding in aging. This decrease resembles the dopaminergic nigro-striatal degeneration in Parkinson's disease (PD). A dysfunction of cytochrome P450IID6 (debrisoquine-4-hydroxylase) is suggested to be involved in the pathogenesis of PD. In this study, binding sites associated with the neuronal form of P450IID6 were studied in the caudate nucleus from individuals in the age range 20-81 years using [3H]GBR 12935 as a radioligand. No significant changes in binding parameters were obtained, while in the same region a significant decrease in number of dopamine uptake sites occurred. Thus, in aging, P450IID6 and dopaminergic degeneration seem not to be functionally related in this region. Whether such a relation exists in PD is still to be examined.

  • 25.
    Pettersson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    McGrath, Aleksandra
    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.
    Kalbermatten, Daniel
    University Hospital of Basel.
    Novikova, Liudmila
    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
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Muscle recovery after repair of short and long peripheral nerve gaps using fibrin conduits2011In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 500, no 1, p. 41-46Article in journal (Refereed)
    Abstract [en]

    Peripheral nerve injuries with loss of nervous tissue are a significant clinical problem and are currently treated using autologous nerve transplants. To avoid the need for donor nerve, which results in additional morbidity such as loss of sensation and scarring, alternative bridging methods have been sought. Recently we showed that an artificial nerve conduit moulded from fibrin glue is biocompatible to nerve regeneration. In this present study, we have used the fibrin conduit or a nerve graft to bridge either a 10 mm or 20 mm sciatic nerve gap and analyzed the muscle recovery in adult rats after 16 weeks. The gastrocnemius muscle weights of the operated side were similar for both gap sizes when treated with nerve graft. In contrast, muscle weight was 48.32 ± 4.96% of the contra-lateral side for the 10 mm gap repaired with fibrin conduit but only 25.20 ± 2.50% for the 20 mm gap repaired with fibrin conduit. The morphology of the muscles in the nerve graft groups showed an intact, ordered structure, with the muscle fibers grouped in fascicles whereas the 20 mm nerve gap fibrin group had a more chaotic appearance. The mean area and diameter of fast type fibers in the 20 mm gap repaired with fibrin conduits were significantly (P < 0.01) worse than those of the corresponding 10 mm gap group. In contrast, both gap sizes treated with nervegraft showed similar fiber size. Furthermore, the 10 mm gaps repaired with either nerve graft or fibrin conduit showed similar muscle fiber size. These results indicate that the fibrin conduit can effectively treat short nerve gaps but further modification such as the inclusion of regenerative cells may be required to attain the outcomes of nerve graft for long gaps.

  • 26.
    Reid, Adam J
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. University of Manchester.
    de Luca, Alba C
    University of Manchester.
    Faroni, Alessandro
    University of Manchester.
    Downes, Sandra
    University of Manchester.
    Sun, Mingzhu
    University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Long term peripheral nerve regeneration using a novel PCL nerve conduit2013In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 544, p. 125-30Article in journal (Refereed)
    Abstract [en]

    The gold standard in surgical management of a peripheral nerve gap is currently autologous nerve grafting. This confers patient morbidity and increases surgical time therefore innovative experimental strategies towards engineering a synthetic nerve conduit are welcome. We have developed a novel synthetic conduit made of poly ε-caprolactone (PCL) that has demonstrated promising peripheral nerve regeneration in short-term studies. This material has been engineered to permit translation into clinical practice and here we demonstrate that histological outcomes in a long-term in vivo experiment are comparable with that of autologous nerve grafting. A 1cm nerve gap in a rat sciatic nerve injury model was repaired with a PCL nerve conduit or an autologous nerve graft. At 18 weeks post surgical repair, there was a similar volume of regenerating axons within the nerve autograft and PCL conduit repair groups, and similar numbers of myelinated axons in the distal stump of both groups. Furthermore, there was evidence of comparable re-innervation of end organ muscle and skin with the only significant difference the lower wet weight of the muscle from the PCL conduit nerve repair group. This study stimulates further work on the potential use of this synthetic biodegradable PCL nerve conduit in a clinical setting.

