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  • 1.
    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, 1334-1350 p.Article 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.

  • 2.
    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, 341-352 p.Article 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).

  • 3.
    Adamczuk, Katarzyna
    et al.
    Katholieke Univ Leuven, Lab Cognit Neurol, B-3000 Louvain, Belgium.;Katholieke Univ Leuven, Leuven Inst Neurosci & Dis, Alzheimer Res Ctr, B-3000 Louvain, Belgium..
    Schaeverbeke, Jolien
    Katholieke Univ Leuven, Lab Cognit Neurol, B-3000 Louvain, Belgium.;Katholieke Univ Leuven, Leuven Inst Neurosci & Dis, Alzheimer Res Ctr, B-3000 Louvain, Belgium..
    Vanderstichele, Hugo M. J.
    ADx NeuroSci, B-9052 Ghent, Belgium..
    Lilja, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. GE Healthcare, S-75125 Uppsala, Sweden..
    Nelissen, Natalie
    Katholieke Univ Leuven, Lab Cognit Neurol, B-3000 Louvain, Belgium.;Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England..
    Van Laere, Koen
    Katholieke Univ Leuven, Leuven Inst Neurosci & Dis, Alzheimer Res Ctr, B-3000 Louvain, Belgium.;Katholieke Univ Leuven, Nucl Med & Mol Imaging Dept, B-3000 Louvain, Belgium.;Katholieke Univ Leuven Hosp, B-3000 Louvain, Belgium..
    Dupont, Patrick
    Katholieke Univ Leuven, Lab Cognit Neurol, B-3000 Louvain, Belgium.;Katholieke Univ Leuven, Leuven Inst Neurosci & Dis, Alzheimer Res Ctr, B-3000 Louvain, Belgium..
    Hilven, Kelly
    Katholieke Univ Leuven, Lab Neuroimmunol, B-3000 Louvain, Belgium..
    Poesen, Koen
    Katholieke Univ Leuven, Lab Mol Neurobiomarker Res, B-3000 Louvain, Belgium.;UZ Leuven, Lab Med, B-3000 Louvain, Belgium..
    Vandenberghe, Rik
    Katholieke Univ Leuven, Lab Cognit Neurol, B-3000 Louvain, Belgium.;Katholieke Univ Leuven, Leuven Inst Neurosci & Dis, Alzheimer Res Ctr, B-3000 Louvain, Belgium.;Univ Hosp Leuven, Dept Neurol, B-3000 Louvain, Belgium..
    Diagnostic value of cerebrospinal fluid A beta ratios in preclinical Alzheimer's disease2015In: Alzheimer's Research & Therapy, ISSN 0065-6755, E-ISSN 1758-9193, Vol. 7, 75Article in journal (Refereed)
    Abstract [en]

    Introduction: In this study of preclinical Alzheimer's disease (AD) we assessed the added diagnostic value of using cerebrospinal fluid (CSF) A beta ratios rather than A beta 42 in isolation for detecting individuals who are positive on amyloid positron emission tomography (PET). Methods: Thirty-eight community-recruited cognitively intact older adults (mean age 73, range 65-80 years) underwent F-18-flutemetamol PET and CSF measurement of A beta 1-42, A beta 1-40, A beta 1-38, and total tau (ttau). F-18-flutemetamol retention was quantified using standardized uptake value ratios in a composite cortical region (SUVRcomp) with reference to cerebellar grey matter. Based on a prior autopsy validation study, the SUVRcomp cut-off was 1.57. Sensitivities, specificities and cut-offs were defined based on receiver operating characteristic analysis with CSF analytes as variables of interest and F-18-flutemetamol positivity as the classifier. We also determined sensitivities and CSF cut-off values at fixed specificities of 90 % and 95 %. Results: Seven out of 38 subjects (18 %) were positive on amyloid PET. A beta 42/ttau, A beta 42/A beta 40, A beta 42/A beta 38, and A beta 42 had the highest accuracy to identify amyloid-positive subjects (area under the curve (AUC) >= 0.908). A beta 40 and A beta 38 had significantly lower discriminative power (AUC = 0.571). When specificity was fixed at 90 % and 95 %, A beta 42/ttau had the highest sensitivity among the different CSF markers (85.71 % and 71.43 %, respectively). Sensitivity of A beta 42 alone was significantly lower under these conditions (57.14 % and 42.86 %, respectively). Conclusion: For the CSF-based definition of preclinical AD, if a high specificity is required, our data support the use of A beta 42/ttau rather than using A beta 42 in isolation.

