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  • 1. Aalto, Kristiina
    et al.
    Korhonen, Laura
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Lahdenne, Pekka
    Pelkonen, Pirkko
    Lindholm, Dan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Nerve growth factor in serum of children with systemic lupus erythematosus is correlated with disease activity2002In: Cytokine, Vol. 20, p. 136-Article in journal (Refereed)
  • 2.
    Aanestad, O
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Flink, R
    Department of Neuroscience.
    Urinary stress incontinence. A urodynamic and quantitative electromyographic study of the perineal muscles.1999In: Acta Obstet. Gynecol. Scand., Vol. 78, p. 245-Article in journal (Refereed)
  • 3.
    Aanestad, Ö
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Flink, R
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Urinary stress incontinence: a urodynamic and quantitative electromyogrpahic study of the perineal muscles.1998In: Acta Obstet. Gynecol. Scand., Vol. 77, p. 1-Article in journal (Refereed)
  • 4. Aanestad, Ö
    et al.
    Flink, R
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Haggman, M
    Department of Surgical Sciences.
    Norlen, BJ
    Department of Surgical Sciences.
    Interference pattern in the urethral sphincter: a quantitative study in patients before and after radical retropubic prostatectomy.1998In: Scand J Urol and Nephrology, Vol. 32, p. 1-Article in journal (Refereed)
  • 5. Aardal-Eriksson, E
    et al.
    Eriksson, T.E
    Holm, A-C
    Lundin, T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Salivary cortisol and serum prolactin in relation to stress rating scales in a group of rescue workers1999In: Biol. Psychiatry, Vol. 46, p. 850-Article in journal (Refereed)
  • 6.
    Aare, Sudhakar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Norman, Holly S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Radell, Peter
    Eriksson, Lars I
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Chen, Yi-Wen
    Hoffman, Eric P
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model2011In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, no 24, p. 1334-1350Article in journal (Refereed)
    Abstract [en]

    Acute quadriplegic myopathy (AQM) is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients which is characterized by tetraplegia/generalized weakness of limb and trunk muscles. Masticatory muscles, on the other hand, are typically spared or less affected, yet the mechanisms underlying this striking muscle-specific difference remain unknown. This study aims to evaluate physiological parameters and the gene expression profiles of masticatory and limb muscles exposed to factors suggested to trigger AQM, such as mechanical ventilation, immobilization, neuromuscular blocking agents (NMBA), corticosteroids (CS) and sepsis for five days by using a unique porcine model mimicking the ICU conditions. Single muscle fiber cross-sectional area and force-generating capacity, i.e., maximum force normalized to fiber cross-sectional area (specific force), revealed maintained masseter single muscle fiber cross-sectional area and specific-force after five days exposure to all triggering factors. This is in sharp contrast to observations in limb and trunk muscles, showing a dramatic decline in specific force in response to five days exposure to the triggering factors. Significant differences in gene expression were observed between craniofacial and limb muscles, indicating a highly complex and muscle specific response involving transcription and growth factors, heat shock proteins, matrix metalloproteinase inhibitor, oxidative stress responsive elements and sarcomeric proteins underlying the relative sparing of cranial versus spinal nerve innervated muscles during exposure to the ICU intervention.

  • 7.
    Aare, Sudhakar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Radell, Peter
    Department of anesthesiology, Karolinska Inistitute.
    Eriksson, Lars
    Department of anesthesiology, Karolinska Inistitute.
    Akkad, Hazem
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Chen, Yi-Wen
    Research center for genetic medicine.
    Hoffman, Eric
    Research center for genetic medicine.
    Lars, Larsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model2013In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, no 8, p. 312-320Article in journal (Refereed)
    Abstract [en]

    Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator and a decreased quality of life post-ICU. The mechanisms underlying limbmuscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization and systemic administration of corticosteroids (CS).  These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for five days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes using microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional up-regulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response , cytoskeletal, sarcomeric and heat shock protein as well as protein synthesis at the translational level appear to play an additive deleterious role for the  limb muscle weakness in immobilized ICU patients.

     

  • 8.
    Aare, Sudhakar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Radell, Peter
    Department of anesthesiology, Karolinska Inistitute.
    Eriksson, Lars
    Department of anesthesiology, Karolinska Inistitute.
    Chen, Yi-Wen
    Research center for genetic medicine.
    Hoffman, Eric P
    Research center for genetic medicine.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model2012In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, no 18, p. 865-877Article in journal (Refereed)
    Abstract [en]

    Severe muscle wasting and loss of muscle function in critically ill mechanically ventilated intensive care unit (ICU) patients have significant negative consequences on their recovery and rehabilitation that persist long after their hospital discharge; moreover the underlying mechanisms are unclear. Mechanical ventilation (MV) and immobilization-induced modifications play an important role in these consequences, including endotoxin induced sepsis. The present study aims to investigate how sepsis aggravates ventilator and immobilization-related limb muscle dysfunction. Hence, biceps femoris muscle gene expression was investigated in pigs exposed to ICU intervention, i.e., immobilization, sedation, and MV, alone or in combination with sepsis for five days. In previous studies, we have shown that ICU intervention alone or in combination with sepsis did not affect muscle fiber size on day 5, but a significant decrease was observed in single fiber maximal force normalized to cross-sectional area (specific force) when sepsis was added to the ICU intervention. According to microarray data, the addition of sepsis to the ICU intervention induced a deregulation of more than 500 genes, such as an increased expression of genes involved in chemokine activity, kinase activity and transcriptional regulation. Genes involved in the regulation of the oxidative stress response, cytoskeletal/sarcomeric and heat shock proteins were on the other hand down-regulated when sepsis was added to the ICU intervention. Thus, sepsis has a significant negative effect on muscle function in critically ill ICU patients and chemokine activity and heat shock protein genes are forwarded to play an instrumental role in this specific muscle wasting condition.

  • 9.
    Aare, Sudhakar Reddy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Acute quadriplegic myopathy (AQM), or critical illness myopathy, is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients characterized by generalized muscle wasting and weakness of limb and trunk muscles. A preferential loss of the thick filament protein myosin is considered pathognomonic of this disorder, but the myosin loss is observed relatively late during the disease progression. In attempt to explore the potential role of factors considered triggering AQM in sedated mechanically ventilated (MV) ICU patients, we have studied the early effects, prior to the myosin loss, of neuromuscular blockade (NMB), corticosteroids (CS) and sepsis separate or in combination in a porcine experimental ICU model. Specific interest has been focused on skeletal muscle gene/protein expression and regulation of muscle contraction at the muscle fiber level. This project aims at improving our understanding of the molecular mechanisms underlying muscle specific differences in response to the ICU intervention and the role played by the different triggering factors.

    The sparing of masticatory muscle fiber function was coupled to an up-regulation of heat shock protein genes and down-regulation of myostatin are suggested to be key factors in the relative sparing of masticatory muscles. Up-regulation of chemokine activity genes and down-regulation of heat shock protein genes play a significant role in the limb muscle dysfunction associated with sepsis. The effects of corticosteroids in the development of limb muscle weakness reveals up-regulation of kinase activity and transcriptional regulation genes and the down-regulation of heat shock protein, sarcomeric, cytoskeletal and oxidative stress responsive genes. In contrast to limb and craniofacial muscles, the respiratory diaphragm muscle responded differently to the different triggering factors. MV itself appears to play a major role for the diaphragm muscle dysfunction. By targeting these genes, future experiments can give an insight into the development of innovative treatments expected at protecting muscle mass and function in critically ill ICU patients.

