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  • 401.
    Han, Jing
    et al.
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR China; Biomat lab, Department of Mechanical Engineering, National University of Singapore, Singapore.
    Li, Danyang
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR China.
    Qu, Chengjuan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wang, Dong
    Biomat lab, Department of Mechanical Engineering, National University of Singapore, 117576, Singapore; Department of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
    Wang, Liyun
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR Chin.
    Guo, Xiong
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR Chin.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR China.
    Altered expression of chondroitin sulfate structure modifying sulfotransferases in the articular cartilage from adult osteoarthritis and Kashin-Beck disease2017In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 25, no 8, p. 1372-1375, article id 28274888Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the expression of enzymes involved in chondroitin sulfate (CS) sulfation in the articular cartilage isolated from adult patients with osteoarthritis (OA) and Kashin-Beck disease (KBD), using normal adults as controls.

    METHODS: Articular cartilage samples were collected from normal, OA and KBD adults aged 38-60 years old, and divided into three groups with six individual subjects in each group. The morphology and pathology grading of knee joint cartilage was examined by Safranin O staining. The localization and expression of enzymes involved in CS sulfation (CHST-3, CHST-11, CHST-12, CHST-13, CHST-15, and UST) were examined by immunohistochemical staining and semi-quantitative analysis.

    RESULTS: Positive staining rates for anabolic enzymes CHST-3, CHST-12, CHST-15, and UST were lower in the KBD and OA groups than those in the control group. Meanwhile, reduced levels of CHST-11, and CHST-13 in KBD group were observed, in contrast to those in OA and control groups. The expressions of all six CS sulfation enzymes were less detected in the superficial and deep zones of KBD cartilage compared with control and OA cartilage.

    CONCLUSION: The reduced expression of the CS structure modifying sulfotransferases in the chondrocytes of both KBD and OA adult patients may provide explanations for their cartilage damages, and therapeutic targets for their treatment.

  • 402. Hansson, A C
    et al.
    Sommer, W H
    Metsis, M
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Agnati, L F
    Fuxe, K
    Corticosterone actions on the hippocampal brain-derived neurotrophic factor expression are mediated by exon IV promoter.2006In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 18, no 2, p. 104-114Article in journal (Refereed)
    Abstract [en]

    Brain-derived neurotrophic factor (BDNF) expression is strongly regulated by adrenocorticosteroids via activated gluco- and mineralocorticoid receptors. Four separate promoters are located upstream of the BDNF noncoding exons I to IV and may thus be involved in adrenocorticosteroid-mediated gene regulation. In adrenalectomised rats, corticosterone (10 mg/kg s.c.) induces a robust down-regulation of both BDNF mRNA and protein levels in the hippocampus peaking at 2-8 h. To study the role of the individual promoters in the corticosterone response, we employed exon-specific riboprobe in situ hybridisation as well as real-time polymerase chain reaction (PCR) in the dentate gyrus. We found a down-regulation, mainly of exon IV and the protein-coding exon V, in nearby all hippocampal subregions, but exon II was only down-regulated in the dentate gyrus. Exon I and exon III transcripts were not affected by corticosterone treatment. The results could be confirmed with real-time PCR in the dentate gyrus. It appears as if the exon IV promoter is the major target for corticosterone-mediated transcriptional regulation of BDNF in the hippocampus.

  • 403.
    Hansson, C
    et al.
    Sahlgrenska Academy at the University of Gothenburg.
    Haage, D
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Sahlgrenska Academy at the University of Gothenburg.
    Taube, M
    Sahlgrenska Academy at the University of Gothenburg.
    Egecioglu, E
    Sahlgrenska Academy at the University of Gothenburg.
    Salomé, N
    Sahlgrenska Academy at the University of Gothenburg.
    Dickson, S L
    Sahlgrenska Academy at the University of Gothenburg.
    Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 180, p. 201-211Article in journal (Refereed)
    Abstract [en]

    The orexigenic and pro-obesity hormone ghrelin targets key hypothalamic and mesolimbic circuits involved in energy balance, appetite and reward. Given that such circuits are closely integrated with those regulating mood and cognition, we sought to determine whether chronic (>2 weeks) CNS exposure to ghrelin alters anxiety- and depression-like behaviour in rats as well as some physiological correlates. Rats bearing chronically implanted i.c.v. catheters were treated with ghrelin (10 μg/d) or vehicle for 4 weeks. Tests used to assess anxiety- and depression-like behaviour were undertaken during weeks 3-4 of the infusion. These revealed an increase in anxiety- and depression-like behaviour in the ghrelin-treated rats relative to controls. At the end of the 4-week infusion, brains were removed and the amygdala dissected for subsequent qPCR analysis that revealed changes in expression of a number of genes representing key systems implicated in these behavioural changes. Finally, given the key role of the dorsal raphe serotonin system in emotional reactivity, we examined the electrophysiological response of dorsal raphe neurons after a ghrelin challenge, and found mainly inhibitory responses in this region. We demonstrate that the central ghrelin signalling system is involved in emotional reactivity in rats, eliciting pro-anxiety and pro-depression effects and have begun to explore novel target systems for ghrelin that may be of importance for these effects.

  • 404.
    Hansson, M
    et al.
    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.
    Forsgren, S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ingrowth of sympathetic innervation occurs concomitantly with a decrease of ANP in the growing rat cardiac ventricles.2001In: Anatomy and Embryology, ISSN 0340-2061, E-ISSN 1432-0568, Vol. 203, no 1, p. 35-44Article in journal (Refereed)
    Abstract [en]

    The relationship between the immunohistochemical expression of atrial natriuretic peptide and the occurrence of sympathetic nerve fibres, as visualized by staining for tyrosine hydroxylase, in the growing rat heart was evaluated. Rats were investigated at four different stages from birth to 21 days postnatally. The effects of chemical destruction of sympathetic nerve terminals in neonatal rats on the cardiac atrial natriuretic peptide content were furthermore examined by use of radioimmunoassay. There was in principle a reciprocal pattern of immunoreaction for atrial natriuretic peptide and tyrosine hydroxylase positive innervation in the ventricular myocardium, atrial natriuretic peptide reaction becoming less and less pronounced with the ingrowth of innervation positive for tyrosine hydroxylase. Furthermore, in the peripheral Purkinje fibre network, there was a marked atrial natriuretic peptide immunoexpression and scarce or no nerve fibres throughout the examination period. The radioimmunoassay measurements showed that chemical sympathectomy lead to elevated cardiac levels of atrial natriuretic peptide. The study shows that sympathetic innervation grows into the ventricular parts concomitantly with the occurrence of a decline in atrial natriuretic peptide expression during development of the heart. Furthermore, it is shown that a reversion of the in growth of sympathetic innervation by destruction of cardiac sympathetic nerves at an early stage leads to increased levels of atrial natriuretic peptide in the heart. The results give new evidence to the phenomenon that the atrial natriuretic peptide levels in the ventricular myocardium and the peripheral parts of the conduction system are under influence of the presence of sympathetic innervation.

  • 405.
    Hansson, Magnus
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Receptor binding occurrence and plasma levels of natriuretic peptides in response to sympathectomy.2005In: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 67, no 2, p. 90-99Article in journal (Refereed)
  • 406.
    Hansson, Magnus
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Expression of brain natriuretic peptide in the rat heart studies during heart growth and in relation to sympathectomy2004In: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 64, no 1, p. 30-42Article in journal (Refereed)
    Abstract [en]

    Brain natriuretic peptide (BNP) might be of importance during heart development and is described to be increasingly expressed in congestive heart failure and to affect the progress of this condition. However, details in the normal expression of BNP are still unclear in various parts of the adult and growing heart, including the conduction system. In this study, we investigated the expression of BNP in relation to that of atrial natriuretic peptide (ANP) in the growing as well as in the adult rat heart. The effects of chemical sympathectomy in adult rats were also examined. Contrary to previous BNP immunohistochemical studies, the BNP antiserum was preabsorbed with an excess of ANP before staining to abolish the crossreactivity with ANP. There was a pronounced BNP immunoreaction in the auricles, the trabeculated ventricular walls, and the peripheral parts of the conduction system at 0-1 days postnatally. The degree of immunoreaction gradually decreased with increasing age. A similar developmental pattern was seen concerning ANP expression, but the magnitude of the latter clearly exceeded that for BNP. Immunoreaction for BNP was never detected in the atrioventricular (AV) node and AV bundle at any stage. In contrast to the situation for ANP previously observed, no obvious changes in BNP immunoreaction patterns were observed in response to sympathectomy. This is the first study to thoroughly demonstrate the expression of BNP in the various regions of the rat heart during growth and in the normal and sympathectomized adult stage. The observations are related to possible functions of natriuretic peptides in the growing and adult heart.

  • 407.
    Hansson, Patrik
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Sunnegårdh-Grönberg, Karin
    Umeå University, Faculty of Medicine, Department of Odontology, Dental Hygiene.
    Bergdahl, Jan
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Bergdahl, Maud
    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.
    Nilsson, Lars-Göran
    Relationship between natural teeth and memory in a healthy elderly population2013In: European Journal of Oral Sciences, ISSN 0909-8836, E-ISSN 1600-0722, Vol. 121, no 4, p. 333-340Article in journal (Refereed)
    Abstract [en]

    The relationship between mastication and cognitive function remains unclear, but both animal and experimental human studies suggest a possible causal relationship. In the present study it was hypothesized that natural teeth are of importance for hippocampus-based cognitive processes, such as episodic long-term memory. A population-based sample of 273 participants (55-80yr of age; 145 women) was investigated in a cross-sectional study. The participants underwent health assessment, completed a battery of cognitive tests, and took part in an extensive clinical oral examination. The number of natural teeth contributed uniquely and significantly to explaining variance (3-4%) in performance on measures of episodic memory and semantic memory over and above individual differences in age, years of education, gender, occupation, living conditions, and medical history. The number of natural teeth did not have an influence on the performance of measures of working memory, visuospatial ability, or processing speed. Within the limitations of the current study, a small, but significant, relationship between episodic memory and number of natural teeth is evident.

  • 408.
    Hao, Manzhao
    et al.
    Institute of Rehabilitation Engineering, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
    He, Xin
    Institute of Rehabilitation Engineering, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
    Xiao, Qin
    Institute of Rehabilitation Engineering, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
    Alstermark, Bror
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Lan, Ning
    Institute of Rehabilitation Engineering, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
    Corticomuscular transmission of tremor signals by propriospinal neurons in Parkinson's disease.2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, article id e79829Article in journal (Refereed)
    Abstract [en]

    Cortical oscillatory signals of single and double tremor frequencies act together to cause tremor in the peripheral limbs of patients with Parkinson's disease (PD). But the corticospinal pathway that transmits the tremor signals has not been clarified, and how alternating bursts of antagonistic muscle activations are generated from the cortical oscillatory signals is not well understood. This paper investigates the plausible role of propriospinal neurons (PN) in C3-C4 in transmitting the cortical oscillatory signals to peripheral muscles. Kinematics data and surface electromyogram (EMG) of tremor in forearm were collected from PD patients. A PN network model was constructed based on known neurophysiological connections of PN. The cortical efferent signal of double tremor frequencies were integrated at the PN network, whose outputs drove the muscles of a virtual arm (VA) model to simulate tremor behaviors. The cortical efferent signal of single tremor frequency actuated muscle spindles. By comparing tremor data of PD patients and the results of model simulation, we examined two hypotheses regarding the corticospinal transmission of oscillatory signals in Parkinsonian tremor. Hypothesis I stated that the oscillatory cortical signals were transmitted via the mono-synaptic corticospinal pathways bypassing the PN network. The alternative hypothesis II stated that they were transmitted by way of PN multi-synaptic corticospinal pathway. Simulations indicated that without the PN network, the alternating burst patterns of antagonistic muscle EMGs could not be reliably generated, rejecting the first hypothesis. However, with the PN network, the alternating burst patterns of antagonist EMGs were naturally reproduced under all conditions of cortical oscillations. The results suggest that cortical commands of single and double tremor frequencies are further processed at PN to compute the alternating burst patterns in flexor and extensor muscles, and the neuromuscular dynamics demonstrated a frequency dependent damping on tremor, which may prevent tremor above 8 Hz to occur.