  • 27.
    Rönnbäck, Annica
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Dahlqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Svensson, Per-Arne
    Jernås, Margareta
    Carlsson, Björn
    Carlsson, Lena M S
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Gene expression profiling of the rat hippocampus one month after focal cerebral ischemia followed by enriched environment2005In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 385, no 2, p. 173-178Article in journal (Refereed)
    Abstract [en]

    Functional recovery after experimental stroke in rats is enhanced by environmental enrichment by stimulating plastic changes in brain regions outside the lesion, but the molecular mechanisms are not known. We investigated the effect of environmental enrichment after focal cerebral ischemia on cognitive recovery and hippocampal gene expression using microarray analysis. Rats placed in enriched environment (EE) for 1 month after middle cerebral artery occlusion (MCAo) showed significantly improved spatial memory in the Morris water maze compared to rats housed alone after MCAo. Microarray analysis suggested several EE-induced differences in neuronal plasticity-related genes, but these changes could not be confirmed by quantitative real-time PCR. This study highlights some of the potential problems associated with gene expression profiling of brain tissues. Further studies at earlier time points and in additional subregions of the brain are of interest in the search for molecular mechanisms behind EE-induced neuronal plasticity after ischemic stroke.

  • 28. Tohill, Mel
    et al.
    Mantovani, Cristina
    Blond McIndoe Research Laboratories, University of Manchester, Manchester, UK.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Terenghi, Giorgio
    Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration2004In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 362, no 3, p. 200-203Article in journal (Refereed)
    Abstract [en]

    Bone marrow mesenchymal stem cells can trans-differentiate into neuronal phenotypes. We examined the differentiation of marrow stromal cells (MSCs) in culture and during nerve regeneration. MSCs from adult rats were exposed to glial growth factor (GGF) to stimulate glial differentiation. Subsequently differentiated MSCs were retrovirally labelled with green fluorescent protein and transplanted into 1 cm nerve conduits in the rat sciatic nerve. Fifteen days post-operatively the conduits were examined for axonal and Schwann cell regeneration and MSC integration. In vitro, MSCs exposed to GGF expressed S100 and glial fibrillary acidic protein. Following transplantation, MSCs maintained S100 expression and enhanced nerve regeneration, with significant Schwann cell regeneration compared to control (2.7 +/- 0.21 vs. 2.05 +/- .21 mm; P < 0.05). MSCs not exposed to GGF prior to transplantation expressed S100 in vivo indicating glial differentiation in response to local cytokines and growth factors.

  • 29.
    Virel, Ana
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Johansson, Jarkko
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Laterveer, Rutger
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Ögren, Mattias
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Jakobson Mo, Susanna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    N-acetylcysteine decreases dopamine transporter availability in the non-lesioned striatum of the 6-OHDA hemiparkinsonian rat2022In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 770, article id 136420Article in journal (Refereed)
    Abstract [en]

    This study aimed to explore the beneficial effects of the antioxidant N-acetylcysteine (NAC) on the degenerated dopamine system. The short- and long-term regulatory mechanisms of NAC on the 6-OHDA hemiparkinsonian rat model were longitudinally investigated by performing positron emission tomography (PET) imaging using the specific dopamine transporter (DAT) radioligand [18F]FE-PE2I. The results demonstrate that after a unilateral dopamine insult NAC has a strong influence on the non-lesioned hemisphere by decreasing the levels of DAT in the striatum early after the lesion. We interpret this early and short-term decrease of DAT in the healthy striatum of NAC-treated animals as a beneficial compensatory effect induced by NAC.