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  • 10.
    Abalo, Xesus
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Boije: Zebrafish Neuronal Networks. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lagman, David
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Bergen, Sars Int Ctr Marine Mol Biol, Bergen, Norway.
    Heras, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    del Pozo, Ana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Boije: Zebrafish Neuronal Networks. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eggert, Joel
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Emory Univ, Dept Med, Atlanta, GA 30322 USA.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
    Circadian regulation of phosphodiesterase 6 genes in zebrafish differs between cones and rods: Implications for photopic and scotopic vision2020In: Vision Research, ISSN 0042-6989, E-ISSN 1878-5646, Vol. 166, p. 43-51Article in journal (Refereed)
    Abstract [en]

    A correlation is known to exist between visual sensitivity and oscillations in red opsin and rhodopsin gene expression in zebrafish, both regulated by the clock gene. This indicates that an endogenous circadian clock regulates behavioural visual sensitivity, apart from the regulation exerted by the pineal organ. However, the specific mechanisms for cones (photopic vision) and rods (scotopic vision) are poorly understood. In this work, we performed gene expression, cosinor and immunohistochemical analyses to investigate other key genes involved in light perception, encoding the different subunits of phosphodiesterase pde6 and transducin G alpha(T), in constant lighting conditions and compared to normal light-dark conditions. We found that cones display prominent circadian oscillations in mRNA levels for the inhibitory subunit gene pde6ha that could contribute to the regulation of photopic sensitivity by preventing overstimulation in photopic conditions. In rods, the mRNA levels of the inhibitory subunit gene pde6ga oscillate under normal conditions and dampen down in constant light but continue oscillating in constant darkness. There is an increase in total relative expression for pde6gb in constant conditions. These observations, together with previous data, suggest a complex regulation of the scotopic sensitivity involving endogenous and non-endogenous components, possibly present also in other teleost species. The G alpha(T) genes do not display mRNA oscillations and therefore may not be essential for the circadian regulation of photosensitivity. In summary, our results support different regulation for the zebrafish photopic and scotopic sensitivities and suggest circadian regulation of pde6ha as a key factor regulating photopic sensitivity, while the regulatory mechanisms in rods appear to be more complex.

  • 11.
    Abbaspour, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotheraphy.
    Lindén, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotheraphy.
    Primärvårdsjukgymnastens yrkesroll och kompetens, nu och i framtiden.2010Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 12.
    Abbey-Lee, Robin N.
    et al.
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Uhrig, Emily J.
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Zidar, Josefina
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Favati, Anna
    Stockholm Univ, Dept Zool, Stockholm, Sweden.
    Almberg, Johan
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Dahlbom, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lövlie, Hanne
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    The Influence of Rearing on Behavior, Brain Monoamines, and Gene Expression in Three-Spined Sticklebacks2018In: Brain, behavior, and evolution, ISSN 0006-8977, E-ISSN 1421-9743, Vol. 91, no 4, p. 201-213Article in journal (Refereed)
    Abstract [en]

    The causes of individual variation in behavior are often not well understood, and potential underlying mechanisms include both intrinsic and extrinsic factors, such as early environmental, physiological, and genetic differences. In an exploratory laboratory study, we raised three-spined sticklebacks (Gasterosteus aculeatus) under 4 different environmental conditions (simulated predator environment, complex environment, variable social environment, and control). We investigated how these manipulations related to behavior, brain physiology, and gene expression later in life, with focus on brain dopamine and serotonin levels, turnover rates, and gene expression. The different rearing environments influenced behavior and gene expression, but did not alter monoamine levels or metabolites. Specifically, compared to control fish, fish exposed to a simulated predator environment tended to be less aggressive, more exploratory, and more neophobic; and fish raised in both complex and variable social environments tended to be less neophobic. Exposure to a simulated predator environment tended to lower expression of dopamine receptor DRD4A, a complex environment increased expression of dopamine receptor DRD1B, while a variable social environment tended to increase serotonin receptor 5-HTR2B and serotonin transporter SLC6A4A expression. Despite both behavior and gene expression varying with early environment, there was no evidence that gene expression mediated the relationship between early environment and behavior. Our results confirm that environmental conditions early in life can affect phenotypic variation. However, the mechanistic pathway of the monoaminergic systems translating early environmental variation into observed behavioral responses was not detected.

  • 13. Abbott, GW
    et al.
    Mercer, EA
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Miller, RT
    Ramesh, B
    Srai, SK
    Conformational changes in a mammalian voltage-dependent potassium channel inactivation peptide1998In: Biochemistry, Vol. 37, p. 1640-Article in journal (Refereed)
  • 14. Abelson, K.
    et al.
    Jacobsen, K. R.
    Kalliokoski, O.
    Teilmann, C.
    Sundbom, Renée
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Hau, J.
    Limitations of the Usefulness of Fecal Corticosterone as Biomarker for Stress in Mice2012In: Journal of the American Association for Laboratory Animal Science, ISSN 1559-6109, Vol. 51, no 5, p. 639-639Article in journal (Refereed)
  • 15.
    Abelson, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Acetylcholine in Spinal Pain Modulation: An in vivo Study in the Rat2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The spinal cord is an important component in the processing and modulation of painful stimuli. Nerve signals from the periphery are relayed and further conducted to the brain (nociception) in the spinal cord, and the most essential modulation of painful information (antinociception) occurs here. Several neurotransmitters are involved in spinal pain modulation, among them acetylcholine. However, the role of acetylcholine has previously been little investigated.

    In the present thesis, the acetylcholine release in the spinal cord was studied in vivo. By using spinal microdialysis on anaesthetised rats, the effects on the intraspinal acetylcholine release of various receptor ligands and analgesic agents were examined. This, together with pain behavioural tests and in vitro pharmacological assays, was used to evaluate the role of acetylcholine in spinal pain modulation. The four studies in this thesis resulted in the following conclusions:

    An increased release of spinal acetylcholine is associated with an elevated pain threshold, while a decreased acetylcholine release is associated with hyperalgesia, as seen after systemic treatment with a muscarinic agonist and an antagonist.

    Lidocaine is a potent analgesic when given systemically. It was found to produce an increase of intraspinal acetylcholine after intravenous injection of analgesic doses. This effect was attenuated after muscarinic, and abolished after nicotinic, receptor blockade.

    Various a2-adrenergic ligands, associated with nociceptive or antinociceptive effects, were found to affect intraspinal acetylcholine release via action on nicotinic receptors.

    Finally, the involvement of spinal acetylcholine in the analgesic effects of aspirin and paracetamol was examined. It was found that spinal acetylcholine could participate in the analgesic effects of aspirin, but not of paracetamol.

    The present thesis provides data that clearly demonstrate a relationship between intraspinal acetylcholine and antinociception, and elucidate interactions between acetylcholine and other mechanisms that mediate antinociception in the spinal cord.