  • 409.
    Harandi, Vahid M.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    A Muscle Perspective on the Pathophysiology of Amyotrophic Lateral Sclerosis: Differences between extraocular and limb muscles2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder. ALS has been traditionally believed to be primarily a motor neuron disease. However, accumulating data indicate that loss of contact between the axons and the muscle fibres occurs early; long before the death of motor neurons and that muscle fibres may initiate motor neuron degeneration. Thus, the view of ALS is changing focus from motor neurons alone to also include the muscle fibres and the neuromuscular junctions (NMJs). While skeletal muscles are affected in ALS, oculomotor disturbances are not dominant features of this disease and extraocular muscles (EOMs) are far less affected than limb muscles. Why oculomotor neurons and EOMs are capable to be more resistant in the pathogenetic process of ALS is still unknown.

    The overall goal of this thesis is to explore the pathophysiology of ALS from a muscle perspective and in particular study the expression and distribution of key neurotrophic factors (NTFs) and Wnt proteins in EOMs and limb muscles from ALS donors and from SOD1G93A transgenic mice. Comparisons were made with age-matched controls to distinguish between changes related to ALS and to ageing.

    Results: Brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4) were present in EOMs and limb muscles at both mRNA and protein levels in control mice. The mRNA levels of BDNF, NT-3 and NT-4 were significantly lower in EOMs than in limb muscles of early and/or late control mice, indicating an intrinsic difference in NTFs expression between EOMs and limb muscles. qRT-PCR analysis showed significantly upregulated mRNA levels of NT-3 and GDNF in EOMs but significantly downregulated mRNA levels of NT-4 in limb muscles from SOD1G93A transgenic mice at early stage. The NTFs were detected immunohistochemically in NMJs, nerve axons and muscle fibres. The expression of BDNF, GDNF and NT-4 on NMJs of limb muscles, but not of EOMs, was significantly decreased in terminal stage ALS animals as compared to the limb muscles of the age-matched controls. In contrast, NTFs expression in intramuscular nerve axons did not present significant changes in either muscle group of early or late ALS mice. NTFs, especially BDNF and NT-4 were upregulated in some small-sized muscle fibres in limb muscles of late stage ALS mice. All the four Wnt isoforms, Wnt1, Wnt3a, Wnt5a and Wnt7a were detected in most axon profiles in all human EOMs with ALS, whereas significantly fewer axon profiles were positive in the human limb muscles except for Wnt5a. Similar differential patterns were found in myofibres, except for Wnt7a, where its expression was elevated within sarcolemma of limb muscle fibres. β-catenin, a marker of the canonical Wnt pathway was activated in a subset of myofibres in the EOMs and limb muscle in all ALS patients. In the SOD1G93A mouse, all four Wnt isoforms were significantly decreased in the NMJs at the terminal stage compared to age matched controls.

    Conclusions: There were clear differences in NTF and Wnt expression patterns between EOM and limb muscle, suggesting that they may play a role in the distinct susceptibility of these two muscle groups to ALS. In particular, the early upregulation of GDNF and NT-3 in the EOMs might play a role in the preservation of the EOMs in ALS. Further studies are needed to determine whether these proteins and the pathways they control may be have a future potential as protecting agents for other muscles.

  • 410.
    Harandi, Vahid M
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Gaied, Aida RN
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Unchanged neurotrophic factors and their receptors correlate with sparing in extraocular muscles in amyotrophic lateral sclerosis2016In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, no 15, p. 6831-6842Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate the impact of amyotrophic lateral sclerosis (ALS) on the extraocular muscles (EOMs) by examining the distribution of neurotrophic factors (NTFs) and their receptors in EOMs and limb muscles from ALS transgenic mice.

    Methods: Muscle samples collected from transgenic mice overexpressing human superoxide dismutase type 1 mutations (SOD1G93A, the most widely used mouse model of ALS) at 50 and 150 days as well as age-matched controls were analyzed with immunohistochemistry using antibodies against brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4), glial cell line-derived neurotrophic factor (GDNF), and the neurotrophin receptors p75NTR, tyrosine kinase (Trk) receptor TrkB and TrkC, and GDNF family receptor alpha-1 (GFRα-1).

    Results: There was an intrinsic difference in NTF expression between EOMs and limb muscles in control mice: EOMs presented significantly lower number of neuromuscular junctions (NMJs) labeled for BDNF and NT-4 at 50 days, and for BDNF and GDNF at 150 days, compared with the control limb muscles of corresponding age. In ALS transgenic mice at 150 days, NTF expression in limb muscles was significantly changed but not in EOMs: the limb muscles presented a significant decline in the number of NMJs labeled for BDNF, NT-4, GDNF, p75NTR, TrkB, and TrkC, which was not observed in EOMs.

    Conclusions: The significant differences in expression of NTFs on NMJs between EOMs and limb muscles in both control and ALS transgenic mice suggest that NTF may be involved in the pathogenesis of ALS and the resistance of EOMs to the disease.

  • 411.
    Hart, Andrew M
    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. Blond-McIndoe Research Laboratories, The University of Manchester, Stopford Building, Room 3.106, Oxford; Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK.
    Terenghi, Giorgio
    Frozen-section fluorescence microscopy and stereology in the quanti cation of neuronal death within dorsal root ganglia2004In: Journal of Molecular Histology, ISSN 1567-2379, E-ISSN 1567-2387, Vol. 35, no 6, p. 565-580Article in journal (Refereed)
    Abstract [en]

    Histochemical and morphological research increasingly relies upon quanti cation of complex biological systems. For such investigations to be meaningful, quanti cation techniques must meet the seemingly conflicting requirements of being theoretically robust, yet sufficiently practical to facilitate widespread applicability. Validity ought to be enhanced by theoretical simplicity, use of measured rather than assumed variables, and minimising observer interpretation. Practicality is facilitated by simplifying and reducing measurements, broadening applicability, and reducing costs and analysis time. As a result, quanti cation systems that rely upon sampling and estimation have been favoured over serial reconstruction techniques. To provide reliable estimates, sampling must be valid at all levels from tissue harvest, to the selection of microscope fields in which quanti cation is performed by techniques that account for the anisotropic distribution, and variable size of many elements in biological systems. These principles are embodied in the development of a stereological approach to the quanti cation of neuronal death within dorsal root ganglia after peripheral nerve injury. This frozen section technique is efficient and flexible, since it permits simultaneous morphological examination, TUNEL, or standard fluorescence immunohistochemistry, broadening its applicability. Section shrinkage is minimal, and counting by optical disection has proved to be time-efficient and sufficiently reproducible to reliably detect losses in the order of 5%, with minimal inter-observer variation. As is discussed, stereology has not yet met with universal acceptance, but by balancing theoretical validity with practical applicability, it has proved an excellent approach to the investigation of neuronal death within dorsal root ganglia.

  • 412. Hart, Andrew M
    et al.
    Terenghi, Giorgio
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
    Neuronal death after peripheral nerve injury and experimental strategies for neuroprotection.2008In: Neurological Research, ISSN 0161-6412, E-ISSN 1743-1328, Vol. 30, no 10, p. 999-1011Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Despite considerable microsurgical innovation in peripheral nerve repair, the outcome has improved little since the 1940s, reflecting surgical inability to adequately address the complex neurobiology of nerve injury and regeneration. Axotomy-induced neuronal death is potentially the most fundamental problem, and given recently published data, a review is timely. METHODS: Initial review of relevant doctoral theses from the University of Umeå, and Blond-McIndoe Research Laboratories, the University of Manchester, plus initial PubMed search including terms 'neuron death' and 'neuroprotection', subsequently expanded to relevant quoted articles. RESULTS: Various factors related to patient (principally age) and injury (Sunderland grade, proximity to cell body and mechanism) determine the extent of neuronal death, the mechanism of which is reviewed. A considerable proportion of sensory neurons (particularly small cutaneous afferents) die after distal injury and death is more widespread after proximal injury. Motor neurons are susceptible to post-ganglionic plexus and spinal root level injury. Root avulsion causes the greatest cell death. The time course of neuronal death is fortuitously slow and mainly occurs by a process akin to apoptosis. A therapeutic window therefore exists, as do potential neuroprotective targets. Nerve repair is partly neuroprotective, but must be performed early. Exogenous neurotrophic factor administration (e.g. in tissue engineered conduits) is beneficial, but not practical for various reasons. In contrast, adjuvant neuroprotective pharmacotherapy is practical, and two clinically safe agents are reviewed. Acetyl-L-carnitine arrests sensory neuronal death and speeds up regeneration. N-acetyl-cysteine provides comparable sensory neuronal protection via mitochondrial preservation and protects motor neurons. Both agents are well characterized experimentally and highly effective even after clinically relevant delays between injury and treatment. Barriers to translational research are being addressed. DISCUSSION: The future of peripheral nerve repair lies in modulating neurobiology at the time of injury, repair and during regeneration. Neuroprotection may be an essential component of that therapeutic package.

  • 413.
    Hart, Andrew McKay
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Blond-McIndoe Laboratories, Royal Free and University College Medical School, University Department of Surgery, Royal Free Campus, Rowland Hill Street, London, UK.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    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
    Blond-McIndoe Laboratories, Royal Free and University College Medical School, University Department of Surgery, Royal Free Campus, Rowland Hill Street, London, UK.
    Primary sensory neurons and satellite cells after peripheral axotomy in the adult rat: timecourse of cell death & elimination2002In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 142, no 3, p. 308-318Article in journal (Refereed)
    Abstract [en]

    The timecourse of cell death in adult dorsal root ganglia after peripheral axotomy has not been fully characterised. It is not clear whether neuronal death begins within I week of axotomy or continues beyond 2 months after axotomy. Similarly, neither the timecourse of satellite cell death in the adult, nor the effect of nerve repair has been described. L4 and L5 dorsal root ganglia were harvested at 1-14 days, 1-6 months after sciatic nerve division in the adult rat, in accordance with the Animals (Scientific Procedures) Act 1986. In separate groups the nerve was repaired either immediately or following a 1-week delay, and the ganglia were harvested 2 weeks after the initial transection. Microwave permeabilisation and triple staining enabled combined TUNEL staining, morphological examination and neuron counting by the stereological optical dissector technique. TUNEL-positive neurons, exhibiting a range of morphologies, were seen at all timepoints (peak 25 cells/group 2 weeks after axotomy) in axotomised ganglia only. TUNEL-positive satellite cell numbers peaked 2 months after axotomy and were more numerous in axotomised than control ganglia. L4 control ganglia contained 13,983 (SD 568) neurons and L5, 16,285 (SD 1,313). Neuron loss was greater in L5 than L4 axotomised ganglia, began at I week (15%, P=0.045) post-axotomy, reached 35% at 2 months (P<0.001) and was not significantly greater at 4 months or 6 months. Volume of axotomised ganglia fell to 19% of control by 6 months (P<0.001). In animals that underwent nerve repair, both the number of TUNEL-positive neurons and neuron loss were reduced. Immediate repair was more protective than repair after a 1-week delay. Thus TUNEL positivity precedes actual neuron loss, reflecting the time taken to complete cell death and elimination. Neuronal death begins within I day of peripheral axotomy, the majority occurs within the first 2 months, and limited death is still occurring at 6 months. Neuronal death is modulated by peripheral nerve repair and by its timing after axotomy. Secondary satellite cell death also occurs, peaking 2 months after axotomy. These results provide a logical framework for future research into neuronal and satellite cell death within the dorsal root ganglia and provide further insight into the process of axotomy induced neuronal death.