  • 4.
    Addo, Rebecka N.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Stockholm Univ, Dept Psychol, Gosta Ekman Lab, Frescati Hagvag 9A, S-10691 Stockholm, Sweden..
    Wiens, Stefan
    Stockholm Univ, Dept Psychol, Gosta Ekman Lab, Frescati Hagvag 9A, S-10691 Stockholm, Sweden..
    Nord, Marie
    Stockholm Univ, Dept Psychol, Gosta Ekman Lab, Frescati Hagvag 9A, S-10691 Stockholm, Sweden..
    Larsson, Maria
    Stockholm Univ, Dept Psychol, Gosta Ekman Lab, Frescati Hagvag 9A, S-10691 Stockholm, Sweden..
    Olfactory Functions in Adults With Autism Spectrum Disorders2017In: Perception, ISSN 0301-0066, E-ISSN 1468-4233, Vol. 46, no 3-4, 530-537 p.Article in journal (Refereed)
    Abstract [en]

    Autism spectrum disorders (ASD) are often characterized by atypical sensory behavior (hyperor hyporeactivity) although evidence is scarce regarding olfactory abilities in ASD; 16 adults with high-functioning ASD (mean age: 38.2, SD: 9.7) and 14 healthy control subjects (mean age: 42.0 years, SD: 12.5) were assessed in odor threshold, free and cued odor identification, and perceived pleasantness, intensity, and edibility of everyday odors. Although results showed no differences between groups, the Bayes Factors (close to 1) suggested that the evidence for no group differences on the threshold and identification tests was inconclusive. In contrast, there was some evidence for no group differences on perceived edibility (BF01 = 2.69) and perceived intensity (BF01 = 2.80). These results do not provide conclusive evidence for or against differences between ASD and healthy controls on olfactory abilities. However, they suggest that there are no apparent group differences in subjective ratings of odors.

  • 5.
    Agosti, F.
    et al.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Cordisco Gonzalez, S.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Martinez Damonte, V.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Tolosa, M. J.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Di Siervi, N.
    Univ Buenos Aires, CONICET, ININFA, Inst Invest Farmacol, Buenos Aires, DF, Argentina..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Davio, C.
    Univ Buenos Aires, CONICET, ININFA, Inst Invest Farmacol, Buenos Aires, DF, Argentina..
    Perello, M.
    CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina.;Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol, IMBICE,Neurophysiol Lab, La Plata, Buenos Aires, Argentina..
    Raingo, J.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Melanocortin 4 Receptor Constitutive Activity Inhibits L-Type Voltage-Gated Calcium Channels In Neurons2017In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 346, 102-112 p.Article in journal (Refereed)
    Abstract [en]

    The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain nuclei playing a crucial role in the regulation of energy balance controlling the homeostasis of the organism. It displays both agonist-evoked and constitutive activity, and moreover, it can couple to different G proteins. Most of the research on MC4R has been focused on agonist-induced activity, while the molecular and cellular basis of MC4R constitutive activity remains scarcely studied. We have previously shown that neuronal N-type voltage-gated calcium channels (Ca(V)2.2) are inhibited by MC4R agonist-dependent activation, while the Ca-V subtypes that carry L- and P/Q-type current are not. Here, we tested the hypothesis that MC4R constitutive activity can affect Ca-V, with focus on the channel subtypes that can control transcriptional activity coupled to depolarization (L-type, Ca(V)1.2/1.3) and neurotransmitter release (N- and P/Q-type, Ca(V)2.2 and Ca(V)2.1). We found that MC4R constitutive activity inhibits specifically Ca(V)1.2/1.3 and Ca(V)2.1 subtypes of Ca-V. We also explored the signaling pathways mediating this inhibition, and thus propose that agonist-dependent and basal MC4R activation modes signal differentially through G(s) and G(i/o) pathways to impact on different Ca-V subtypes. In addition, we found that chronic incubation with MC4R endogenous inverse agonist, agouti and agouti-related peptide (AgRP), occludes Ca-V inhibition in a cell line and in amygdaloid complex cultured neurons as well. Thus, we define new mechanisms of control of the main mediators of depolarization-induced calcium entry into neurons by a GPCR that displays constitutive activity.