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  • 16.
    Abelson, Klas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Adem, Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Royo, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Carlsson, Hans-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Hau, Jann
    High plasma corticosterone levels persist during frequent automatic blood sampling in rats2005In: In Vivo, ISSN 0258-851X, E-ISSN 1791-7549, Vol. 19, no 5, p. 815-19Article in journal (Refereed)
    Abstract [en]

    Corticosterone levels in blood may be used as a marker of stress in rodents, provided that the blood sampling procedure itself is non-stressful. Automated blood sampling equipment (Accusampler®) allows blood sampling without any interference with the animal and might be useful as a tool for an on-line measurement of stress markers in blood. However, the impact of the blood sampling itself on the corticosterone levels in blood is unknown. The present study was designed to evaluate whether the frequency of blood sampling influences the plasma corticosterone levels in male and female rats. During anaesthesia, a catheter was placed in the jugular vein and attached to an Accusampler®. Blood samples (200 μl) were withdrawn with a high (24 samples) or low frequency (3 samples) during a six-hour period immediately after the catheter insertion. The corticosterone levels in the plasma were quantified with ELISA. The corticosterone levels persisted at high post-operation concentrations when blood was collected frequently, while the levels steadily declined significantly during low-frequency sampling. The corticosterone levels were higher in female than in male rats, but the curves were similar. The present study elucidates the importance of considering the frequency of blood withdrawal during automated blood sampling. This parameter may have an impact on the experimental results when using blood corticosterone levels as a stress marker, but also during any in vivo study where blood is collected, since high corticosterone levels may affect the normal physiology of the animals.

  • 17.
    Abelson, Klas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Hau, Jann
    Carlsson, Hans-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Undergraduate and postgraduate students' responses to mandatory courses (FELASA category C) in laboratory animal science 1997-20032005In: Internationalisation and Harmonisation of Laboratory Animal Care and Use Issues: Proceedings of the Ninth FELASA Symposium 14-17 June 2004, Nantes, France / [ed] M. R. Gamble, 2005Conference paper (Other academic)
  • 18.
    Abelson, Klas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Höglund, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Intravenously administered lidocaine in therapeutic doses increases the intraspinal release of acetylcholine in rats2002In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 317, no 2, p. 93-6Article in journal (Refereed)
    Abstract [en]

    The local anesthetic lidocaine suppresses different pain conditions when administered systemically. Part of the antinociceptive effect appears to be mediated via receptor mechanisms. We have previously shown that muscarinic and nicotinic agonists that produce antinociception increase the intraspinal release of acetylcholine. In the present study it was hypothesized that systemically administered lidocaine is acting through the same mechanisms as cholinergic agonists and affects the intraspinal release of acetylcholine. Microdialysis probes were placed in anesthetized rats for sampling of acetylcholine. Ten and 30 mg/kg lidocaine injected intravenously significantly increased the intraspinal release of acetylcholine. The effect of lidocaine could be reduced by pretreatment with intraspinally administered atropine or mecamylamine. Our results suggest that the antinociceptive effect produced by systemically administered lidocaine is mediated through an action on muscarinic and nicotinic receptors.

  • 19.
    Abelson, Klas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Höglund, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Intravenously administered oxotremorine and atropine, in doses known to affect pain threshold, affect the intraspinal release of acetylcholine in rats2002In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 90, no 4, p. 187-192Article in journal (Refereed)
    Abstract [en]

    Abstract:Both systemically and intrathecally administered cholinergic agonists produce antinociception while cholinergic antagonists decrease pain threshold. The mechanism and the site of action of these substances are not known. In the present study it was hypothesized that systemically administered muscarinic agonists and antagonists modify nociceptive threshold by affecting intraspinal release of acetylcholine (ACh). Catheters were inserted into the femoral vein in rats maintained on isoflurane anaesthesia for administration of oxotremorine (10–300 μg/kg) and atropine (0.1, 10, 5000 μg/kg). Spinal microdialysis probes were placed intraspinally at approximately the C2–C5 spinal level for sampling of acetylcholine and dialysis delivery of atropine (0.1, 1, 10 nM). Additionally, the tail-flick behaviour was tested on conscious rats injected intraperitoneally with saline, atropine (10, 100 and 5000 μg/kg), or subcutaneously with oxotremorine (30, 100, 300 μg/kg). Subcutaneous administration of oxotremorine (30, 100, 300 μg/kg) significantly increased the tail-flick latency. These doses of oxotremorine dose-dependently increased the intraspinal release of acetylcholine. Intravenously administered atropine, in a dose that produced hyperalgesia (5000 μg/kg) in the tail-flick test, significantly decreased the intraspinal release of acetylcholine. Our results suggest an association between pain threshold and acetylcholine release in spinal cord. It is also suggested that an approximately 30% increase in basal ACh release produces antinociception and that a 30% decrease in basal release produces hyperalgesia.

  • 20.
    Abelson, Klas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Höglund, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat2004In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 94, no 4, p. 153-60Article in journal (Refereed)
    Abstract [en]

    Cholinergic agonists produce spinal antinociception via mechanisms involving an increased release of intraspinalacetylcholine. The cholinergic receptor system interacts with several other receptor types, such as a2-adrenergic receptors.To fully understand these interactions, the effects of various receptor ligands on the cholinergic system must be investigatedin detail. This study was initiated to investigate the effects of the a2-adrenergic receptor agonists clonidine and rilmenidineand the a2-adrenergic receptor antagonists yohimbine and efaroxan on spinal cholinergic receptors in the rat. Spinalmicrodialysis was used to measure in vivo changes of acetylcholine after administration of the ligands, with or withoutnicotinic receptor blockade. In addition, in vitro binding properties of the ligands on muscarinic and nicotinic receptorswere investigated. It was found that clonidine and rilmenidine increased, while yohimbine decreased spinal acetylcholinerelease. Efaroxan affected acetylcholine release differently depending on concentration. Nicotinic receptor blockade atten-uated the effect of all ligands. All ligands showed poor binding affinity for muscarinic receptors. On the other hand, allligands possessed affinity for nicotinic receptors. Clonidine and yohimbine binding was best fit to a one site binding curveand rilmenidine and efaroxan to a two site binding curve. The present study demonstrates that the tested a2-adrenergicreceptor ligands affect intraspinal acetylcholine release in the rat evoked by nicotinic receptor mechanisms in vivo, andthat they possess binding affinity to nicotinic receptors in vitro. The binding of a2-adrenergic receptor ligands to nicotinicreceptors might affect the intraspinal release of acetylcholine.

  • 21.
    Abelson, Klas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Kommalage, Mahinda
    Höglund, Urban
    Spinal cholinergic involvement after treatment with aspirin and paracetamol in rats2004In: Neurosci. Lett., ISSN 0304-3940, Vol. 368, no 1, p. 116-120Article in journal (Refereed)
  • 22.
    Abelson, Klas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Kommalage, Mahinda
    Höglund, Urban
    Spinal cholinergic involvement after treatment with aspirin and paracetamol in rats2004In: Neuroscience Letters, ISSN 0304-3940, Vol. 368, no 1, p. 116-120Article in journal (Refereed)
  • 23.
    Abelson, Klas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Försöksdjursvetenskap.
    Röstlinger Goldkuhl, Renée
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Försöksdjursvetenskap.
    Nylund, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Försöksdjursvetenskap.
    Höglund, Urban
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Försöksdjursvetenskap.
    The effect of ketamine on intraspinal acetylcholine release: Involvement of spinal nicotinic receptors2006In: Eur J Pharmacol, Vol. 534, p. 122-128Article in journal (Refereed)
  • 24.
    Abelson, Klas S. P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Fard, Shahrzad Shirazi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Nyman, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Goldkuhl, Renée
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Hau, Jann
    Distribution of [3H]-corticosterone in urine, feces and blood of male Sprague-Dawley rats after tail vein and jugular vein injections2009In: In Vivo, ISSN 0258-851X, E-ISSN 1791-7549, Vol. 23, no 3, p. 381-386Article in journal (Refereed)
    Abstract [en]