  • 414.
    Hart, Andrew McKay
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
    Terenghi, Giorgio
    Kellerth, Jan-Olof
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
    Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of N-acetyl-cysteine after nerve injury.2004In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 125, no 1, p. 91-101Article in journal (Refereed)
    Abstract [en]

    Neuronal death is a major factor in many neuropathologies, particularly traumatic, and yet no neuroprotective therapies are currently available clinically, although antioxidants and mitochondrial protection appear to be fruitful avenues of research. The simplest system involving neuronal death is that of the dorsal root ganglion after peripheral nerve trauma, where the loss of approximately 40% of primary sensory neurons is a major factor in the overwhelmingly poor clinical outcome of the several million nerve injuries that occur each year worldwide. N-acetyl-cysteine (NAC) is a glutathione substrate which is neuroprotective in a variety of in vitro models of neuronal death, and which may enhance mitochondrial protection. Using TdT uptake nick-end labelling (TUNEL), optical disection, and morphological studies, the effect of systemic NAC treatment upon L4 and 5 primary sensory neuronal death after sciatic nerve transection was investigated. NAC (150 mg/kg/day) almost totally eliminated the extensive neuronal loss found in controls both 2 weeks (no treatment 21% loss, NAC 3%, P=0.03) and 2 months after axotomy (no treatment 35% loss, NAC 3%, P=0.002). Glial cell death was reduced (mean number TUNEL positive cells 2 months after axotomy: no treatment 51/ganglion pair, NAC 16/ganglion pair), and mitochondrial architecture was preserved. The effects were less profound when a lower dose was examined (30 mg/kg/day), although significant neuroprotection still occurred. This provides evidence of the importance of mitochondrial dysregulation in axotomy-induced neuronal death in the peripheral nervous system, and suggests that NAC merits investigation in CNS trauma. NAC is already in widespread clinical use for applications outside the nervous system; it therefore has immediate clinical potential in the prevention of primary sensory neuronal death, and has therapeutic potential in other neuropathological systems.

  • 415.
    Hart, Andrew McKay
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    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
    Blond–McIndoe Centre, Royal Free and University College Medical School, London, UK.
    Exogenous leukaemia inhibitory factor enhances nerve regeneration after late secondary repair using a bioartificial nerve conduit2003In: British Journal of Plastic Surgery, ISSN 0007-1226, E-ISSN 1465-3087, Vol. 56, no 5, p. 444-450Article in journal (Refereed)
    Abstract [en]

    The clinical outcome of peripheral nerve injuries remains disappointing, even in the ideal situation of a primary repair performed with optimal microsurgical techniques. Primary repair is appropriate for only about 85% of injuries, and outcome is worse following secondarynerverepair, partly owing to the reduced regenerative potential of chronically axotomised neurons. Leukaemiainhibitoryfactor (LIF) is a gp-130 neurocytokine that is thought to act as an ‘injury factor’, triggering the early-injury phenotype within neurons and potentially boosting their regenerative potential aftersecondarynerverepair. At 2–4 months after sciatic nerve axotomy in the rat, 1 cm gaps were repaired using either nerve isografts or poly-3-hydroxybutyrate conduits containing a calcium alginate and fibronectin hydrogel.

    Regeneration was determined by quantitative immunohistochemistry 6 weeks afterrepair, and the effect of incorporating recombinant LIF (100 ng/ml) into the conduits was assessed. LIF increased the regeneration distance in repairs performed after both 2 months (69%, P=0.019) and 4 months (123%, P=0.021), and was statistically comparable to nerve graft. The total area of axonal immunostaining increased by 21% (P>0.05) and 63% (P>0.05), respectively. Percentage immunostaining area was not increased in the 2 months group, but increased by 93% in the repairs performed 4 months after axotomy. Exogenous LIF, therefore, has a potential role in promoting peripheral nerveregenerationaftersecondaryrepair, and can be effectively delivered within poly-3-hydroxybutyrate bioartificialconduits used for nerverepair.

  • 416.
    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.

  • 417.
    Hart, Andrew McKay
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Blond-McIndoe Centre, Royal Free & 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.
    Youle, Mike
    Royal Free Centre for HIV Medicine, Royal Free Hospital, London, UK.
    Terenghi, Giorgio
    Blond-McIndoe Centre, Royal Free & University College Medical School, University Department of Surgery, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK.
    Systemic acetyl-L-carnitine eliminates sensory neuronal loss after peripheral axotomy: a new clinical approach in the management of peripheral nerve trauma2002In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 145, no 2, p. 182-189Article in journal (Refereed)
    Abstract [en]

    Several hundred thousand peripheral nerve injuries occur each year in Europe alone. Largely due to the death of around 40% of primary sensory neurons, sensory outcome remains disappointingly poor despite considerable advances in surgical technique; yet no clinical therapies currently exist to prevent this neuronal death. Acetyl-L-carnitine (ALCAR) is a physiological peptide with roles in mitochondrial bioenergetic function, which may also increase binding of nerve growth factor by sensory neurons. Following unilateral sciatic nerve transection, adult rats received either one of two doses of ALCAR or sham, or no treatment. Either 2 weeks or 2 months later, L4 and L5 dorsal root ganglia were harvested bilaterally, in accordance with the Animal (Scientific Procedures) Act 1986. Neuronal death was quantified with a combination of TUNEL [TdT (terminal deoxyribonucleotidyl transferase) uptake nick end labelling] and neuron counts obtained using the optical disector technique. Sham treatment had no effect upon neuronal death. ALCAR treatment caused a large reduction in the number of TUNEL-positive neurons 2 weeks after axotomy (sham treatment 33/group; low-dose ALCAR 6/group, P=0.132; high-dose ALCAR 3/group, P<0.05), and almost eliminated neuron loss (sham treatment 21%; low-dose ALCAR 0%, P=0.007; high-dose ALCAR 2%, P<0.013). Two months after axotomy the neuroprotective effect of high-dose ALCAR treatment was preserved for both TUNEL counts (no treatment five/group; high-dose ALCAR one/group) and neuron loss (no treatment 35%; high-dose ALCAR -4%, P<0.001). These results provide further evidence for the role of mitochondrial bioenergetic dysfunction in post-traumatic sensory neuronal death, and also suggest that acetyl-L-carnitine may be the first agent suitable for clinical use in the prevention of neuronal death after peripheral nerve trauma.

  • 418.
    Hart, Andrew
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Terenghi, Giorgio
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Tissue Engineering for Peripheral Nerve Regeneration2011In: Tissue Engineering: From Lab to Clinic / [ed] Norbert Pallua, Christoph V. Suscheck, Berlin: Springer Berlin/Heidelberg, 2011, p. 245-262Chapter in book (Other academic)
    Abstract [en]

    The outcome of peripheral nerve repair has changed very little over the past 50 years, and clinical outcomes remain generally poor. Surgical technique has evolved to a high level of technical microsurgical proficiency, but this approach remains unable to adequately address the neurobiological barriers to the optimization of nerve regeneration. Reconstruction of complex segmental injuries, as in the brachial plexus, additionally requires a considerable length of interpositional nerve autograft, which may be unobtainable without considerable donor morbidity.

    Research has therefore turned to the modulation of the repair-site environment to optimise nerve regeneration across neurorraphies, and to the creation of nerve conduits to reduce the need for nerve autograft. Tissue engineering has involved the use of growth factors to modulate neuronal and glial cell behaviour, and the creation of macro, micro and nanoscale constructs from a variety of materials in order to replace the connective tissue functions of nerve autograft. Implantation of cultured Schwann and stem cells is an area of particular development given the necessity of viable support cells to facilitate neuronal growth. These approaches are reviewed in the light of current published work.

    The future of peripheral nerve repair lies in the modulation of neuronal and glial cell responses to nerve injury, and during regeneration, while taking account of the clinical requirements and practical limitations. The peripheral nervous system also provides a simpler model for nerve regeneration than the central nervous system, but with translational potential.

  • 419. Hascup, E. R.
    et al.
    Hascup, K. N.
    Talauliker, P. M.
    Price, D. A.
    Pomerleau, F.
    Quintero, J. E.
    Huettl, P.
    Gratton, A.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gerhardt, G. A.
    Sub-second measurements of glutamate and other neurotransmitter signaling using enzyme-based ceramic microelectrode arrays2013In: Microelectrode Biosensors (Part II) / [ed] Stéphane Marinesco and Nicholas Dale, Humana Press, 2013, p. 179-199Conference paper (Refereed)
    Abstract [en]

    We have set out to develop a novel, implantable microelectrode array that has the capabilities to detect neurotransmitters with enhanced sensitivity, selectivity, and temporal sampling capabilities compared to other current technologies. We have shown that this device maintains recording performance during chronic measurements of extracellular neurotransmitter levels for at least 7 days postimplantation, single-unit neuronal activity for as long as 6 months, and provides enhanced biocompatibility compared to current technologies. As we continue to refine and improve our recording capability, we are able to incorporate the chronic microelectrode array technology into multimodal experimental paradigms, such as behavioral testing, pharmacological intervention (local and systemic), or combined measurements of neurotransmitter levels and neuronal activity (local field potential). Furthermore, the improvements made with the microelectrode technology discussed in this chapter have the potential to conduct longitudinal analyses that can benefit a wide range of translational efforts, including studies on learning and memory, aging, neurodegenerative disease progression, and traumatic brain injury neuropathology.

  • 420. Hascup, Erin R
    et al.
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Hascup, Kevin N
    Pomerleau, Francois
    Huettl, Peter
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gerhardt, Greg A
    Histological studies of the effects of chronic implantation of ceramic-based microelectrode arrays and microdialysis probes in rat prefrontal cortex.2009In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1291, p. 12-20Article in journal (Refereed)
    Abstract [en]

    Chronic implantation of neurotransmitter measuring devices is essential for awake, behavioral studies occurring over multiple days. Little is known regarding the effects of long term implantation on surrounding brain parenchyma and the resulting alterations in the functional properties of this tissue. We examined the extent of tissue damage produced by chronic implantation of either ceramic microelectrode arrays (MEAs) or microdialysis probes. Histological studies were carried out on fixed tissues using stains for neurons (cresyl violet), astrocytes (GFAP), microglia (Iba1), glutamatergic nerve fibers (VGLUT1), and the blood-brain barrier (SMI-71). Nissl staining showed pronounced tissue body loss with microdialysis implants compared to MEAs. The MEAs produced mild gliosis extending 50-100 microm from the tracks, with a significant change in the affected areas starting at 3 days. By contrast, the microdialysis probes produced gliosis extending 200-300 microm from the track, which was significant at 3 and 7 days. Markers for microglia and glutamatergic fibers supported that the MEAs produce minimal damage with significant changes occurring only at 3 and 7 days that return to control levels by 1 month. SMI-71 staining supported the integrity of the blood-brain barrier out to 1 week for both the microdialysis probes and the MEAs. This data support that the ceramic MEA's small size and biocompatibility are necessary to accurately measure neurotransmitter levels in the intact brain. The minimal invasiveness of the MEAs reduce tissue loss, allowing for long term (>6 month) electrochemical and electrophysiological monitoring of brain activity.