  • 6. Agosti, Francina
    et al.
    Lopez Soto, Eduardo J.
    Cabral, Agustina
    Castrogiovanni, Daniel
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perello, Mario
    Raingo, Jesica
    Melanocortin 4 receptor activation inhibits presynaptic N-type calcium channels in amygdaloid complex neurons2014In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 40, no 5, 2755-2765 p.Article in journal (Refereed)
    Abstract [en]

    The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor involved in food intake and energy expenditure regulation. MC4R activation modifies neuronal activity but the molecular mechanisms by which this regulation occurs remain unclear. Here, we tested the hypothesis that MC4R activation regulates the activity of voltage-gated calcium channels and, as a consequence, synaptic activity. We also tested whether the proposed effect occurs in the amygdala, a brain area known to mediate the anorexigenic actions of MC4R signaling. Using the patch-clamp technique, we found that the activation of MC4R with its agonist melanotan II specifically inhibited 34.5 +/- 1.5% of N-type calcium currents in transiently transfected HEK293 cells. This inhibition was concentration-dependent, voltage-independent and occluded by the G(s) pathway inhibitor cholera toxin. Moreover, we found that melanotan II specifically inhibited 25.9 +/- 2.0% of native N-type calcium currents and 55.4 +/- 14.4% of evoked inhibitory postsynaptic currents in mouse cultured amygdala neurons. Invivo, we found that the MC4R agonist RO27-3225 increased the marker of cellular activity c-Fos in several components of the amygdala, whereas the N-type channel blocker conotoxin GVIA increased c-Fos expression exclusively in the central subdivision of the amygdala. Thus, MC4R specifically inhibited the presynaptic N-type channel subtype, and this inhibition may be important for the effects of melanocortin in the central subdivision of the amygdala.

  • 7.
    Agoston, Denes V.
    et al.
    Uniformed Serv Univ Hlth Sci, Dept Anat, Bethesda, MD 20814 USA.;Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Sköld, Mattias K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Editorial: When Physics Meets Biology; Biomechanics and Biology of traumatic Brain injury2016In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 7, 91Article in journal (Other academic)
  • 8.
    Ahlström, Isabell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy.
    Hellström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy.
    Emtner, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotheraphy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Anens, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy.
    Reliability of the Swedish version of the Exercise Self-Efficacy Scale (S-ESES): a test-retest study in adults with neurological disease2015In: Physiotherapy Theory and Practice, ISSN 0959-3985, E-ISSN 1532-5040, Vol. 31, no 3, 194-199 p.Article in journal (Refereed)
    Abstract [en]

    Objective: To examine the test-retest reliability of the Swedish translated version of the Exercise Self-Efficacy Scale (S-ESES) in people with neurological disease and to examine internal consistency.

    Design: Test-retest study.

    Subjects: A total of 30 adults with neurological diseases including: Parkinson's disease; Multiple Sclerosis; Cervical Dystonia; and Charcot Marie Tooth disease.

    Method: The S-ESES was sent twice by surface mail. Completion interval mean was 16 days apart. Weighted kappa, intraclass correlation coefficient 2,1 [ICC (2,1)], standard error of measurement (SEM), also expressed as a percentage value (SEM%), and Cronbach's alpha were calculated.

    Results: The relative reliability of the test-retest results showed substantial agreement measured using weighted kappa (MD = 0.62) and a very high-reliability ICC (2,1) (0.92). Absolute reliability measured using SEM was 5.3 and SEM% was 20.7. Excellent internal consistency was shown, with an alpha coefficient of 0.91 (test 1) and 0.93 (test 2).

    Conclusion: The S-ESES is recommended for use in research and in clinical work for people with neurological diseases. The low-absolute reliability, however, indicates a limited ability to measure changes on an individual level.

  • 9.
    Ahmad, Abdulbaghi
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Childhood trauma and posttraumatic stress disorder: A developmental and cross-cultural approach1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis aims to identify child-specific cross-cultural protecting and vulnerability factors regarding traumatic experiences and posttraumatic stress reactions. Children between 6-18 years were interviewed from three different socio-cultural backgrounds. In Iraqi Kurdistan, 20 participants in a mass-escape tragedy (MET), 54 orphans and 45 survivors of the genocide operation "Anfal" were interviewed. In Sweden, a sample of 32 Kurdistanian refugee children and a comparable Swedish sample were included. The frequencies of posttraumatic stress disorder (PTSD) were 20%, 43%. 87%, 9,7% and 12.5% respectively.