    The present study aimed to investigate the time-course and distribution of [(3)H]-corticosterone in urine, feces and blood of male Sprague-Dawley rats after intravenous administration of a low dose (1 microCi), and to investigate whether different intravenous routes of administration may affect the dynamics of excreted [(3)H]-corticosterone in the feces. One microCi [(3)H]-corticosterone was injected intravenously either through the tail vein in manually restrained rats or through a jugular vein catheter three days after surgical implantation. Urine and feces were collected at different time points over 78 h from the rats injected in the tail vein, and blood and feces were collected over 48 h from rats injected in the jugular vein. In the blood, radioactivity peaked immediately and decreased rapidly within 90 minutes. The radioactivity was excreted in urine within six h and in feces after at least 12 h. Sixty percent of the radioactivity was detected in the urine and 40% in feces during the study period of 78 h. The detected amount of radioactivity in feces was higher and displayed a more pronounced peak 12 h after injection when the substance was administered through a jugular vein catheter compared to tail vein injection. The data obtained in the present study may serve as an important benchmark when choosing time points for fecal collection for quantification of corticosterone or corticosterone metabolites as a non-invasive measure of preceding HPA-axis activation.

  • 25. Abelson, Klas S. P.
    et al.
    Jacobsen, Kirsten R.
    Sundbom, Renée
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Kalliokoski, Otto
    Hau, Jann
    Voluntary ingestion of nut paste for administration of buprenorphine in rats and mice2012In: Laboratory Animals, ISSN 0023-6772, E-ISSN 1758-1117, Vol. 46, no 4, p. 349-351Article in journal (Refereed)
    Abstract [en]

    An adequate analgesic strategy is important to improve the postoperative recovery and welfare of laboratory rats and mice. It is desirable that the method for administering the drug is non-invasive and stress-free. We have previously validated a method for administering buprenorphine in a nut paste for voluntary ingestion. This method has many advantages over parenteral administration. To use the method in a successful way, however, it is important to prepare and administer the mix correctly. The present paper describes in detail how to implement the method, by means of habituation, presentation, adequate concentrations and amounts of buprenorphine/nut paste, and dosage of buprenorphine to rats and mice.

  • 26.
    Aberg, AC
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lindmark, B
    Department of Neuroscience.
    Lithell, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Development and reliability of the General Motor Function Assessment Scale(GMF)-A performance-based measure of function-related dependence, pain andinsecurity.2003In: Disabil Rehabil, Vol. 25, p. 11-Article in journal (Refereed)
  • 27.
    Aberg, AC
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lindmark, B
    Department of Neuroscience.
    Lithell, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Evaluation and application of the General Motor Function assessment scalein geriatric rehabilitation.2003In: Disabil Rehabil, Vol. 25, p. 9-Article in journal (Refereed)
  • 28.
    Aberg, Fredrik
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Kozlova, Elena N
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Metastasis-associated Mts1 (S100A4) protein in the developing and adult central nervous system2000In: J Comp Neurology, Vol. 424, p. 269-Article in journal (Refereed)
  • 29. Aberg-Wistedt, A
    et al.
    Agren, H
    Ekselius, Lisa
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Bengtsson, F
    Akerblad, AC
    Sertraline vs Paroxetine in major depression: Clinical outcome after6 months of continuation therapy.2000In: J Clin Psychopharmacol. , Vol. 20, p. 645-Article in journal (Refereed)
  • 30.
    Abrahamsson, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Quick, Linnéa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Datorbaserad fonologisk lästräning för barn med hörselnedsättning: En undersökning av fonologisk medvetenhet och ordavkodning2015Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Randomized controlled trials evaluating the effect of various forms of literacy training with reliable tests are lacking in Sweden today. The aim of the present study was to investigate whether a cross-over design and the use of phonologically matched wordlists specifically designed to detect transfer, would yield a more thorough method and reliable results. Six children with hearing impairment using hearing aids between 7 and 9 years of age took part in the study. The schools in which the children had their education were randomized into either an intervention group that started to practice phonics by means of a computer-assisted program after the first testing, or a control group that, continued as usual in school. Children were informed to practice daily with the program during four weeks in school. Children were tested with a battery of tests for phonological awareness, letter knowledge and word decoding at three occasions separated by four weeks. Results showed that the wordlists seemed reliable in establishing children’s decoding strategies as well as how word length affected reading speed. Both children who took part in the intervention and the control group improved their scores at the second testing. Thus, the computer-assisted reading intervention did not prove to be more effective than usual school activities. Due to a small number of participants, a large heterogeneity of the group and insufficient practice time, effects were difficult to detect. The present investigation should be considered a pilot study towards the use of more careful testing methods with adapted wordlists that enables the detection of transfer. But, to accomplish this, it is crucial to use a larger number of participants.

    Randomiserade kontrollerade studier som utvärderar effekten av olika former av läs- och skrivträning med tillförlitliga tester saknas i Sverige idag. Syftet med denna undersökning var att genomföra en interventionsstudie med cross-over design och använda fonologiskt matchade ordlistor specifikt utformade för att upptäcka transfer, för att ge utdelning för en mer grundlig metod och reliabla resultat. Sex barn mellan 7 och 9 års ålder som använde hörapparat deltog i studien. Skolorna som barnen gick i randomiserades till att antingen utgöra en interventionsgrupp, som började träna med ett ljudbaserat lästräningsprogram via dator efter första testningen, eller kontrollgrupp som fortsatte med vanlig skolundervisning. Barnen informerades att träna med programmet under fyra veckor dagligen i skolan. Barnen utförde ett testbatteri innehållande tester för fonologisk medvetenhet, bokstavskännedom och ordavkodning vid tre tillfällen med fyra veckors mellanrum. Resultaten visade att ordlistorna på ett reliabelt sätt kunde fastställa barns avkodningsstrategier samt hur ordlängd påverkade läshastigheten. Både interventions- och kontrollgruppen påvisade förbättring vid andra testningen. Dock kunde det inte påvisas att den datorbaserade lästräningen var mer effektiv än sedvanlig skolundervisning. Då deltagarantalet var litet, spridningen stor och träningstiden vid datorn var låg kan detta ha bidragit till att effekterna uteblev. Studien bör ses som en pilotstudie som går mot en noggrannare form av testmetod där användandet av anpassade ordlistor möjliggör upptäckt av transfer. För att åstadkomma detta är det emellertid avgörande att det ingår ett större deltagarantal.