  • 421.
    Hashemian, Sanaz Alsadat
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marschinke, Franziska
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Blocking cd47/ox101 makes the astrocytes permissive for nerve fiber growth2011In: Glia: 10th European meeting on Glial Cells in Health and Disease, New York, N.Y.: Wiley-Liss, Inc. , 2011, Vol. 59, p. S105-S106Conference paper (Refereed)
    Abstract [en]

    Crosstalk between astroglia and nerve fiber outgrowth might be an underlying mechanism for regeneration of nerve fibers and can be used in treatment of neurodegenerative diseases. This crosstalk might occur through the integrin-associated protein (CD47 in mouse or OX101 in rat), which serves as a ligand for signal regulatory protein-α (Sirpα) (P84/SHPS-1 in mouse or OX41 in rat), and as a receptor for thrombospondin (TSP). In the present study the localization of OX101 was assessed in organotypic tissue cultures from ventral mesencephalon (VM) of embryonic day (E) 14 rat fetuses, and its presence in astrocytes was observed. Thereafter, the effect of OX101 was blocked in E14 VM cultures by treatment with OX101 antibodies. A robust tyrosine hydroxylase (TH)- positive nerve fiber outgrowth was observed using immuohistochemistry. In addition, the neurons had migrated from the tissue slice. This result was in parallel with results achieved from E14 cultures of CD47 knockout mice, in which TH–positive nerve fiber growth was robust and independent of the presence of astrocytes, whilst in wildtype cultures nerve fibers were restricted to the astrocytes. Thus, these data demonstrate that CD47/OX101 can be an important molecule, which normally is produced by astrocytes and in its absence, the astrocytes become more permissive for nerve fiber growth.

  • 422.
    Hashemian, Sanaz
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marschinke, Franziska
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Degradation of proteoglycans affects astrocytes and neurite formation in organotypic tissue cultures2014In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1564, p. 22-32Article in journal (Refereed)
    Abstract [en]

    Chondroitin sulfate proteoglycans (CSPGs) promote nerve growth during development, and inhibit axonal growth in the adult CNS after injury. Chondroitinase ABC (ChABC) and methyl-umbelliferyl-β-d-xyloside (β-xyloside), two enzymes that degrade CSPGs, promote regeneration after injury, however, they demonstrate opposing results in tissue culture. To elucidate the effect of the two enzymes, organotypic tissue cultures, treated with ChABC or β-xyloside, were employed to monitor nerve fiber outgrowth and astrocytic migration. Rat ventral mesencephalon (VM) and spinal cord (SC) from embryonic day (E) 14 and E18 were treated early, from the plating day for 14 days in vitro, or late where treatment was initiated after being cultured for 14 days. In the early treatment of E14 VM and SC cultures, astrocytic migration and nerve fiber outgrowth were hampered using both enzymes. Early treatment of E18 cultures reduced the astrocytic migration, while nerve growth was promoted by β-xyloside, but not by ChABC. In the late treated cultures of both E14 and E18 cultures, no differences in distances that astrocytes migrated or nerve fiber growth were observed. However, in β-xyloside-treated cultures, the confluency of astrocytic monolayer was disrupted. In E18 cultures both early and late treatments, neuronal migration was present in control cultures, which was preserved using ChABC but not β-xyloside. In conclusion, ChABC and β-xyloside had similar effects and hampered nerve fiber growth and astrocytic migration in E14 cultures. In E18 cultures nerve fiber growth was stimulated and neuronal migration was hampered after β-xyloside treatment while ChABC treatment did not exert these effects.

  • 423.
    Hashemian, Sanaz
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    O'Rourke, Caitriona
    Phillips, James B.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Embryonic and mature astrocytes exert different effects on neuronal growth in rat ventral mesencephalic slice cultures2015In: SpringerPlus, E-ISSN 2193-1801, Vol. 4, article id 558Article in journal (Refereed)
    Abstract [en]

    One obstacle with grafting of dopamine neurons in Parkinson's disease is the insufficient ability of the transplant to reinnervate the host striatum. Another issue is the prospective interaction between the donor fetal tissue and the adult astrocytes of the host. To study nerve fiber growth and its interaction with immature/mature astrocytes, ventral mesencephalic (VM) organotypic rat tissue cultures from embryonic days (E) 12, E14, and E18 were studied up to 35 days in vitro (DIV), and co-cultures of E14 VM tissue and mature green fluorescent protein (GFP)-positive astrocytes were performed. Generally, nerve fibers grew from the tissue slice either in association with a monolayer of migrated astroglia surrounding the tissue (glial-associated), or distal to the astroglia as non-glial-associated outgrowth. The tyrosine hydroxylase (TH)-positive glial-associated nerve fiber outgrowth reached a plateau at 21 DIV in E12 and E14 cultures. In E18 cultures, TH-positive neurons displayed short processes and migrated onto the astrocytes. While the non-glial-associated nerve fiber outgrowth dominated the E14 cultures, it was found absent in E18 cultures. The GFP-positive cells in the VM and GFP-positive astrocyte co-cultures were generally located distal to the monolayer of migrated fetal astrocytes, a few GFP-positive cells were however observed within the astrocytic monolayer. In those cases TH-positive neurons migrated towards the GFP-positive cells. Both the non-glial-and glial-associated nerve fibers grew onto the GFP-positive cells. Taken together, the glial-associated growth has limited outgrowth compared to the non-glial-associated nerve fibers, while none of the outgrowth types were hampered by the mature astrocytes.

  • 424.
    Hashemian, Sanaz
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Phillips, James B
    Department of Life Health & Chemical Sciences, The Open University.
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    The age of the astrocytes affects neuronal growthManuscript (preprint) (Other academic)
  • 425.
    Hashemian, Sanazalsadat
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Interaction between nerve fiber formation and astrocytes2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parkinson’s disease, the second most common neurodegenerative disorder,is characterized by loss of nigrostriatal dopaminergic neurons. To date,there is no defined cause and cure for the disease. An ideal treatmentstrategy is to replace the lost neurons by transplanting fetal dopaminergicneurons to the brain of parkinsonian patients. Clinical trials have beenperformed and the outcome was variable where one significant obstaclewas the limited graft reinnervation of the host brain. To study this issue,organotypic tissue culture can be utilized to monitor dopaminergic nervefiber outgrowth in vitro and their association with astrocytes. Using thisculture technique, dopaminergic nerve fibers appear in twomorphologically and temporally different types. The early appearing nervefibers are formed in the absence of astrocytes, reach long distances, andare called non-glial-associated tyrosine hydroxylase (TH) -positive nervefibers. After a few days, the second sequence of nerve fibers, the glialassociatedTH-positive nerve fibers, are formed, and their growth arelimited to the presence of astrocytes, that migrate and form a monolayersurrounding the plated tissue. The aim of this thesis was to study theinteraction between nerve fiber formation and astrocytes with a specialfocus on the long-distance growing nerve fibers. Ventral mesencephalic(VM) organotypic slice cultures from embryonic day (E) 12, E14, and E18were incubated for 14, 21, 28, and 35 days in vitro (DIV). The resultsrevealed that the two morphologically different processes were found incultures from the younger stages, while no non-glial-associated growthwas found in cultures of tissue from E18. Instead neurons had migratedonto the migrating astrocytes. Astrocytes migrated longer distances intissue from older stages, and the migration reached a plateau at 21 DIV.Co-cultures of E14 VM tissue pieces and cell suspension of matureastrocytes promoted migration of neurons, as seen in E18 cultures. Thus,9the maturity of the astrocytes was an important factor for nerve fiberoutgrowth. Hence, targeting molecules secreted by astrocytes might bebeneficial for regeneration. Chondroitin sulfate proteoglycan (CSPG), amember of proteoglycan family, is produced by the astrocytes and has adual role of being permissive during development and inhibitory afterbrain injury in adult brain. Cultures were treated with chondroitinase ABC(ChABC) or methyl-umbelliferyl-β-D-xyloside (β-xyloside) in twodifferent protocols, early and late treatments. The results from the earlytreated cultures showed that both compounds inhibited the outgrowth ofnerve fibers and astrocytic migration in cultures from E14 tissue, while β-xyloside but not ChABC promoted the non-glial-associated growth incultures derived from E18 fetuses. In addition, β-xyloside but not ChABCinhibited neuronal migration in E18 cultures. Taken together, β-xylosideappeared more effective than ChABC in promoting nerve fiber growth.Another potential candidate, integrin-associated protein CD47, was studiedbecause of its role in synaptogenesis, which is important for nerve fibergrowth. Cultures from E14 CD47 knockout (CD47-/-) mice were plated andcompared to their wildtypes. CD47-/- cultures displayed a massive and longnon-glial-associated TH-positive nerve fiber outgrowth despite theirnormal astrocytic migration. Blocking either signal regulatory protein-α(SIRPα) or thrombospondin-1 (TSP-1), which bind to CD47, had nogrowth promoting effect. In conclusion, to promote nerve growth, youngertissue can grow for longer distances than older tissue, and inhibiting CSPGproduction promotes nerve growth in older tissue, while gene deletion ofCD47 makes the astrocytes permissive for a robust nerve fiber growth.

  • 426. Havton, Leif A
    et al.
    Hotson, John R
    Kellerth, Jan-Olof
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Correlation of median forearm conduction velocity with carpal tunnel syndrome severity.2007In: Clinical Neurophysiology, ISSN 1388-2457, Vol. 118, no 4, p. 781-5Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Median nerve entrapment neuropathy at the wrist can be accompanied by slowed motor conduction within the forearm. Existing studies conflict regarding a correlation between the severity of the entrapment neuropathy in carpal tunnel syndrome (CTS) and slowing of median motor nerve conduction velocity (MNCV) in the forearm. Here, it was asked if there is a correlation between markers of CTS severity and median forearm MNCV, and if there is an explanation for the preceding conflicting results. METHODS: Median MNCV in the forearm was correlated with neurophysiologic markers of severity of a median neuropathy at the wrist in 91 hands from 64 patients with clinical and electrodiagnostic evidence of CTS. RESULTS: Median MNCV within the forearm segment was negatively correlated with the median nerve distal motor latency (r=-0.64, P<0.001, n=91) and positively correlated with the CMAP amplitude of the abductor pollicis brevis muscle (r=0.45, P<0.001, n=91). These correlations only occurred in patients with a prolonged median distal motor latency. Previous investigations that failed to find such correlations used variable or non-standardized methods or analyzed smaller numbers of patients. CONCLUSIONS: Slowing of median MNCV in the forearm is related to the severity of the entrapment of median motor fibers at the wrist. SIGNIFICANCE: Slowed forearm median MNCV can be a marker of motor nerve injury at the wrist.