    The relatively low frequencies of PTSD in the follow-up sample 2 months, 4 months, 14 months and 26 months after the MET suggest the child functioning in a complete, authoritative family, as a protecting factor. The significant of this developmentally based child-specific functioning level within the supportive family system can also explain the fluctuating PTSD-related symptom scores in this sample parallel to the changes in the socio-economic situation in the region. The over time decrease in behavioural problems among fostercare orphans and their low PTSD frequencies as compared with the increase in behavioural problems and the high PTSD frequencies among orphanage samples further support this suggestion. Child trauma scores and captivity duration predicted for PTSD in "Anfal" survivors, irrespective of parents' trauma scores and PTSD or fathers re-union with the family, suggesting child-specific vulnerability more than contagion effect. Despite PTSD, children in Kurdistan performed high functioning levels, probably indicating a child-specific manifestation of hypervigilance. The Kurdistanian refugee sample revealed lower lifetime reexperiencing PTSD symptom scores than the Swedish sample, indicating a healing effect on the former coming to Sweden and a resilience deficit for the later growing up in a highly sheltered society.

    There are more similarities than differences between children from Kurdistan and Sweden in reporting traumatic experiences and exhibiting posttraumatic stress symptoms. Developmentally based child characteristics have a determinant role as protective or vulnerability factors in childhood trauma and PTSD, even if socio-cultural factors also play a role.

  • 10. Aho, Leena
    et al.
    Karkola, Kari
    Juusela, Jari
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Heavy alcohol consumption and neuropathological lesions: a post-mortem human study2009In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 87, no 12, 2786-2792 p.Article in journal (Refereed)
    Abstract [en]

    Epidemiological studies have indicated that excessive alcohol consumption leads to cognitive impairment, but the specific pathological mechanism involved remains unknown. The present study evaluated the association between heavy alcohol intake and the neuropathological hallmark lesions of the three most common neurodegenerative disorders, i.e., Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular cognitive impairment (VCI), in post-mortem human brains. The study cohort was sampled from the subjects who underwent a medicolegal autopsy during a 6-month period in 1999 and it included 54 heavy alcohol consumers and 54 age- and gender-matched control subjects. Immunohistochemical methodology was used to visualize the aggregation of beta-amyloid, hyperphosphorylated tau, and alpha-synuclein and the extent of infarcts. In the present study, no statistically significant influence was observed for alcohol consumption on the extent of neuropathological lesions encountered in the three most common degenerative disorders. Our results indicate that alcohol-related dementia differs from VCI, AD, and DLB; i.e., it has a different etiology and pathogenesis.

  • 11.
    Akerstedt, T.
    et al.
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden.;Stockholm Univ, Stress Res Inst, Stockholm, Sweden..
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Gruber, G.
    Siesta Grp, Vienna, Austria..
    Schwarz, J.
    Stockholm Univ, Stress Res Inst, Stockholm, Sweden..
    The polysomnographical characteristics of women who have sought medical help for sleep problems - a large study of sleep macro and micro architeture2016In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 25, 90-90 p.Article in journal (Other academic)
  • 12.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Aho, L
    Helisalmi, S
    Mannermaa, A
    Soininen, H
    Beta-amyloid deposition in brains of subjects with diabetes2009In: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 35, no 1, 60-68 p.Article in journal (Refereed)
    Abstract [en]

    AIM:

    A causative association between diabetes mellitus (DM) and Alzheimer's disease (AD) has been suggested based on clinical and epidemiological studies. One hypothesis is that the link between DM and AD is related to the function of insulin-degrading enzyme (IDE), an enzyme that degrades not only insulin and pancreatic amylin but also beta-amyloid (Abeta). Thus, in diabetics, insulin and Abeta might compete for IDE and this might lead to an increase in Abeta. The objective of this study was to test the hypothesis that hyperinsulinaemia can elevate Abeta levels and thus contribute to AD pathology in humans.

    METHODS:

    Neuropathological examination was carried out employing conventional and immunohistochemical (IHC) methods of the brains obtained post mortem from 701 aged subjects.

    RESULTS:

    The loads of IHC/Abeta, silver stained neuritic plaques (NP) and neurofibrillary tangles (NFT) were significantly higher in subjects carrying the Apolipoprotein E e4 allele. In contrast, the loads of Abeta, NPs and NFT in the brains were not influenced by hyperglycaemia when comparing 134 diabetic with 567 non-diabetic subjects.

    CONCLUSIONS:

    We conclude that the hypothesis that hyperinsulinaemia would significantly elevate the Abeta load and thus increase the extent of AD pathology cannot be supported. Our result challenges the claim that DM is a direct risk factor of developing AD. Thus further studies on pathological lesions in demented diabetics should be conducted.