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  • 31. Abrahamsson, Hasse
    et al.
    Ostlund-Lindqvist, Ann-Margret
    Nilsson, Ralf
    Simren, Magnus
    Gillberg, Per-Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Altered bile acid metabolism in patients with constipation-predominant irritable bowel syndrome and functional constipation2008In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 43, no 12, p. 1483-1488Article in journal (Refereed)
    Abstract [en]

    Objective. Bile acids are derived from cholesterol and are potent physiological laxatives. The aim of this study was to investigate whether bile acid synthesis is altered in constipation. Material and methods. Female patients with constipation (23 IBS-C, 4 functional constipation (FC)) were studied and compared with non-constipated subjects (16 IBS-D, 20 healthy women). Body mass index (BMI), blood lipids, lanosterol, sitosterol, colonic transit (oro-anal transit time (OATT), reference=4.3 days) and stool frequency were measured. C4 (7--hydroxy-4-cholesten-3-one) levels reflecting bile acid synthesis were measured at 0800 h and 1300 h. Results. When all the groups of constipated and non-constipated subjects were compared, it was found that only stool frequency and OATT differed between groups (p 0.001). When constipated patients were categorized according to OATT, absence of the usual C4 increase at lunchtime was noted in 82% of patients with delayed OATT compared with 17% in subjects with normal OATT (p 0.001). Symptom severity did not differ between groups. A subset of the patients with severely delayed OATT had markedly elevated C4 levels. Conclusions. Patients with IBS-C and FC have marked changes in bile acid synthesis in relation to colonic transit. The diurnal rhythm is altered in the slow transit colon when there is no C4 peak at lunchtime. Alterations in bile acid metabolism may be implicated in the pathophysiology of constipation.

  • 32.
    Abrahamsson, Lotta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Ljung, Ida-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Bliss i interaktion: - En samtalsanalytisk fallstudie av hur blissanvändare och tolkare tillsammans bygger upp yttranden2008Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
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  • 33.
    Abreu, Murilo S.
    et al.
    Fed Univ Santa Maria UFSM, Grad Program Pharmacol, BR-97105900 Santa Maria, RS, Brazil.
    Messias, Joao P. M.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal.
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Soares, Marta C.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal.
    Monoaminergic levels at the forebrain and diencephalon signal for the occurrence of mutualistic and conspecific engagement in client reef fish2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 7346Article in journal (Refereed)
    Abstract [en]

    Social interactions are commonly found among fish as in mammals and birds. While most animals interact socially with conspecifics some however are also frequently and repeatedly observed to interact with other species (i.e. mutualistic interactions). This is the case of the (so-called) fish clients that seek to be cleaned by other fish (the cleaners). Clients face an interesting challenge: they raise enough motivation to suspend their daily activities as to selectively visit and engage in interactions with cleaners. Here we aimed, for the first time, to investigate the region-specific brain monoaminergic level differences arising from individual client fish when facing a cleaner (interspecific context) compared to those introduced to another conspecific (socio-conspecific context). We show that monoaminergic activity differences occurring at two main brain regions, the diencephalon and the forebrain, are associated with fish clients' social and mutualistic activities. Our results are the first demonstration that monoaminergic mechanisms underlie client fish mutualistic engagement with cleanerfish. These pathways should function as a pre-requisite for cleaning to occur, providing to clients the cognitive and physiological tools to seek to be cleaned.

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  • 34.
    Abu Hamdeh, Sami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Clinical Consequences of Axonal Injury in Traumatic Brain Injury2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Traumatic brain injury (TBI), mainly caused by road-traffic accidents and falls, is a leading cause of mortality. Survivors often display debilitating motor, sensory and cognitive symptoms, leading to reduced quality of life and a profound economic burden to society. Additionally, TBI is a risk factor for future neurodegenerative disorders including Alzheimer’s disease (AD). Commonly, TBI is categorized into focal and diffuse injuries, and based on symptom severity into mild, moderate and severe TBI. Diffuse axonal injury (DAI), biomechanically caused by rotational acceleration-deceleration forces at impact, is characterized by widespread axonal injury in superficial and deep white substance. DAI comprises a clinical challenge due to its variable course and unreliable prognostic methods. Furthermore, axonal injury may convey the link to neurodegeneration since molecules associated with neurodegenerative events aggregate in injured axons.

    The aim of this thesis was to study clinical consequences of axonal injury, its detection and pathological features, and potential link to neurodegeneration in severe TBI patients treated at the neurointensive care unit at Uppsala University Hospital. In paper I and IV DAI patients were studied for the relation of elevated intracranial pressure (ICP) and poor outcome to axonal injury on magnetic resonance imaging. In paper II, soluble amyloid-beta aggregates (oligomers and protofibrils), characteristic of AD pathology, were investigated in surgically resected brain tissue from severe TBI patients, using highly-selective Enzyme-Linked ImmunoSorbent Assays. In paper III, brain tissue biopsy samples from TBI patients with either focal injury or DAI were examined for differential proteome profiles using mass spectrometry-based proteomics.

    The results provide evidence that axonal injury, located in the central brain stem, in substantia nigra and the mesencephalic tegmentum, is particularly related to poor outcome and increased ICP during neurointensive care of DAI patients. A novel classification system for prognostication after DAI is proposed. Furthermore, the thesis shows that severe TBI induces rapid accumulation of neurotoxic soluble amyloid-beta oligomers and protofibrils. In addition, DAI initiates unique proteome profiles different from that of focal TBI in structurally normal-appearing brain. These findings have implication for the clinical management of DAI patients, and provide new insight in the neuropathological consequences of axonal injury.

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  • 35.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia..
    Marklund, Niklas
    Department of Clinical Sciences Lund, Neurosurgery, Skåne University Hospital Lund University, Lund, Sweden .
    Differential DNA methylation of the genes for amyloid precursor protein, tau and neurofilaments in human traumatic brain injury2021In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 38, no 12, p. 1679-1688Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration, e.g. amyloid beta precursor protein (APP), microtubule associated protein tau (MAPT), neurofilament heavy (NEFH), neurofilament medium (NEFM) and neurofilament light (NEFL), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients to iNPH controls. Thirty-eight CpG sites in the APP, MAPT, NEFH and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828 888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain and may have implications for the neurodegenerative disorders associated at long-term with TBI. 

  • 36.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Ericson, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Increased CSF Levels of Apolipoproteins and Complement Factors in Trigeminal Neuralgia Patients-In Depth Proteomic Analysis Using Mass Spectrometry2020In: Journal of Pain, ISSN 1526-5900, E-ISSN 1528-8447, Vol. 21, no 9-10, p. 1075-1084Article in journal (Refereed)
    Abstract [en]

    The main cause of trigeminal neuralgia (TN) is compression of a blood vessel at the root entry zone of the trigeminal nerve. However, a neurovascular conflict does not seem to be the only etiology and other mechanisms are implicated in the development of the disease. We hypothesized that TN patients may have distinct protein expression in the CSF. In this study, lumbar CSF from TN patients (n = 17), scheduled to undergo microvascular decompression, and from controls (n = 20) was analyzed and compared with in depth mass spectrometry TMTbased quantitative proteomics. We identified 2552 unique proteins, of which 46 were significantly altered (26 increased, and 20 decreased, q-value < .05) in TN patients compared with controls. An over-representation analysis showed proteins involved in high-density lipoprotein, such as Apolipoprotein A4, Apolipoprotein M, and Apolipoprotein A1, and the extracellular region, including proteins involved in the complement cascade to be over-represented. We conclude that TN patients have distinct protein expression in the CSF compared to controls. The pathophysiological background of the protein alterations found in this study warrants further investigation in future studies. Perspective: In this article, cerebrospinal fluid from patients with trigeminal neuralgia was analyzed using in depth shotgun proteomics, revealing 46 differentially expressed proteins compared to controls. Among these, apolipoproteins and proteins involved in the complement system were elevated and signif-icantly over-represented, implying an inflammatory component in the pathophysiology of the disease.