  • 427. Havton, Leif A
    et al.
    Kellerth, Jan-Olof
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Plasticity of lumbosacral monosynaptic reflexes after a ventral root transection injury in the adult cat.2004In: Experimental Brain Research, ISSN 0014-4819, Vol. 155, no 1, p. 111-4Article in journal (Refereed)
    Abstract [en]

    Injuries to spinal ventral roots may induce plastic changes in adjacent segmental reflex pathways. Earlier studies in the cat have demonstrated that a partial loss of target motoneurons, following a ventral root avulsion injury, induces a compensatory enhancement of monosynaptic reflexes in adjacent segments. Here, we studied electrophysiologically the effects of a primarily non-lethal motoneuron injury of lumbosacral ventral roots on monosynaptic reflexes in adjacent intact motoneurons in the adult cat. A unilateral L7 or a combined L7 and S1 ventral root transection was first performed. We next recorded bilaterally monosynaptic reflexes from the L6 and S1 ventral roots while stimulating the bilateral L6, L7 and S1 dorsal roots at 6 and 12 weeks postoperatively. We demonstrated a prominent strengthening of monosynaptic reflexes in the immediately adjacent spinal cord segments. The reflexes had almost doubled in size at 6 and 12 weeks postoperatively. Possible mechanisms and factors contributing to the reflex enhancement are discussed.

  • 428.
    Hedner, Margareta
    et al.
    Stockholm University, Stockholm Brain Institute.
    Nilsson, Lars-Göran
    Stockholm University, Stockholm Brain Institute.
    Olofsson, Jonas K
    Stockholm University, Stockholm Brain Institute.
    Bergman, Olle
    Göteborg University.
    Eriksson, Elias
    Göteborg University.
    Nyberg, Lars
    Umeå University, Faculty of Social Sciences, Centre for Population Studies (CPS). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Larsson, Maria
    Stockholm University, Stockholm Brain Institute.
    Age-related olfactory decline is associated with the BDNF Val66met Polymorphism: Evidence from a population-based study2010In: Frontiers in aging neuroscience, ISSN 1663-4365, Vol. 2, p. 24-Article in journal (Refereed)
    Abstract [en]

    The present study investigates the effect of the brain-derived neurotrophic factor (BDNF) val66met polymorphism on change in olfactory function in a large scale, longitudinal population-based sample (n = 836). The subjects were tested on a 13 item force-choice odor identification test on two test occasions over a 5-year-interval. Sex, education, health-related factors, and semantic ability were controlled for in the statistical analyses. Results showed an interaction effect of age and BDNF val66met on olfactory change, such that the magnitude of olfactory decline in the older age cohort (70-90 years old at baseline) was larger for the val homozygote carriers than for the met carriers. The older met carriers did not display larger age-related decline in olfactory function compared to the younger group. The BDNF val66met polymorphism did not affect the rate of decline in the younger age cohort (45-65 years). The findings are discussed in the light of the proposed roles of BDNF in neural development and maintenance.

  • 429.
    Henriksson, Maria L
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Colorectal Cancer Cells Activate Adjacent Fibroblasts Resulting in FGF1/FGFR3 Signaling and Increased Invasion.2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, no 3, p. 1387-1394Article in journal (Refereed)
    Abstract [en]

    Cancer-associated fibroblasts expressing fibroblast activation protein (FAP) have been implicated in the invasive behavior of colorectal cancer. In this study, we use FAP expression as a marker of fibroblast activation and analyze the effect of activated fibroblasts on colorectal cancer migration and invasion in experimental cell studies. We also investigated the expression pattern of FAP in cancer-associated fibroblasts during transformation from benign to malignant colorectal tumors. In immunohistochemical analyses, FAP was expressed in fibroblasts in all colorectal cancer samples examined, whereas all normal colon, hyperplastic polyps, or adenoma samples were negative. In in vitro studies, conditioned medium from colon cancer cells, but not adenoma cells, activated fibroblasts by inducing FAP expression. These activated fibroblasts increased the migration and invasion of colon cancer cells in Boyden chamber experiments and in a three-dimensional cell culture model. We identify fibroblast growth factor 1/fibroblast growth factor receptor 3 (FGF1/FGFR-3) signaling as mediators leading to the increased migration and invasion. Activated fibroblasts increase their expression of FGF1, and by adding a fibroblast growth factor receptor inhibitor, as well as an FGF1-neutralizing antibody, we reduced the migration of colon cancer cells. Our findings provide evidence of a possible molecular mechanism involved in the cross talk between cancer cells and fibroblasts leading to cancer cell invasion.

  • 430.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Modulation of serous salivary gland function by the sympathetic nervous system: a biochemical and ultrastructural study with special reference to β-adrenoceptor subtypes1981Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of the present investigation was to study the influence of the sympathetic nervous system and of various adrenoceptor agents on enzyme secretion and morphology in rat parotid and guinea-pig submandibular glands. Biochemical methods were combined with electron microscopical techniques.

    Two different in vitro systems were employed, batch-incubation and microperifusion, to characterize the sympathetically evoked amylase release and its correlation to cyclic AMP. By using various selective β-adrenoceptor agonists and antagonists a dominance of the β1-adrenoceptor over the β2 - in regulating amylase release - was establ ished. Continuous noradrenaline perifusion caused a rapid initial amylase discharge, closely correlated to tissue levels of cyclic AMP; no correlation between the two was observed during the later phase. Prenalterol (a β1-agonist) failed to elevate glandular cyclic AMP. This was in contrast to its potent secretagogic effect. On the other hand, terbutaline (a β2-agonist) was a weak secretagogue but markedly raised the levels of cyclic AMP. Thus, β-adrenoceptor activation may lead to release of large amounts of amylase despite minimal or no increase in cyclic AMP. Moreover, these effects seemed to be dissociated in salivary glands with regard to the β-adrenoceptor subtypes. This was further substantiated by the findings that repeated injections of prenalterol induced qualitative changes in the granule populations, similar to those caused by the non-selective β-agonist isoprenaline. Terbutaline was without effect. However, acinar cells size was increased following both prenalterol and terbutaline treatment. The data suggest that the 3-adrenergic effects on acinar cell size and granule population may be independently regulated.

    A decreased sympathetic activity of long duration was induced by neonatal or adult extirpation of the superior cervical ganlion on one side. Acinar cell size, as well as granule and amylase content was reduced 9 weeks after neonatal denervation. Ganglionectomy performed in adult animals was without significant effects.

    The secretory behaviour of neonatally denervated glands was characterized by an increased postjunctional sensitivity to 3-adrenoceptor agonists. Of special interest was the finding that neonatal denervation seemed to transform terbutaline from a partial to a full secretory agonist, thus changing its effects in the direction of those of prenalterol and noradrenaline. Moreover, increased levels of cyclic AMP as well as an enhanced response to DBcAMP were noted in the denervated glands as were intracellular changes. The denervation supersensitivity after neonatal denervation seems to differ from that observed in adult denervated glands. The results of the studies on denervated glands suggest that the sympathetic nervous system plays a fundamental role in the early maturation of the rat parotid gland as well as for the development of the β-adrenoceptor subtypes.

  • 431.
    Henriksson-Larsén, Karin
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Distribution, total number and size of different types of fibres in male and female skeletal muscles: an enzyme histochemical study of whole muscle cross-sections1984Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In order to investigate the total number, relative proportions, size variations and distribution patterns of fibres of different types in human skeletal muscles, a technique was developed which allows whole muscle cross-sections to be collected and stained enzyme histochemically. Necropsy material was obtained from m. tibialis anterior and m. vastus lateralis of previously healthy young adults who had suffered sudden accidental deaths. The muscle specimens were extirpated within 72 hours post morten, frozen in liquid nitrogen, embedded in carboxymethylcellu- lose, sectioned and enzyme histochemically stained for myofibrillar ATPase in order to permit light microscopic identification of type 1 and type 2 muscle fibres.

    The present results show that there is a large variation in both the total number of fibres and the size of the whole muscle cross-sectional area between different individuals and, also, between different levels of the same muscle. The distribution of fibres of different types over the muscle cross-section was heterogeneous. Usually the relative proportion of type 2 fibres showed a peak along a medio- lateral line passing through the centre of the muscle cross-section. When comparing the left and right m. tibialis anterior of the same individual, one of the- muscles (usually the left one) was found to contain a larger number of fibres than the contralateral one. However, the pattern of distribution of fibres of different types was similar in the two muscles. The fibre sizes were also found to vary between different regions of the muscle cross-section. Both type 1 and type 2 fibres were significantly larger in the deep muscle region compared to the central or superficial sites. The mean fibre size as well as the total number of fibres correlated strongly with the whole muscle cross-sectional area. The female m. tibialis anterior contained fewer and smaller fibres than the corresponding male muscle, although the whole muscle cross-sectional area was of similar magnitude. The distribution of fibre types over the muscle cross-section differed somewhat between females and males. The variation in fibre sizes between different muscle sites was less pronounced in the females, but as in male muscles the type 2 fibres were always larger than the type 1 fibres.

    In conclusion, systematic variations in fibre type distribution and fibre size occurs over the muscle cross-section. The total number of fibres in the cross- section seems to vary with individual, sex, distance from muscle origin and left- right leg. The combination of fewer and smaller fibres in females compared to males leads to about 40 % smaller total muscle fibre cross-sectional area in female m. tibialis anterior. The results are discussed in relation to previous studies using muscle biopsy techniques. The possible contibution of variations in number, sizes or distribution patterns of muscle fibres to adaptation of muscle to varying functional demands is also discussed.