  • 13.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Thal, Dietmar R.
    Arzberger, Thomas
    Bogdanovic, Nenad
    Al-Sarraj, Safa
    Bodi, Istvan
    Boluda, Susan
    Bugiani, Orso
    Duyckaerts, Charles
    Gelpi, Ellen
    Gentleman, Stephen
    Giaccone, Giorgio
    Graeber, Manuel
    Hortobagyi, Tibor
    Höftberger, Romana
    Ince, Paul
    Ironside, James W.
    Kavantzas, Nikolaos
    King, Andrew
    Korkolopoulou, Penelope
    Kovács, Gábor G.
    Meyronet, David
    Monoranu, Camelia
    Nilsson, Tatjana
    Parchi, Piero
    Patsouris, Efstratios
    Pikkarainen, Maria
    Revesz, Tamas
    Rozemuller, Annemieke
    Seilhean, Danielle
    Schulz-Schaeffer, Walter
    Streichenberger, Nathalie
    Wharton, Stephen B.
    Kretzschmar, Hans
    Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium2009In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 117, no 3, 309-320 p.Article in journal (Refereed)
    Abstract [en]

    beta-Amyloid (A-beta) related pathology shows a range of lesions which differ both qualitatively and quantitatively. Pathologists, to date, mainly focused on the assessment of both of these aspects but attempts to correlate the findings with clinical phenotypes are not convincing. It has been recently proposed in the same way as iota and alpha synuclein related lesions, also A-beta related pathology may follow a temporal evolution, i.e. distinct phases, characterized by a step-wise involvement of different brain-regions. Twenty-six independent observers reached an 81% absolute agreement while assessing the phase of A-beta, i.e. phase 1 = deposition of A-beta exclusively in neocortex, phase 2 = additionally in allocortex, phase 3 = additionally in diencephalon, phase 4 = additionally in brainstem, and phase 5 = additionally in cerebellum. These high agreement rates were reached when at least six brain regions were evaluated. Likewise, a high agreement (93%) was reached while assessing the absence/presence of cerebral amyloid angiopathy (CAA) and the type of CAA (74%) while examining the six brain regions. Of note, most of observers failed to detect capillary CAA when it was only mild and focal and thus instead of type 1, type 2 CAA was diagnosed. In conclusion, a reliable assessment of A-beta phase and presence/absence of CAA was achieved by a total of 26 observers who examined a standardized set of blocks taken from only six anatomical regions, applying commercially available reagents and by assessing them as instructed. Thus, one may consider rating of A-beta-phases as a diagnostic tool while analyzing subjects with suspected Alzheimer's disease (AD). Because most of these blocks are currently routinely sampled by the majority of laboratories, assessment of the A-beta phase in AD is feasible even in large scale retrospective studies.

  • 14.
    Ali, Zafar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Klar, Joakim
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Jameel, Mohammad
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Khan, Kamal
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Fatima, Ambrin
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Baig, Shahid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Dahl, Niklas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Novel SACS mutations associated with intellectual disability, epilepsy and widespread supratentorial abnormalities2016In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 371, 105-111 p.Article in journal (Refereed)
    Abstract [en]

    We describe eight subjects from two consanguineous families segregating with autosomal recessive childhood onset spastic ataxia, peripheral neuropathy and intellectual disability. The degree of intellectual disability varied from mild to severe and all four affected individuals in one family developed aggressive behavior and epilepsy. Using exome sequencing, we identified two novel truncating mutations (c.2656C>T (p.Gln886*)) and (c.4756_4760delAATCA (p.Asn1586Tyrfs*3)) in the SACS gene responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). MRI revealed typical cerebellar and pontine changes associated with ARSACS as well as multiple supratentorial changes in both families as likely contributing factors to the cognitive symptoms. Intellectual disability and behavioral abnormalities have been reported in some cases of ARSACS but are not a part of the characteristic triad of symptoms that includes cerebellar ataxia, spasticity and peripheral neuropathy. Our combined findings bring further knowledge to the phenotypic spectrum, neurodegenerative changes and genetic variability associated with the SACS gene of clinical and diagnostic importance.

  • 15.
    Alit, Abir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Federspiel, B.
    Dept Pathol, Copenhagen, Denmark..
    Hjortland, G. O.
    Dept Oncol, Oslo, Norway..
    Ladekarl, M.
    Dept Oncol, Aarhus, Denmark..
    Langer, S. W.
    Dept Oncol, Copenhagen, Denmark..
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Knigge, U.
    Dept Surg C, Copenhagen, Denmark.;Dept Endocrinol PE, Copenhagen, Denmark..
    Sorbye, H.
    Dept Oncol, Bergen, Norway..
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Expression of Mutated p53 Protein in Gastroenteropancreatic Neuroendocrine Carcinoma (WHO G3)2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, 43-43 p.Article in journal (Refereed)
  • 16.
    Alm, Per A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Is it Thinking and not Feeling that influence variability of stuttering in social situations?: About stuttering and social cognition2015In: 10Th Oxford Dysfluency Conference, ODC 2014, 2015, 289-290 p.Conference paper (Refereed)
  • 17.
    Alm, Per A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Dreimanis, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Neuropathic pain: transcranial electric motor cortex stimulation using high frequency random noise: Case report of a novel treatment2013In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 6, 479-486 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Electric motor cortex stimulation has been reported to be effective for many cases of neuropathic pain, in the form of epidural stimulation or transcranial direct current stimulation (tDCS). A novel technique is transcranial random noise stimulation (tRNS), which increases the cortical excitability irrespective of the orientation of the current. The aim of this study was to investigate the effect of tRNS on neuropathic pain in a small number of subjects, and in a case study explore the effects of different stimulation parameters and the long-term stability of treatment effects.