  • 30.
    Wang, Chao
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Iashchishyn, Igor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kara, John
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Fodera, Vito
    Vetri, Valeria
    Sancataldo, Giuseppe
    Marklund, Niklas
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Proinflammatory and amyloidogenic S100A9 induced by traumatic brain injury in mouse model2019In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 699, p. 199-205Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) represents a significant risk factor for development of neurodegenerative diseases such as Alzheimer's and Parkinson's. The S100A9-driven amyloid-neuroinflammatory cascade occurring during primary and secondary TBI events can serve as a mechanistic link between TBI and Alzheimer's as demonstrated recently in the human brain tissues. Here by using immunohistochemistry in the controlled cortical impact TBI mouse model we have found pro-inflammatory S100A9 in the brain tissues of all mice on the first and third post- TBI days, while 70% of mice did not show any S100A9 presence on seventh post-TBI day similar to controls. This indicates that defensive mechanisms effectively cleared S100A9 in these mouse brain tissues during post-TBI recovery. By using sequential immunohistochemistry we have shown that S100A9 was produced by both neuronal and microglial cells. However, A beta peptide deposits characteristic for Alzheimer's disease were not detected in any post-TBI animals. On the first and third post-TBI days S100A9 was found to aggregate intracellularly into amyloid oligomers, similar to what was previously observed in human TBI tissues. Complementary, by using Rayleigh scatting, intrinsic fluorescence and atomic force microscopy we demonstrated that in vitro S100A9 self- assembles into amyloid oligomers within minutes. Its amyloid aggregation is highly dependent on changes of environmental conditions such as variation of calcium levels, pH, temperature and reduction/oxidation, which might be relevant to perturbation of cellular and tissues homeostasis under TBI. Present results demonstrate that S100A9 induction mechanisms in TBI are similar in mice and humans, emphasizing that S100A9 is an important marker of brain injury and therefore can be a potential therapeutic target.

  • 31.
    Westermark, T
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Isaksson, T
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Holmberg, P
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kjörell, U
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Increase in bombesin-like peptides in the spinal cord after dexamethasone treatment of adrenalectomized rats1999In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 275, no 3, p. 179-182Article in journal (Refereed)
    Abstract [en]

    The potential influence of corticosteroids on the bombesin (BN)-like peptide family is unknown. Therefore, the effects of adrenalectomy (ADX) on the nervous system of Sprague-Dawley rats, some of them being treated with high doses of the synthetic glucocorticoid dexamethasone (DEX), were investigated. After 8-10 days of treatment, the rats were sacrificed and tissues were prepared for radioimmunoassay (RIA) and immunohistochemical examination. We found an increase in BN-like immunoreactivity in the superficial layers of the dorsal horn of the lumbar spinal cord in the ADX + DEX animals. This increase was confirmed by RIA (P < 0.05). The observations show that the expression of BN-like peptides is influenced by glucocorticoids. The altered levels of BN-like peptides may be related to the trophic and antinociceptive effects previously reported for these peptides. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

  • 32.
    Öhman, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    NMR metabonomics of cerebrospinal fluid distinguishes between Parkinson's disease and controls2015In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 594, p. 36-39Article in journal (Refereed)
    Abstract [en]

    This study assesses if nuclear magnetic resonance (NMR) metabonomics can discriminate between Parkinson's disease (PD) patients and control subjects, and consequently identify metabolic markers for the disease. One-dimensional H-1 NMR spectroscopy was used for quantitative analysis of metabolites in the cerebrospinal fluid (CSF) from 10 PD patients and 10 control individuals, together with uni- and multivariate statistical analysis to discriminate between the groups and to identify significantly altered metabolite concentrations. In total 60 metabolites were identified and of those 38 were quantified in all CSF samples. An overall lowering of metabolite content was observed in PD patients compared to control subjects (fold change of 0.85 +/- 0.30). Multivariate statistics reveal significant changes (vertical bar w*vertical bar>0.2) among nine metabolites (alanine, creatinine, dimethylamine, glucose, lactate, mannose, phenylalanine, 3-hydroxyisobutyric acid and 3-hydroxyisovaleric acid). Three of these (alanine, creatinine and mannose) are identified as significantly changed also by univariate statistics (p < 0.00132, Bonferroni corrected). Panels with all or a selected set of these metabolites were successfully used for discriminating between the two groups. In conclusion, NMR metabonomics can readily determine metabolite concentrations in CSF, identify putative biomarkers that distinguish between the PD patients and control subjects, and thus potentially become a tool for diagnostic purposes.

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