  • 432. Hibar, Derrek P.
    et al.
    Adams, Hieab H. H.
    Jahanshad, Neda
    Chauhan, Ganesh
    Stein, Jason L.
    Hofer, Edith
    Renteria, Miguel E.
    Bis, Joshua C.
    Arias-Vasquez, Alejandro
    Ikram, M. Kamran
    Desrivieres, Sylvane
    Vernooij, Meike W.
    Abramovic, Lucija
    Alhusaini, Saud
    Amin, Najaf
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Arfanakis, Konstantinos
    Aribisala, Benjamin S.
    Armstrong, Nicola J.
    Athanasiu, Lavinia
    Axelsson, Tomas
    Beecham, Ashley H.
    Beiser, Alexa
    Bernard, Manon
    Blanton, Susan H.
    Bohlken, Marc M.
    Boks, Marco P.
    Bralten, Janita
    Brickman, Adam M.
    Carmichael, Owen
    Chakravarty, M. Mallar
    Chen, Qiang
    Ching, Christopher R. K.
    Chouraki, Vincent
    Cuellar-Partida, Gabriel
    Crivello, Fabrice
    Den Braber, Anouk
    Doan, Nhat Trung
    Ehrlich, Stefan
    Giddaluru, Sudheer
    Goldman, Aaron L.
    Gottesman, Rebecca F.
    Grimm, Oliver
    Griswold, Michael E.
    Guadalupe, Tulio
    Gutman, Boris A.
    Hass, Johanna
    Haukvik, Unn K.
    Hoehn, David
    Holmes, Avram J.
    Hoogman, Martine
    Janowitz, Deborah
    Jia, Tianye
    Jorgensen, Kjetil N.
    Karbalai, Nazanin
    Kasperaviciute, Dalia
    Kim, Sungeun
    Klein, Marieke
    Kraemer, Bernd
    Lee, Phil H.
    Liewald, David C. M.
    Lopez, Lorna M.
    Luciano, Michelle
    Macare, Christine
    Marquand, Andre F.
    Matarin, Mar
    Mather, Karen A.
    Mattheisen, Manuel
    McKay, David R.
    Milaneschi, Yuri
    Maniega, Susana Munoz
    Nho, Kwangsik
    Nugent, Allison C.
    Nyquist, Paul
    Loohuis, Loes M. Olde
    Oosterlaan, Jaap
    Papmeyer, Martina
    Pirpamer, Lukas
    Puetz, Benno
    Ramasamy, Adaikalavan
    Richards, Jennifer S.
    Risacher, Shannon L.
    Roiz-Santianez, Roberto
    Rommelse, Nanda
    Ropele, Stefan
    Rose, Emma J.
    Royle, Natalie A.
    Rundek, Tatjana
    Saemann, Philipp G.
    Saremi, Arvin
    Satizabal, Claudia L.
    Schmaal, Lianne
    Schork, Andrew J.
    Shen, Li
    Shin, Jean
    Shumskaya, Elena
    Smith, Albert V.
    Sprooten, Emma
    Strike, Lachlan T.
    Teumer, Alexander
    Tordesillas-Gutierrez, Diana
    Toro, Roberto
    Trabzuni, Daniah
    Trompet, Stella
    Vaidya, Dhananjay
    Van der Grond, Jeroen
    Van der Lee, Sven J.
    Van der Meer, Dennis
    Van Donkelaar, Marjolein M. J.
    Van Eijk, Kristel R.
    Van Erp, Theo G. M.
    Van Rooij, Daan
    Walton, Esther
    Westlye, Lars T.
    Whelan, Christopher D.
    Windham, Beverly G.
    Winkler, Anderson M.
    Wittfeld, Katharina
    Woldehawariat, Girma
    Wolf, Christiane
    Wolfers, Thomas
    Yanek, Lisa R.
    Yang, Jingyun
    Zijdenbos, Alex
    Zwiers, Marcel P.
    Agartz, Ingrid
    Almasy, Laura
    Ames, David
    Amouyel, Philippe
    Andreassen, Ole A.
    Arepalli, Sampath
    Assareh, Amelia A.
    Barral, Sandra
    Bastin, Mark E.
    Becker, Diane M.
    Becker, James T.
    Bennett, David A.
    Blangero, John
    van Bokhoven, Hans
    Boomsma, Dorret I.
    Brodaty, Henry
    Brouwer, Rachel M.
    Brunner, Han G.
    Buckner, Randy L.
    Buitelaar, Jan K.
    Bulayeva, Kazima B.
    Cahn, Wiepke
    Calhoun, Vince D.
    Cannon, Dara M.
    Cavalleri, Gianpiero L.
    Cheng, Ching-Yu
    Cichon, Sven
    Cookson, Mark R.
    Corvin, Aiden
    Crespo-Facorro, Benedicto
    Curran, Joanne E.
    Czisch, Michael
    Dale, Anders M.
    Davies, Gareth E.
    De Craen, Anton J. M.
    De Geus, Eco J. C.
    De Jager, Philip L.
    De Zubicaray, Greig I.
    Deary, Ian J.
    Debette, Stephanie
    DeCarli, Charles
    Delanty, Norman
    Depondt, Chantal
    DeStefano, Anita
    Dillman, Allissa
    Djurovic, Srdjan
    Donohoe, Gary
    Drevets, Wayne C.
    Duggirala, Ravi
    Dyer, Thomas D.
    Enzinger, Christian
    Erk, Susanne
    Espeseth, Thomas
    Fedko, Iryna O.
    Fernandez, Guillen
    Ferrucci, Luigi
    Fisher, Simon E.
    Fleischman, Debra A.
    Ford, Ian
    Fornage, Myriam
    Foroud, Tatiana M.
    Fox, Peter T.
    Francks, Clyde
    Fukunaga, Masaki
    Gibbs, J. Raphael
    Glahn, David C.
    Gollub, Randy L.
    Goring, Harald H. H.
    Green, Robert C.
    Gruber, Oliver
    Gudnason, Vilmundur
    Guelfi, Sebastian
    Haberg, Asta K.
    Hansell, Narelle K.
    Hardy, John
    Hartman, Catharina A.
    Hashimoto, Ryota
    Hegenscheid, Katrin
    Heinz, Andreas
    Le Hellard, Stephanie
    Hernandez, Dena G.
    Heslenfeld, Dirk J.
    Ho, Beng-Choon
    Hoekstra, Pieter J.
    Hoffmann, Wolfgang
    Hofman, Albert
    Holsboer, Florian
    Homuth, Georg
    Hosten, Norbert
    Hottenga, Jouke-Jan
    Huentelman, Matthew
    Pol, Hilleke E. Hulshoff
    Ikeda, Masashi
    Jack, Clifford R., Jr.
    Jenkinson, Mark
    Johnson, Robert
    Joensson, Erik G.
    Jukema, J. Wouter
    Kahn, Rene S.
    Kanai, Ryota
    Kloszewska, Iwona
    Knopman, David S.
    Kochunov, Peter
    Kwok, John B.
    Lawrie, Stephen M.
    Lemaitre, Herve
    Liu, Xinmin
    Longo, Dan L.
    Lopez, Oscar L.
    Lovestone, Simon
    Martinez, Oliver
    Martinot, Jean-Luc
    Mattay, Venkata S.
    McDonald, Colm
    McIntosh, Andrew M.
    McMahon, Francis J.
    McMahon, Katie L.
    Mecocci, Patrizia
    Melle, Ingrid
    Meyer-Lindenberg, Andreas
    Mohnke, Sebastian
    Montgomery, Grant W.
    Morris, Derek W.
    Mosley, Thomas H.
    Muhleisen, Thomas W.
    Mueller-Myhsok, Bertram
    Nalls, Michael A.
    Nauck, Matthias
    Nichols, Thomas E.
    Niessen, Wiro J.
    Nothen, Markus M.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Ohi, Kazutaka
    Olvera, Rene L.
    Ophoff, Roel A.
    Pandolfo, Massimo
    Paus, Tomas
    Pausova, Zdenka
    Penninx, Brenda W. J. H.
    Pike, G. Bruce
    Potkin, Steven G.
    Psaty, Bruce M.
    Reppermund, Simone
    Rietschel, Marcella
    Roffman, Joshua L.
    Romanczuk-Seiferth, Nina
    Rotter, Jerome I.
    Ryten, Mina
    Sacco, Ralph L.
    Sachdev, Perminder S.
    Saykin, Andrew J.
    Schmidt, Reinhold
    Schmidt, Helena
    Schofield, Peter R.
    Sigursson, Sigurdur
    Simmons, Andrew
    Singleton, Andrew
    Sisodiya, Sanjay M.
    Smith, Colin
    Smoller, Jordan W.
    Soininen, Hilkka
    Steen, Vidar M.
    Stott, David J.
    Sussmann, Jessika E.
    Thalamuthu, Anbupalam
    Toga, Arthur W.
    Traynor, Bryan J.
    Troncoso, Juan
    Tsolaki, Magda
    Tzourio, Christophe
    Uitterlinden, Andre G.
    Hernandez, Maria C. Valdes
    Van der Brug, Marcel
    van der Lugt, Aad
    van der Wee, Nic J. A.
    Van Haren, Neeltje E. M.
    van't Ent, Dennis
    Van Tol, Marie-Jose
    Vardarajan, Badri N.
    Vellas, Bruno
    Veltman, Dick J.
    Voelzke, Henry
    Walter, Henrik
    Wardlaw, Joanna M.
    Wassink, Thomas H.
    Weale, Michael E.
    Weinberger, Daniel R.
    Weiner, Michael W.
    Wen, Wei
    Westman, Eric
    White, Tonya
    Wong, Tien Y.
    Wright, Clinton B.
    Zielke, Ronald H.
    Zonderman, Alan B.
    Martin, Nicholas G.
    Van Duijn, Cornelia M.
    Wright, Margaret J.
    Longstreth, W. T.
    Schumann, Gunter
    Grabe, Hans J.
    Franke, Barbara
    Launer, Lenore J.
    Medland, Sarah E.
    Seshadri, Sudha
    Thompson, Paul M.
    Ikram, M. Arfan
    Novel genetic loci associated with hippocampal volume2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 13624Article in journal (Refereed)
    Abstract [en]

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

  • 433. Hoernke, M.
    et al.
    Mohan, J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kahra, Dana
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Westenhoff, S.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Schwieger, C.
    Determining membrane bound protein structures by infrared reflection-absorption spectroscopy2017In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 46, p. S161-S161Article in journal (Other academic)
  • 434. Hoernke, M
    et al.
    Mohan, Jagan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Blomberg, J
    Kahra, Dana
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Daumke, O
    Westenhof, S
    Schweiger, C
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    TP driven stabilization of a membrane bound open confirmation of the ATPase EHD2 restrains caveolae dynamicsManuscript (preprint) (Other academic)
  • 435. Hoernke, Maria
    et al.
    Mohan, Jagan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Elin
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kahra, Dana
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Westenhoff, Sebastian
    Schwieger, Christian
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    EHD2 restrains dynamics of caveolae by an ATP-dependent, membrane-bound, open conformation2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 22, p. E4360-E4369Article in journal (Refereed)
    Abstract [en]

    The EH-domain-containing protein 2 (EHD2) is a dynamin-related ATPase that confines caveolae to the cell surface by restricting the scission and subsequent endocytosis of these membrane pits. For this, EHD2 is thought to first bind to the membrane, then to oligomerize, and finally to detach, in a stringently regulated mechanistic cycle. It is still unclear how ATP is used in this process and whether membrane binding is coupled to conformational changes in the protein. Here, we show that the regulatory N-terminal residues and the EH domain keep the EHD2 dimer in an autoinhibited conformation in solution. By significantly advancing the use of infrared reflection-absorption spectroscopy, we demonstrate that EHD2 adopts an open conformation by tilting the helical domains upon membrane binding. We show that ATP binding enables partial insertion of EHD2 into the membrane, where G-domain-mediated oligomerization occurs. ATP hydrolysis is related to detachment of EHD2 from the membrane. Finally, we demonstrate that the regulation of EHD2 oligomerization in a membrane-bound state is crucial to restrict caveolae dynamics in cells.

  • 436. Hohsfield, Lindsay A.
    et al.
    Daschil, Nina
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Humpel, Christian
    Vascular pathology of 20-month-old hypercholesterolemia mice in comparison to triple-transgenic and APPSwDI Alzheimer's disease mouse models2014In: Molecular and cellular neuroscience, ISSN 1044-7431, Vol. 63, p. 83-95Article in journal (Refereed)
    Abstract [en]

    Several studies have shown that elevated plasma cholesterol levels (i.e. hypercholesterolemia) serve as a risk factor for late-onset Alzheimer's disease (AD). However, it remains unclear how hypercholesterolemia may contribute to the onset and progression of AD pathology. In order to determine the role of hypercholesterolemia at various stages of AD, we evaluated the effects of high cholesterol diet (5% cholesterol) in wild-type (WT; C57BL6) and triple-transgenic AD (3xTg-AD: Psen1, APPSwe, tauB301L) mice at 7, 14, and 20 months. The transgenic APP-Swedish/Dutch/Iowa AD mouse model (APPSwDI) was used as a control since these animals are more pathologically-accelerated and are known to exhibit extensive plaque deposition and cerebral amyloid angiopathy. Here, we describe the effects of high cholesterol diet on: (1) cognitive function and stress, (2) AD-associated pathologies, (3) neuroinflammation, (4) blood-brain barrier disruption and ventricle size, and (5) vascular dysfunction. Our data show that high dietary cholesterol increases weight, slightly impairs cognitive function, promotes glial cell activation and complement-related pathways, enhances the infiltration of blood-derived proteins and alters vascular integrity, however, it does not induce AD-related pathologies. While normal-fed 3xTg-AD mice display a typical AD-like pathology in addition to severe cognitive impairment and neuroinflammation at 20 months of age, vascular alterations are less pronounced. No microbleedings were seen by MRI, however, the ventricle size was enlarged. Triple-transgenic AD mice, on the other hand, fed a high cholesterol diet do not survive past 14 months of age. Our data indicates that cholesterol does not markedly potentiate AD-related pathology, nor does it cause significant impairments in cognition. However, it appears that high cholesterol diet markedly increases stress-related plasma corticosterone levels as well as some vessel pathologies. Together, our findings represent the first demonstration of prolonged high cholesterol diet and the examination of its effects at various stages of cerebrovascular- and AD-related disease.