    METHODS: THE STUDY WAS DIVIDED INTO THREE PHASES: (1) a double-blind crossover study, with four subjects; (2) a double-blind extended case study with one responder; and (3) open continued treatment. The motor cortex stimulation consisted of alternating current random noise (100-600 Hz), varying from 0.5 to 10 minutes and from 50 to 1500 μA, at intervals ranging from daily to fortnightly.

    RESULTS: One out of four participants showed a strong positive effect (also compared with direct-current-sham, P = 0.006). Unexpectedly, this effect was shown to occur also for very weak (100 μA, P = 0.048) and brief (0.5 minutes, P = 0.028) stimulation. The effect was largest during the first month, but remained at a highly motivating level for the patient after 6 months.

    DISCUSSION: The study suggests that tRNS may be an effective treatment for some cases of neuropathic pain. An important result was the indication that even low levels of stimulation may have substantial effects.

  • 18.
    Alping, P.
    et al.
    Danderyd Hosp, Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Svenningsson, A.
    Danderyd Hosp, Karolinska Inst, Clin Sci, Stockholm, Sweden..
    Salzer, J.
    Umea Univ, Pharmacol & Clin Neurosci, Umea, Sweden..
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala Univ, Neurosci, Uppsala, Sweden..
    Dahle, C.
    Linkoping Univ, Clin & Expt Med, Linkopin, Sweden..
    Fink, K.
    Danderyd Hosp, Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Hillert, J.
    Danderyd Hosp, Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Lycke, J.
    Univ Gothenburg, Clin Neurosci & Rehabil, Gothenburg, Sweden..
    Landtblom, A-M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Martin, C.
    Danderyd Hosp, Karolinska Inst, Clin Sci, Stockholm, Sweden..
    Nilsson, P.
    Lund Univ, Neurol, Lund, Sweden..
    Walentin, F.
    Orebro Univ Hosp, Neurol, Orebro, Sweden..
    Olsson, T.
    Danderyd Hosp, Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Frisell, T.
    Karolinska Inst, Med Solna, Stockholm, Sweden..
    Piehl, F.
    Danderyd Hosp, Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Rituximab in multiple sclerosis; data from the swedish MS registry.2016In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, no suppl. 3, 49-49 p.Article in journal (Refereed)
  • 19.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chavan, Rohit A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Exposure to a high-fat high-sugar diet causes strong up-regulation of proopiomelanocortin and differentially affects dopamine D1 and D2 receptor gene expression in the brainstem of rats2014In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 559, 18-23 p.Article in journal (Refereed)
    Abstract [en]

    A strong link between obesity and dopamine (DA) has been established by studies associating body weight status to variants of genes related to DA signalling. Human and animal studies investigating this relationship have so far focused mainly on the role of DA within the mesolimbic pathway. The aim of this study was to investigate potential DA receptor dysregulation in the brainstem, where these receptors play a potential role in meal termination, during high-fat high-sugar diet (HFHS) exposure. Expression of other key genes, including proopiomelanocortin (POMC), was also analyzed. We randomized rats into three groups; ad libitum access to HFHS (n=24), restricted HFHS access (n=10), or controls (chow-fed, n=10). After 5 weeks, brainstem gene expression was investigated by qRT-PCR. We observed an increase in POMC expression in ad libitum HFHS-fed rats compared to chow-fed controls (p<0.05). Further, expression of DA D2 receptor mRNA was down-regulated in the brainstem of the HFHS ad libitum-fed rats (p<0.05), whereas expression of the DA D1 receptor was upregulated (p<0.05) in these animals compared to chow-fed rats. In control experiments, we observed no effect relative to chow-fed controls on DA-receptor or POMC gene expression in the hypothalamus of HFHS diet-exposed rats, or in the brainstem of acutely food deprived rats. The present findings suggest brainstem POMC to be responsive to palatable foods, and that DA dysregulation after access to energy-dense diets occurs not only in striatal regions, but also in the brainstem, which could be relevant for overeating and for the development and maintenance of obesity.