  • 37.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lytsy, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Ronne-Engström, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Surgical site infections in standard neurosurgery procedures-a study of incidence, impact and potential risk factors2014In: British Journal of Neurosurgery, ISSN 0268-8697, E-ISSN 1360-046X, Vol. 28, no 2, p. 270-275Article in journal (Refereed)
    Abstract [en]

    Objectives. Surgical site infections (SSIs) may be devastating for the patient and they carry high economic costs. Studies of SSI after neurosurgery report an incidence of 1 - 11%. However, patient material, follow-up time and definition of SSI have varied. In the present study we prospectively recorded the prevalence of SSI 3 months after standard intracranial neurosurgical procedures. The incidence, impact and risk factors of SSI were analysed. Methods. We included patients admitted during 2010 to our unit for postoperative care after standard neurosurgical procedures. SSI was defined as evident with positive cultures from surgical samples or CSF, and/or purulent discharge during reoperation. Follow-up was done after 3 and 12 months and statistics was obtained after 3 months. The predictive values on the outcome of demographic and clinical factors describing the surgical procedure were evaluated using linear regression. Results. A total of 448 patients were included in the study and underwent a total of 466 procedures. Within 3 and 12 months, 33 and 88 patients, respectively, had died. Of the surviving patients, 20 (4.3% of procedures) developed infections within 3 months and another 3 (4.9% of procedures) within 12 months. Risk factors for SSI were meningioma, longer operation time, craniotomy, dural substitute, and staples in wound closure. Patients with SSI had significantly longer hospital stay. Multivariate analysis showed that factors found significant in univariate analysis frequently occur together. Discussion. We studied the prevalence of SSI after 3 and 12 months in a prospective 1-year material with standard neurosurgical procedures and found it to be 4.3% and 4.9%, respectively. The analysis of the results showed that a combination of parameters indicating a longer and more complicated procedure predicted the development of SSI. Our conclusion is that the prevention of SSI has to be done at many levels, especially with patients undergoing long surgical procedures.

  • 38.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannsjö, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rehabilitation Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Howells, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Extended anatomical grading in diffuse axonal injury using MRI: Hemorrhagic lesions in the substantia nigra and mesencephalic tegmentum indicate poor long-term outcome2017In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 5, no 34, p. 341-352Article in journal (Refereed)
    Abstract [en]

    Clinical outcome after traumatic diffuse axonal injury (DAI) is difficult to predict. In this study, three magnetic resonance imaging (MRI) sequences were used to quantify the anatomical distribution of lesions, to grade DAI according to the Adams grading system, and to evaluate the value of lesion localization in combination with clinical prognostic factors to improve outcome prediction. Thirty patients (mean 31.2 years ±14.3 standard deviation) with severe DAI (Glasgow Motor Score [GMS] <6) examined with MRI within 1 week post-injury were included. Diffusion-weighted (DW), T2*-weighted gradient echo and susceptibility-weighted (SWI) sequences were used. Extended Glasgow outcome score was assessed after 6 months. Number of DW lesions in the thalamus, basal ganglia, and internal capsule and number of SWI lesions in the mesencephalon correlated significantly with outcome in univariate analysis. Age, GMS at admission, GMS at discharge, and low proportion of good monitoring time with cerebral perfusion pressure <60 mm Hg correlated significantly with outcome in univariate analysis. Multivariate analysis revealed an independent relation with poor outcome for age (p = 0.005) and lesions in the mesencephalic region corresponding to substantia nigra and tegmentum on SWI (p  = 0.008). We conclude that higher age and lesions in substantia nigra and mesencephalic tegmentum indicate poor long-term outcome in DAI. We propose an extended MRI classification system based on four stages (stage I—hemispheric lesions, stage II—corpus callosum lesions, stage III—brainstem lesions, and stage IV—substantia nigra or mesencephalic tegmentum lesions); all are subdivided by age (≥/<30 years).

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  • 39.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannsjö, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rehabilitation Medicine.
    Howells, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    MRI analysis of diffuse axonal injury - Hemorrhagic lesions in the mesencephalon idicate poor long-term outcome2016In: MRI analysis of diffuse axonal injury - Hemorrhagic lesions in the mesencephalon idicate poor long-term outcome, Springer, 2016, Vol. 7, Suppl. 1, article id B-0814Conference paper (Refereed)
    Abstract [en]

    Purpose: Clinical outcome after traumatic diffuse axonal injury (DAI) is difficult to predict. Three MRI techniques were compared in demonstrating acute brain lesions.  Relationship of the anatomical distribution of the lesions in combination with clinical prognostic factors to outcome after 6 months was evaluated.  

    Methods and Materials: Thirty patients, aged 16-60 years (mean 31.2 years) with severe DAI (Glasgow Motor Score = GMS < 6) were examined with MRI at 1.5T within one week after the injury. A diffusion-weighted (DW) sequence (SE-EPI, b value 1000 s/mm2), a T2*-weighted gradient echo (T2*GRE) sequence and a susceptibility-weighted (SWI) sequence were evaluated by two independent reviewers with short and long neuroradiological experiences. Clinical outcome was assessed with Extended Glasgow Outcome Score (GOSE) after ≥ 6 months.

    Results: Interreviewer agreement for DAI classification was very good (ҡ 0.82 – 0.91) with all three sequences. SWI visualized more lesions than the T2*GRE or DW sequence.  In univariate analysis, number of DW lesions in the deep gray matter area including the internal capsules, number of SWI lesions in the mesencephalon, age, and GMS at admission and discharge correlated significantly with poor outcome.  Multivariate analysis only revealed an independent relation with poor outcome for age (p = 0.011) and lesions in the mesencephalic region including crura cerebri, substantia nigra and tegmentum on SWI (p = 0.032).

    Conclusion: SWI is the most sensitive technique to visualize lesions in DAI. Age over 30 years and hemorrhagic mesencephalic lesions anterior to the tectum are indicators of poor long-term outcome in DAI.

  • 40.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Howells, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Intracranial pressure elevations in diffuse axonal injury: association with nonhemorrhagic MR lesions in central mesencephalic structures2019In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 131, no 2, p. 604-611Article in journal (Refereed)
    Abstract [en]

    Objective: Increased intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI) with diffuse axonal injury (DAI) is not well defined. This study investigated the occurrence of increased ICP and whether clinical factors and lesion localization on MRI were associated with increased ICP in patients with DAI.

    Methods: Fifty-two patients with severe TBI (median age 24 years, range 9–61 years), who had undergone ICP monitoring and had DAI on MRI, as determined using T2*-weighted gradient echo, susceptibility-weighted imaging, and diffusion-weighted imaging (DWI) sequences, were enrolled. The proportion of good monitoring time (GMT) with ICP > 20 mm Hg during the first 120 hours postinjury was calculated and associations with clinical and MRI-related factors were evaluated using linear regression.