  • 437.
    Holm, Cecilia Koskinen
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Engman, Sara
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sulniute, Rima
    Umeå University, Faculty of Medicine, Department of Odontology.
    Matozaki, Takashi
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lack of SIRP alpha phosphorylation and concomitantly reduced SHP-2-PI3K-Akt2 signaling decrease osteoblast differentiation2016In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 478, no 1, p. 268-273Article in journal (Refereed)
    Abstract [en]

    Normal differentiation of bone forming osteoblasts is a prerequisite for maintenance of skeletal health and is dependent on intricate cellular signaling pathways, including the essential transcription factor Runx2. The cell surface glycoprotein CD47 and its receptor signal regulatory protein alpha (SIRP alpha) have both been suggested to regulate bone cell differentiation. Here we investigated osteoblastic differentiation of bone marrow stromal cells from SIRP alpha mutant mice lacking the cytoplasmic signaling domain of SIRPa. An impaired osteoblastogenesis in SIRP alpha-mutant cell cultures was demonstrated by lower alkaline phosphatase activity and less mineral formation compared to wild-type cultures. This reduced osteoblastic differentiation potential in SIRPa-mutant stromal cells was associated with a significantly reduced expression of Runx2, osterix, osteocalcin, and alkaline phosphatase mRNA, as well as a reduced phosphorylation of SHP-2 and Akt2, as compared with that in wild-type stromal cells. Addition of a PI3K-inhibitor to wild-type stromal cells could mimic the impaired osteoblastogenesis seen in SIRP alpha-mutant cells. In conclusion, our data suggest that SIRPa signaling through SHP-2-PI3K-Akt2 strongly influences osteoblast differentiation from bone marrow stromal cells. 

  • 438.
    Holst, Mikkel Roland
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Vidal-Quadras, Maite
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hubert, Madlen
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lundborg, Magnus
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, no 8, p. 1893-1905Article in journal (Refereed)
    Abstract [en]

    Cellular blebbing, caused by local alterations in cellsurface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrinindependent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension- mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol- interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.

  • 439. Honkanen, Juuso
    et al.
    Turunen, Mikael
    Freedman, Jonathan
    Saarakkala, Simo
    Grinstaff, Mark
    Ylärinne, Janne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Jurvelin, Jukka
    Töyräs, Juha
    Cationic contrast agent diffusion differs between cartilage and meniscus2016In: Annals of Biomedical Engineering, ISSN 0090-6964, E-ISSN 1573-9686, Vol. 44, no 10, p. 2913-2921Article in journal (Refereed)
    Abstract [en]

    Contrast enhanced computed tomography (CECT) is a non-destructive imaging technique used for the assessment of composition and structure of articular cartilage and meniscus. Due to structural and compositional differences between these tissues, diffusion and distribution of contrast agents may differ in cartilage and meniscus. The aim of this study is to determine the diffusion kinematics of a novel iodine based cationic contrast agent (CA(2+)) in cartilage and meniscus. Cylindrical cartilage and meniscus samples (d = 6 mm, h ≈ 2 mm) were harvested from healthy bovine knee joints (n = 10), immersed in isotonic cationic contrast agent (20 mgI/mL), and imaged using a micro-CT scanner at 26 time points up to 48 h. Subsequently, normalized X-ray attenuation and contrast agent diffusion flux, as well as water, collagen and proteoglycan (PG) contents in the tissues were determined. The contrast agent distributions within cartilage and meniscus were different. In addition, the normalized attenuation and diffusion flux were higher (p < 0.05) in cartilage. Based on these results, diffusion kinematics vary between cartilage and meniscus. These tissue specific variations can affect the interpretation of CECT images and should be considered when cartilage and meniscus are assessed simultaneously.

  • 440. Houston, Catriona M.
    et al.
    Diamanti, Efthymia
    Diamantaki, Maria
    Kutsarova, Elena
    Cook, Anna
    Sultan, Fahad
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Department Cognitive Neurology, HertieInstitute for Clinical Brain Research, University of Tübingen, Germany.
    Brickley, Stephen G.
    Exploring the significance of morphological diversity for cerebellar granule cell excitability2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 46147Article in journal (Refereed)
    Abstract [en]

    The relatively simple and compact morphology of cerebellar granule cells (CGCs) has led to the view that heterogeneity in CGC shape has negligible impact upon the integration of mossy fibre (MF) information. Following electrophysiological recording, 3D models were constructed from high-resolution imaging data to identify morphological features that could influence the coding of MF input patterns by adult CGCs. Quantification of MF and CGC morphology provided evidence that CGCs could be connected to the multiple rosettes that arise from a single MF input. Predictions from our computational models propose that MF inputs could be more densely encoded within the CGC layer than previous models suggest. Moreover, those MF signals arriving onto the dendrite closest to the axon will generate greater CGC excitation. However, the impact of this morphological variability on MF input selectivity will be attenuated by high levels of CGC inhibition providing further flexibility to the MF. CGC pathway. These features could be particularly important when considering the integration of multimodal MF sensory input by individual CGCs.

  • 441.
    Hubert, Madlen
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Caveolae dynamics is strongly influenced by the lipid composition of the plasma membrane2017In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 46, p. S121-S121Article in journal (Other academic)
  • 442. Huisman, Elise S.
    et al.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    Reno, Carol R.
    Hart, David A.
    Thornton, Gail M.
    Regional molecular and cellular differences in the female rabbit Achilles tendon complex: potential implications for understanding responses to loading2014In: Journal of Anatomy, ISSN 0021-8782, E-ISSN 1469-7580, Vol. 224, no 5, p. 538-547Article in journal (Refereed)
    Abstract [en]

    The aim of this study was: (i) to analyze the morphology and expression of extracellular matrix genes in six different regions of the Achilles tendon complex of intact normal rabbits; and (ii) to assess the effect of ovariohysterectomy (OVH) on the regional expression of these genes. Female New Zealand White rabbits were separated into two groups: (i) intact normal rabbits (n = 4); and (ii) OVH rabbits (n = 8). For each rabbit, the Achilles tendon complex was dissected into six regions: distal gastrocnemius (DG); distal flexor digitorum superficialis; proximal lateral gastrocnemius (PLG); proximal medial gastrocnemius; proximal flexor digitorum superficialis; and paratenon. For each of the regions, hematoxylin and eosin staining was performed for histological evaluation of intact normal rabbit tissues and mRNA levels for proteoglycans, collagens and genes associated with collagen regulation were assessed by real-time reverse transcription-quantitative polymerase chain reaction for both the intact normal and OVH rabbit tissues. The distal regions displayed a more fibrocartilaginous phenotype. For intact normal rabbits, aggrecan mRNA expression was higher in the distal regions of the Achilles tendon complex compared with the proximal regions. Collagen Type I and matrix metalloproteinase-2 expression levels were increased in the PLG compared to the DG in the intact normal rabbit tissues. The tendons from OVH rabbits had lower gene expressions for the proteoglycans aggrecan, biglycan, decorin and versican compared with the intact normal rabbits, although the regional differences of increased aggrecan expression in distal regions compared with proximal regions persisted. The tensile and compressive forces experienced in the examined regions may be related to the regional differences found in gene expression. The lower mRNA expression of the genes examined in the OVH group confirms a potential effect of systemic estrogen on tendon.

  • 443.
    Hult, Andreas
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Towards a detailed understanding of the red blood cell storage lesion: and its consequences for in vivo survival following transfusion2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Red blood cells (RBCs) are vital for oxygen delivery to tissues and constitute the vast majority of all cells in blood. After leaving the red bone marrow as mature cells, RBCs have a lifespan of approximately 120 days before they are removed from the circulation by macrophages, mainly in the spleen and liver. RBC transfusion is a common therapy in modern healthcare. Major surgery, numerous cancer treatments and other, often lifesaving, interventions would be unthinkable without available blood supply. For this reason, hospitals store donated RBCs in blood banks.

    The metabolic and structural changes that occur during prolonged storage of RBCs (the storage lesion) have been studied in detail in vitro and include oxidative stress, a reduction in glycolysis, increased membrane rigidity and shedding of microparticles from the RBC membrane. Stored RBCs share several features of senescent RBCs, but also with RBCs undergoing an apoptotic-like process called eryptosis. A consequence of the storage lesion is the fact that as much as 25% of stored RBCs could be rapidly removed from the circulation within 24 hours after transfusion. The mechanisms behind this rapid macrophage-mediated recognition and removal of stored RBCs, and its immunological consequences, remain largely unknown. Therefore, the aims of this thesis were to investigate if cryopreserved human RBCs induced an inflammatory response following autologous transfusion into healthy volunteers, and to further understand the mechanisms behind macrophage recognition of stored RBCs in vitro and in vivo.

    Autologous transfusion of two units of cryopreserved RBCs into healthy human recipients was found to be associated with an increased extravascular RBC elimination already at 2 hours after transfusion. However, there were no signs of an increased production of any of the investigated pro-inflammatory cytokines, indicating that an increase in the destruction of RBCs per se did not induce an inflammatory response.

    Eryptosis is a form of induced RBC death associated with an increased cytoplasmic Ca2+ uptake. We found that a subset of human RBCs increased their Ca2+ permeability during prolonged storage at +4°C. Using a murine model, to further understand how RBCs with an increased Ca2+ permeability were eliminated by phagocytic cells in the spleen, it was found that such RBCs were taken up by marginal zone macrophages and dendritic cells (DCs) in a manner distinct from that of naturally senescent RBCs. The DC population particularly efficient in this process expressed CD207 and are known for their ability to promote immunological tolerance. Eryptotic cell uptake was not regulated by the phagocytosis-inhibitory protein CD47 on the RBCs.

    To investigate how RBCs damaged during liquid storage are recognized and taken up by macrophages, a model to store and transfuse murine RBCs was developed. This storage model generated murine RBCs with several characteristics similar to that of stored human RBCs (i.e. loss of ATP, formation of RBC microparticles and rapid clearance of up to 35% of the RBCs during the first 24 h after transfusion). In vitro phagocytosis of human as well as murine stored RBCs was serum dependent and could be inhibited by blocking class A scavenger receptors using fucoidan or dextran sulphate.

    In conclusion, the findings of this thesis contribute to further understanding how changes inflicted to RBCs during storage direct the fate of these cells in their interaction with cells of the immune system after transfusion. The observation of an increased Ca2+ permeability of stored RBCs, and the possible recognition of such cells by tolerance-promoting DCs, in combination with the findings that class A scavenger receptors and serum factors may mediate recognition of stored RBCs, may result in novel new directions of research within the field of transfusion medicine.