  • 20.
    Althini, Susanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Experimental Studies of BMP Signalling in Neuronal Cells2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The developing nervous system depends largely on extracellular cues to shape its complex network of neurons. Classically, neurotrophins are known to be important mediators in this process. More recently, Bone Morphogenetic Proteins (BMPs), belonging to the Transforming Growth Factor beta (TGFβ) superfamily of secreted cytokines, have been shown to exert a wide range of effects, such as cellular growth, differentiation, survival and apoptosis, both in the developing and adult nervous system. They signal via serine/threonine kinase receptor essentially to the Smad pathway, which carries the signal to the nucleus where the transcription of target genes is regulated.

    This thesis investigates the functions of BMPs in the nervous system, using a set of different models. Firstly, a targeted deletion of GDF10 (BMP3b) in the mouse was established to evaluate the role of this growth/differentiation factor in the hippocampal formation, a brain area known to be involved in memory processing. Other members of the TGFβ superfamily likely compensate for the lack of GDF10, since no detectable alterations in hippocampal function or gene transcription profile have been found. Secondly, a mouse model was set up, with the aim to study impaired BMP-signalling in dopaminergic neurons. The tyrosine hydroxylase (TH) locus was used to drive the expression of dominant negative BMP receptors by means of bicistronic mRNAs. TH is the rate-limiting enzyme in the biosynthesis of catecholamine and the mice described, show a graded decrease of TH-activity resulting in severe to mild dopamine deficiency. The contribution of the dominant negative BMP receptors to the phenotype is however secondary to the apparent TH hypomorphism. The final theme of this thesis is the potentiating effects of BMPs on neurotrophin-induced neurite outgrowth as studied in explanted ganglia from chick embryos and in the rat phaeochromocytoma cell line PC12. A number of pharmacological inhibitors of intracellular signalling kinases were applied to the cultures in order to reveal the contribution of different pathways to the enhanced neurite outgrowth. We made the unexpected finding that inhibition of MEK signalling mimicked the potentiating effects of BMP stimulation in the chick system. The underlying mechanisms for the synergistic effects, however, are still an enigma.

    List of papers
    1. Targeted Deletion of GDF10 has no Effect on Long Term Potentiation, Contextual Learning Ability or Gene Transcription in the Hippocampus
    Open this publication in new window or tab >>Targeted Deletion of GDF10 has no Effect on Long Term Potentiation, Contextual Learning Ability or Gene Transcription in the Hippocampus
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    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90335 (URN)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2010-01-13Bibliographically approved
    2. Normal Nigrostriatal Innervation but Dopamine Dysfunction in Mice Carrying Hypomorphic Tyrosine Hydroxylase Alleles
    Open this publication in new window or tab >>Normal Nigrostriatal Innervation but Dopamine Dysfunction in Mice Carrying Hypomorphic Tyrosine Hydroxylase Alleles
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    2003 (English)In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 72, no 4, 444-453 p.Article in journal (Refereed) Published
    Abstract [en]

    We investigated the use of the mouse tyrosine hydroxylase (TH) gene to drive knock-in constructs in catecholaminergic neurons. Two targeting constructs representing truncated forms of either of the BMP receptors ALK-2 or BMPR-II preceded by an internal ribosome entry site (IRES) were introduced into the 3' untranslated region of TH. An frt-flanked neomycin-resistance (neo(r)) cassette was placed in the 3' end of the targeting constructs. Mice homozygous for the knock-in alleles showed various degrees of hypokinetic behavior, depending mainly on whether the neo(r) cassette was removed. In situ hybridization and immunohistochemistry showed that TH mRNA and protein were variously down-regulated in these mouse strains. Reduced levels of dopamine and noradrenalin were found in several brain areas. However, number and morphology of neurons in substantia nigra and their projections to striatum appeared normal in the neo(r)-positive TH hypomorphic mice as examined by markers for L-aromatic amino acid decarboxylase and the dopamine transporter. Elimination of the neo(r) cassette from the knock-in alleles partially restored TH and dopamine levels. The present neo(r)-positive TH hypomorphic mice show that nigrostriatal innervation develops independently of TH and should find use as a model for conditions of reduced catecholamine synthesis, as seen in, for example, L-dihydroxyphenylalanine-responsive dystonia/infantile parkinsonism.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91750 (URN)10.1002/jnr.10606 (DOI)12704806 (PubMedID)
    Note

    De två första författarna delar första författarskapet.