    Results: All patients had episodes of ICP > 20 mm Hg. The mean proportion of GMT with ICP > 20 mm Hg was 5%, and 27% of the patients (14/52) spent more than 5% of GMT with ICP > 20 mm Hg. The Glasgow Coma Scale motor score at admission (p = 0.04) and lesions on DWI sequences in the substantia nigra and mesencephalic tegmentum (SN-T, p = 0.001) were associated with the proportion of GMT with ICP > 20 mm Hg. In multivariable linear regression, lesions on DWI sequences in SN-T (8% of GMT with ICP > 20 mm Hg, 95% CI 3%–13%, p = 0.004) and young age (−0.2% of GMT with ICP > 20 mm Hg, 95% CI −0.07% to −0.3%, p = 0.002) were associated with increased ICP.

    Conclusions: Increased ICP occurs in approximately one-third of patients with severe TBI who have DAI. Age and lesions on DWI sequences in the central mesencephalon (i.e., SN-T) are associated with elevated ICP. These findings suggest that MR lesion localization may aid prediction of increased ICP in patients with DAI.

    Abbreviations: ADC = apparent diffusion coefficient; CPP = cerebral perfusion pressure; DAI = diffuse axonal injury; DWI = diffusion-weighted imaging; EVD = external ventricular drain; GCS = Glasgow Coma Scale; GMT = good monitoring time; GOSE = Glasgow Outcome Scale–Extended; ICC = intraclass correlation coefficient; ICP = intracranial pressure; MAP = mean arterial blood pressure; NICU = neurointensive care unit; SN-T = substantia nigra and mesencephalic tegmentum; SWI = susceptibility-weighted imaging; TBI = traumatic brain injury; T2*GRE = T2*-weighted gradient echo.

  • 41.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Howells, Timothy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Intracranial pressure elevations in diffuse axonal injury are associated with non-hemorrhagic MR lesions in central mesencephalic structuresIn: Article in journal (Other academic)
    Abstract [en]

    Objective: Increased intracranial pressure (ICP) in severe traumatic brain injury (TBI) patients with diffuse axonal injury (DAI) is not well defined. This study investigated the occurrence of increased ICP and whether clinical factors and lesion localization on MRI were associated with increased ICP in DAI patients.

    Methods: Fifty-two severe TBI patients (median 24, range 9-61 years), with ICP-monitoring and DAI on MRI, using T2*-weighted gradient echo, susceptibility-weighted and diffusion-weighted (DW) sequences, were enrolled. Proportion of good monitoring time (GMT) with ICP>20 mmHg during the first 120 hours post-injury was calculated and associations with clinical and MRI-related factors were evaluated using linear regression. 

    Results: All patients had episodes of ICP>20 mmHg. The mean proportion of GMT with ICP>20 mmHg was 5% and 27% of the patients (14/52) had more than 5% of GMT with ICP>20 mmHg. Glasgow Coma Scale motor score at admission (P=0.04) and lesions on DW images in the substantia nigra and mesencephalic tegmentum (SN-T, P=0.001) were associated with the proportion of GMT with ICP>20 mmHg. In multivariate linear regression, lesions on DW images in SN-T (8% of GMT with ICP>20 mmHg, 95% CI 3–13%, P=0.004) and young age (-0.2% of GMT with ICP>20 mmHg, 95% CI -0.07–-0.3%, P=0.0008) were associated with increased ICP.   

    Conclusions: Increased ICP occurs in ~1/3 of severe TBI patients with DAI. Age and lesions on DW images in the central mesencephalon (SN-T) associate with elevated ICP. These findings suggest that MR lesion localization may aid prediction of increased ICP in DAI patients.

  • 42.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rollman Waara, Erik
    BioArctic Neurosci AB, Stockholm, Sweden.
    Möller, Christer
    BioArctic Neurosci AB, Stockholm, Sweden.
    Söderberg, Linda
    BioArctic Neurosci AB, Stockholm, Sweden.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury2018In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, no 4, p. 451-462Article in journal (Refereed)
    Abstract [en]

    Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.

  • 43.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Proteomic Differences Between Focal And Diffuse Traumatic Brain Injury In Human Brain Tissue2018In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A238-A239Article in journal (Other academic)
  • 44.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 6807Article in journal (Refereed)
    Abstract [en]

    The early molecular response to severe traumatic brain injury (TBI) was evaluated using biopsies of structurally normal-appearing cortex, obtained at location for intracranial pressure (ICP) monitoring, from 16 severe TBI patients. Mass spectrometry (MS; label free and stable isotope dimethyl labeling) quantitation proteomics showed a strikingly different molecular pattern in TBI in comparison to cortical biopsies from 11 idiopathic normal pressure hydrocephalus patients. Diffuse TBI showed increased expression of peptides related to neurodegeneration (Tau and Fascin, p < 0.05), reduced expression related to antioxidant defense (Glutathione S-transferase Mu 3, Peroxiredoxin-6, Thioredoxin-dependent peroxide reductase; p < 0.05) and increased expression of potential biomarkers (e.g. Neurogranin, Fatty acid-binding protein, heart p < 0.05) compared to focal TBI. Proteomics of human brain biopsies displayed considerable molecular heterogeneity among the different TBI subtypes with consequences for the pathophysiology and development of targeted treatments for TBI.

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  • 45.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Tenovuo, Olli
    Univ Turku, Turku Brain Injury Ctr, Turku, Finland; Turku Univ Hosp, Turku, Finland.
    Peul, Wilco
    Leiden Univ, HAGA, Neurosurg Ctr Holland, HMC, The Hague, Netherlands; Leiden Univ, LUMC, Neurosurg Ctr Holland, HMC, The Hague, Netherlands; Leiden Univ, HAGA, Neurosurg Ctr Holland, HMC, Leiden, Netherlands; Leiden Univ, LUMC, Neurosurg Ctr Holland, HMC, Leiden, Netherlands.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery. Lund Univ, Skåne Univ Hosp, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.
    "Omics" in traumatic brain injury: novel approaches to a complex disease2021In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 163, no 9, p. 2581-2594Article, review/survey (Refereed)
    Abstract [en]

    Background

    To date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete understanding of the vast complexity of the biological cascades and failure to appreciate the diversity of secondary injury mechanisms in TBI. In recent years, techniques for high-throughput characterization and quantification of biological molecules that include genomics, proteomics, and metabolomics have evolved and referred to as omics.

    Methods

    In this narrative review, we highlight how omics technology can be applied to potentiate diagnostics and prognostication as well as to advance our understanding of injury mechanisms in TBI.

    Results

    The omics platforms provide possibilities to study function, dynamics, and alterations of molecular pathways of normal and TBI disease states. Through advanced bioinformatics, large datasets of molecular information from small biological samples can be analyzed in detail and provide valuable knowledge of pathophysiological mechanisms, to include in prognostic modeling when connected to clinically relevant data. In such a complex disease as TBI, omics enables broad categories of studies from gene compositions associated with susceptibility to secondary injury or poor outcome, to potential alterations in metabolites following TBI.

    Conclusion

    The field of omics in TBI research is rapidly evolving. The recent data and novel methods reviewed herein may form the basis for improved precision medicine approaches, development of pharmacological approaches, and individualization of therapeutic efforts by implementing mathematical “big data” predictive modeling in the near future.