  • 444.
    Hult, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Transfusion of cryopreserved human red blood cells into healthy humans is associated with rapid extravascular hemolysis without a proinflammatory cytokine response2013In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 53, no 1, p. 28-33Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Transfusion of stored red blood cells (RBCs) can be associated with adverse side effects. Recent studies in mice transfused with stored RBCs showed that a strong proinflammatory cytokine storm was induced due to extravascular hemolysis already at 2 hours after transfusion. Therefore, we here investigated if transfusion of 2 units of cryopreserved autologous RBCs induced a proinflammatory response in healthy human volunteers.

    STUDY DESIGN AND METHODS: Two units of autologous RBCs, cryopreserved for 16 weeks, were transfused into 10 healthy human volunteers. Serum and blood samples taken at 2 hours before and at 2 and 48 hours after transfusion were analyzed for signs of extravascular hemolysis and the presence of proinflammatory cytokines.

    RESULTS: At 2 hours after transfusion, transferin-bound serum iron, as well as transferin saturation and total bilirubin, were already significantly increased. These measures all returned back toward that in pretransfusion samples at 48 hours after transfusion. No increases in the production of the proinflammatory cytokines interleukin (IL)-1β, IL-6, IL-8, monocyte chemotactic protein-1, macrophage inflammatory protein-1β, or tumor necrosis factor-α were detected at any time point after transfusion.

    CONCLUSION: Although a significant level of extravascular hemolysis already occurred at 2 hours after transfusion of cryopreserved RBCs, there were no signs of proinflammatory cytokine production up to 48 hours after transfusion.

  • 445.
    Hult, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin.
    Toss, Fredrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Phagocytosis of liquid-stored red blood cells in vitro requires serum and macrophage scavenger receptorsManuscript (preprint) (Other academic)
    Abstract [en]

    BACKGROUND: Red blood cells (RBCs) undergo structural and metabolic changes with prolonged storage, which ultimately may decrease their survival after transfusion. Although the storage-induced damage to RBCs has been rather well described biochemically, little is known about the mechanisms underlying the recognition and rapid clearance of the damaged cells by macrophages.STUDY DESIGN AND METHODS: We here used a murine model for cold (+4°C) RBC storage and transfusion. Phagocytosis of human or murine RBCs, liquid stored for 6-8 weeks or 10-14 days respectively, was investigated in murine peritoneal macrophages.RESULTS: The effects of storage on murine RBCs resembled that described for stored human RBCs with regard to decreased adenosine triphosphate (ATP) levels, accumulation of microparticles during storage, and RBC recovery kinetics after transfusion. Under serum-free conditions, phagocytosis of stored human or murine RBCs was reduced by 70-75%, as compared with that in the presence of heat-inactivated fetal calf serum (FCS). Human serum promoted phagocytosis of stored human RBCs similar to that seen with FCS. By blocking macrophage class A scavenger receptors with fucoidan or dextran sulphate, phagocytosis of human or murine RBCs was reduced by more than 90%. Phagocytosis of stored human RBCs was also sensitive to inhibition by the phosphatidylinositol 3 kinase-inhibitor LY294002, the ERK1/2-inhibitor PD98059, or the p38 MAPK-inhibitor SB203580.CONCLUSIONS: RBCs damaged during liquid storage may be recognized by macrophage class A scavenger receptors and serum-dependent mechanisms. This species-independent recognition mechanism may help to further understand the rapid clearance of stored RBCs shortly after transfusion.

  • 446.
    Hultin, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Edin, Benoni B.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Two Years Experiences of a new Swedish National Proficiency Test for Doctors of Medicine.2018In: Abstract book, undee, 2018Conference paper (Refereed)
  • 447.
    Hultin, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Edin, Benoni
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Warglo, Zara
    Socialstyrelsen.
    Wennberg, Åsa
    Socialstyrelsen.
    Sänkta krav på utländska läkare vore förödande2018In: Dagens Samhälle, ISSN 1652-6511, no 4 decArticle in journal (Other (popular science, discussion, etc.))
    Abstract [sv]

    Det är avgörande att det ställs samma höga krav på läkare från länder utanför EU som på svenskutbildade. Bilden av att det ställs olika krav på olika grupper vore förödande, skriver ansvariga för kunskapsprovet för läkare vid Umeå universitet ihop med Socialstyrelsen.

  • 448.
    Häger Ross, Charlotte
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    To grip and not to slip: sensorimotor mechanisms in reactive control of grasp stability1995Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The reactive control of fingertip forces maintaining grasp stability was examined in man during a prehensile task. Blindfolded subjects used the precision grip between the tips of index finger and thumb to restrain an object that was subjected to unpredictable load forces. These were delivered tangential to the parallel grip surfaces of the object. Load forces, grip forces (perpendicular to the grip surfaces) and position of the object were recorded.Subjects automatically adjusted the grip forces to loads of various amplitudes and rates. Thereby they maintained a reliable safety margin against frictional slips without using excessive grip forces. A rapid rise in grip force lasting about 0.2 s was triggered after a short delay following the onset of a sustained ramp load increase. This 'catch-up' response caused a quick restoration of an adequate grip:load force ratio that prevented frictional slips. If the ramp load continued to increase after the catchup response, the grip force also increased in parallel with the load change in a 'tracking' manner. Consequently, during the hold phases of 'ramp-and-hold' loads, the employed grip forces were approximately proportional to the load amplitude. Sensory information about the rate of change of the load force parametrically scaled the 'catchup' and 'tracking' responses.Following anesthetic block of sensory input from the digits, the grip responses were both delayed and attenuated or even abolished. To compensate for these impairments, subjects had to voluntarily maintain exceedingly high grip forces to prevent the object from slipping. The grip control improved slightly during hand and forearm support conditions that allowed marked wrist movements to occur in response to the loading. This indicates that signals from receptors in muscles, joints or skin areas proximal to the digits can to some extent be used to adjust grip forces during impaired digital sensibility. In contrast, these signals had only minor influence on the control during normal digital sensibility.Grip responses to loads delivered in various directions revealed that the load direction, in relation to gravity and to the hand's geometry, represents intrinsic task variables in the automatic processes that maintain a stable grasp. The load direction influenced both the response latencies and the magnitudes of the grip responses. The response latencies were shortest for loads in directions that were the most critical with regard to the consequences of frictional slippage, i.e., loads directed away from the palm or in the direction of gravity. Recordings of signals in cutaneous afferents innervating the finger tips demonstrated that these effects on the response latencies depended on differences in the time needed by the central nervous system to implement the motor responses. The short latencies in the most ‘criticar load directions may reflect the preparation of a default response, while additional central processing would be needed to execute the response to loads in other directions. Adjustments to local frictional anisotropies at the digit-object interface largely explained the magnitude effects.In conclusion, grip responses are automatically adjusted to the current loading condition during unpredictable loading of a hand held object. Subjects call up a previously acquired sensorimotor transform that supports grasp stability by preventing both object slippage and excessive grip forces. Cutaneous sensory information about tangential forces and frictional conditions at the digit-object interface is used to initiate and scale the grip responses to the current loading conditions, largely in a predictive manner.

  • 449.
    Häger-Ross, Charlotte
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Cole, KJ
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Grip-force responses to unanticipated object loading: load direction reveals body- and gravity-referenced intrinsic task variables1996In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 110, no 1, p. 142-150Article in journal (Refereed)
    Abstract [en]

    Humans preserve grasp stability by automatically regulating the grip forces when loads are applied tangentially to the grip surfaces of a manipulandum held in a precision grip. The effects of the direction of the load force in relation to the palm, trunk, and gravity were investigated in blindfolded subjects. Controlled, tangential load-forces were delivered in an unpredictable manner to the grip surface in contact with the index finger either in the distal and proximal directions (away from and toward the palm) or in the ulnar and radial directions (transverse to the palm). The hand was oriented in: (1) a standard position, with the forearm extended horizontally and anteriorly in intermediate pronosupination; (2) an inverted position, reversing the direction of radial and ulnar loads in relation to gravity; and (3) a horizontally rotated position, in which distal loads were directed toward the trunk. The amplitude of the grip-force responses (perpendicular to the grip surface) varied with the direction of load in a manner reflecting frictional anisotropies at the digit-object interface; that is, the subjects automatically scaled the grip responses to provide similar safety margins against frictional slips. For all hand positions, the time from onset of load increase to start of the grip-force increase was shorter for distal loads, which tended to pull the object out of the hand, than for proximal loads. Furthermore, this latency was shorter for loads in the direction of gravity, regardless of hand position. Thus, shorter latencies were observed when frictional forces alone opposed the load, while longer latencies occurred when gravity also opposed the load or when the more proximal parts of the digits and palm were positioned in the path of the load. These latency effects were due to different processing delays in the central nervous system and may reflect the preparation of a default response in certain critical directions. The response to loads in other directions would incur delays required to implement a new frictional scaling and a different muscle activation pattern to counteract the load forces. We conclude that load direction, referenced to gravity and to the hand's geometry, represents intrinsic task variables in the automatic processes that maintain a stable grasp on objects subjected to unpredictable load forces. In contrast, the grip-force safety margin against frictional slips did not vary systematically with respect to these task variables. Instead, the magnitude of the grip-force responses varied across load direction and hand orientation according to frictional differences providing similar safety margins supporting grasp stability.

  • 450.
    Häger-Ross, Charlotte
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Nondigital afferent input in reactive control of fingertip forces during precision grip1996In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 110, no 1, p. 131-141Article in journal (Refereed)
    Abstract [en]

    Sensory inputs from the digits are important in initiating and scaling automatic reactive grip responses that help prevent frictional slips when grasped objects are subjected to destabilizing load forces. In the present study we analyzed the contribution to grip-force control from mechanoreceptors located proximal to the digits when subjects held a small manipulandum between the tips of the thumb and index finger. Loads of various controlled amplitudes and rates were delivered tangential to the grip surfaces at unpredictable times. Grip forces (normal to the grip surfaces) and the position of the manipulandum were recorded. In addition, movements of hand and arm segments were assessed by recording the position of markers placed at critical points. Subjects performed test series during normal digital sensibility and during local anesthesia of the index finger and thumb. To grade the size of movements of tissues proximal to the digits caused by the loadings, three different conditions of arm and hand support were used; (1) in the hand-support condition the subjects used the three ulnar fingers to grasp a vertical dowel support and the forearm was supported in a vacuum cast; (2) in the forearm-support condition only the forearm was supported; finally, (3) in the no-support condition the arm was free. With normal digital sensibility the size of the movements proximal to the digits had small effects on the grip-force control. In contrast, the grip control was markedly influenced by the extent of such movements during digital anesthesia. The poorest control was observed in the hand-support condition, allowing essentially only digital movements. The grip responses were either absent or attenuated, with greatly prolonged onset latencies. In the forearm and no-support conditions, when marked wrist movements took place, both the frequency and the strength of grip-force responses were higher, and the grip response latencies were shorter. However, the performance never approached normal. It is concluded that sensory inputs from the digits are dominant in reactive grip control. However, nondigital sensory input may be used for some grip control during impaired digital sensibility. Furthermore, the quality of the control during impaired sensibility depends on the extent of movements evoked by the load in the distal, unanesthetized parts of the arm. The origin of these useful sensory signals is discussed.

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