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  • 46.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Virhammar, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Cesarini, Kristina G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Brain tissue Aβ42 levels are linked to shunt response in idiopathic normal pressure hydrocephalus2019In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 130, no 1, p. 121-129Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE The authors conducted a study to test if the cortical brain tissue levels of soluble amyloid beta (Aβ) reflect the propensity of cortical Aβ aggregate formation and may be an additional factor predicting surgical outcome following idiopathic normal pressure hydrocephalus (iNPH) treatment. METHODS Highly selective ELISAs (enzyme-linked immunosorbent assays) were used to quantify soluble Aβ40, Aβ42, and neurotoxic Aβ oligomers/protofibrils, associated with Aβ aggregation, in cortical biopsy samples obtained in patients with iNPH (n = 20), sampled during ventriculoperitoneal (VP) shunt surgery. Patients underwent pre- and postoperative (3-month) clinical assessment with a modified iNPH scale. The preoperative CSF biomarkers and the levels of soluble and insoluble Aβ species in cortical biopsy samples were analyzed for their association with a favorable outcome following the VP shunt procedure, defined as a ≥ 5-point increase in the iNPH scale. RESULTS The brain tissue levels of Aβ42 were negatively correlated with CSF Aβ42 (Spearman's r = -0.53, p < 0.05). The Aβ40, Aβ42, and Aβ oligomer/protofibril levels in cortical biopsy samples were higher in patients with insoluble cortical Aβ aggregates (p < 0.05). The preoperative CSF Aβ42 levels were similar in patients responding (n = 11) and not responding (n = 9) to VP shunt treatment at 3 months postsurgery. In contrast, the presence of cortical Aβ aggregates and high brain tissue Aβ42 levels were associated with a poor outcome following VP shunt treatment (p < 0.05). CONCLUSIONS Brain tissue measurements of soluble Aβ species are feasible. Since high Aβ42 levels in cortical biopsy samples obtained in patients with iNPH indicated a poor surgical outcome, tissue levels of Aβ species may be associated with the clinical response to shunt treatment.

  • 47.
    Abzhandadze, Tamar
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Occupat Therapy & Physiotherapy, Gothenburg, Sweden..
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Buvarp, Dongni
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Eriksson, Marie
    Umeå Univ, Dept Stat, USBE, Umeå, Sweden..
    Quinn, Terence J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Sunnerhagen, Katharina
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Neurocare, Gothenburg, Sweden..
    Development of a short-form Swedish version of the Montreal Cognitive Assessment (s-MoCA-SWE): protocol for a cross-sectional study2021In: BMJ Open, E-ISSN 2044-6055, Vol. 11, no 5, article id e049035Article in journal (Refereed)
    Abstract [en]

    Introduction Short forms of the Montreal Cognitive Assessment (MoCA) have allowed quick cognitive screening. However, none of the available short forms has been created or validated in a Swedish sample of patients with stroke. The aim is to develop a short-form Swedish version of the MoCA (s-MoCA-SWE) in a sample of patients with acute and subacute stroke. The specific objectives are: (1) to identify a subgroup of MoCA items that have the potential to form the s-MoCA-SWE; (2) to determine the optimal cut-off value of s-MoCA-SWE for predicting cognitive impairment and (3) and to compare the psychometric properties of s-MoCA-SWE with those of previously developed MoCA short forms. Methods and analysis This is a statistical analysis protocol for a cross-sectional study. The study sample will comprise patients from Vaststroke, a local stroke registry from Gothenburg, Sweden and Efficacy oF Fluoxetine-a randomisEd Controlled Trial in Stroke (EFFECTS), a randomised controlled trial in Sweden. The s-MoCA-SWE will be developed by using exploratory factor analysis and the boosted regression tree algorithm. The cut-off value of s-MoCA-SWE for impaired cognition will be determined based on binary logistic regression analysis. The psychometric properties of s-MoCA-SWE will be compared with those of other MoCA short forms by using cross-tabulation and area under the receiving operating characteristic curve analyses. Ethics and dissemination The Vaststroke study has received ethical approval from the Regional Ethical Review Board in Gothenburg (346-16) and the Swedish Ethical Review Authority (amendment 2019-04299). The handling of data generated within the framework of quality registers does not require written informed consent from patients. The EFFECTS study has received ethical approval from the Stockholm Ethics Committee (2013/1265-31/2 on 30 September 2013). All participants provided written consent. Results will be published in an international, peer-reviewed journal, presented at conferences and communicated to clinical practitioners in local meetings and seminars.

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  • 48.
    Abé, Christoph
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Rahman, Qazi
    Kings Coll London, Inst Psychiat, Dept Psychol, London, England.
    Långström, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Rydén, Eleonore
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Ingvar, Martin
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Landén, Mikael
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden; Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden; Univ Gothenburg, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Cortical brain structure and sexual orientation in adult females with bipolar disorder or attention deficit hyperactivity disorder2018In: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 8, no 7Article in journal (Refereed)
    Abstract [en]

    Background: Nonheterosexual individuals have higher risk of psychiatric morbidity. Together with growing evidence for sexual orientation‐related brain differences, this raises the concern that sexual orientation may be an important factor to control for in neuroimaging studies of neuropsychiatric disorders.

    Methods: We studied sexual orientation in adult psychiatric patients with bipolar disorder (BD) or ADHD in a large clinical cohort (N = 154). We compared cortical brain structure in exclusively heterosexual women (HEW, n = 29) with that of nonexclusively heterosexual women (nHEW, n = 37) using surface‐based reconstruction techniques provided by FreeSurfer.

    Results: The prevalence of nonheterosexual sexual orientation was tentatively higher than reported in general population samples. Consistent with previously reported cross‐sex shifted brain patterns among homosexual individuals, nHEW patients showed significantly larger cortical volumes than HEW in medial occipital brain regions.

    Conclusion: We found evidence for a sex‐reversed difference in cortical volume among nonheterosexual female patients, which provides insights into the neurobiology of sexual orientation, and may provide the first clues toward a better neurobiological understanding of the association between sexual orientation and mental health. We also suggest that sexual orientation is an important factor to consider in future neuroimaging studies of populations with certain mental health disorders.

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  • 49. Adam, GIR
    et al.
    Reneland, R
    Andersson, M
    Risinger, C
    Nilsson, M
    Lewander, T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Pharmacogenomics to predict drug response2000In: Pharmacogenomics, Vol. 1Article in journal (Refereed)
  • 50.
    Adan, Saida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Winberg: Behavioral Neuroendocrinology.
    Applying automatic operant boxes (“Skinner boxes”) for studies on behavioural flexibility in zebrafish (Danio rerio) 2020Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The most successful and widely used animal models in neuroscience are rats and mice, which has been vital for the understanding of the human brain. Another model that has become more prominent during recent years is the zebrafish (Danio rerio). Due to its well-elaborated visual system and learning of aversive events, the zebrafish has become a suitable model for learning and memorizing. In this paper, the relationship between coping styles and learning in different zebrafish strains has been studied by using automatic operant boxes. The strains that were compared are the Tupfel Long Fin (TL). offspring of wild-caught zebrafish (WT) and the Spiegel danio (Spd). The results from the novel tank diving test suggest that there is a difference in coping style depending on the strain of zebrafish. The TL was characterized as a reactive (shy) fish as it had the longest cumulative duration time at the bottom of the tank. The Spd was characterized as a proactive (bold) fish as it had the longest cumulative duration time at the top of the tank. While, the WT characterized as a reactive fish as it exhibited the longest time not moving at all in the tank, indicating a high-stress response profile. An automatic operant box was used to study learning in the different strains. The purpose of the script used was for the fish to associate the feeder mechanism noise and the white light feeder with a food reward. However, no tendency of learning could be observed for any of the strains. 

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