    Available from: 2004-04-21 Created: 2004-04-21 Last updated: 2017-12-14Bibliographically approved
    3. Blocked MAP kinase activity selectively enhances neurotrophic growth responses
    Open this publication in new window or tab >>Blocked MAP kinase activity selectively enhances neurotrophic growth responses
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    2004 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 25, no 2, 345-354 p.Article in journal (Refereed) Published
    Abstract [en]

    Bone morphogenetic proteins (BMPs) 4 and 6 as well as MEK inhibitors PD98059 and U0126 potentiate neurotrophin 3 (NT3)- and neurturin (NTN)-induced neurite outgrowth and survival of peripheral neurons from the E9 chicken embryo. Preexposure to BMP4 or PD98059 was sufficient to prime the potentiation of subsequently added NT3. Phosphorylation of Erk2, induced by NT3, was reduced by MEK inhibition but unaffected by BMP signaling. Real-time PCR showed that neither BMP stimulation nor MEK inhibition increased Trk receptor expression and that the BMP-induced genes Smad6 and Id1 were not upregulated by PD98059. In contrast, both MEK inhibition and BMP signaling suppressed transcription of the serum-response element (SRE)-driven Egr1 gene. A reporter assay using NGF-stimulated PC12 cells demonstrated that MEK/Erk/Elk-driven transcriptional activity was inhibited by Smad1/5 and by PD98059. Thus, suppression of SRE-controlled transcription represents a likely convergence point for pathways regulating neurotrophic responses.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90337 (URN)10.1016/j.mcn.2003.10.015 (DOI)15019950 (PubMedID)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2017-12-14Bibliographically approved
    4. Bone morphogenetic protein signalling in NGF-stimulated PC12 cells
    Open this publication in new window or tab >>Bone morphogenetic protein signalling in NGF-stimulated PC12 cells
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    2003 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 307, no 3, 632-639 p.Article in journal (Refereed) Published
    Abstract [en]

    Bone morphogenetic proteins (BMPs) are shown to potentiate NGF-induced neuronal differentiation in PC12 phaeochromocytoma cells grown on collagen under low-serum conditions. Whereas, cell bodies remained rounded in control medium or with only BMPs present, addition of BMP4 or BMP6 robustly increased the neuritogenic effect of NGF within 2 days. NGF-increased phosphorylation of p44(Erk1) and p42(Erk2) between 2 and 24h was unaffected by addition of BMP6. PC12 cells transfected with the SBE(4x)-luc reporter showed that BMP4 significantly increased receptor-activated Smad activity. Expression of constitutively active BMP receptor ALK2 activating Smad1 and Smad5 resulted in a strong increase in the SBE(4x)-luc reporter response. Adding the inhibitory Smad7 drastically reduced this signal. In contrast to wild-type (wt) Smad5, a Smad5 variant lacking five Erk phosphorylation sites in the linker region (designated Smad5/5SA) showed a strong background transcriptional activity. A fusion construct (Gal4-Smad5/5SA) was also highly transcriptionally active. Addition of the MEK inhibitor U0126 to PC12 cells expressing Gal4-Smad5/wt did not increase background transcriptional activity. However, upon activation by constitutively active ALK2 both Gal4-Smad5/wt and Gal4-Smad5/5SA strongly stimulated transcription. The data show that serine residues of the linker region of Smad5 reduce spontaneous transcriptional activity and that NGF-activated Erk does not antagonise BMP signalling at this site. Hence, NGF and BMP signals are likely to interact further downstream at the transcriptional level in neuronal differentiation of the PC12 cells.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90338 (URN)10.1016/S0006-291X(03)01236-1 (DOI)12893270 (PubMedID)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2017-12-14Bibliographically approved
  • 21.
    Ammoun, Sylwia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Orexin Receptors in Recombinant CHO Cells: Signaling to Short- and Long-Term Cell Responses2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Recently discovered neuropeptides orexins (orexin-A and -B) act as endogenous ligands for G-protein-coupled receptors called OX1 and OX2 receptors. Our previous studies have established model systems for investigation of the pharmacology and signaling of these receptors in recombinant CHO cells. OX1 receptor-expressing CHO cells were mainly utilized in this thesis.

    Orexin-A and -B activate both OX1 and OX2 receptors. However, orexin-B is less potent in activating OX1 receptors than orexin-A, whereas the peptides are equipotent on OX2 receptors. We have performed mutagenesis on orexin-A to investigate the basis for this selectivity. We show that OX2 receptor is generally less affected by the mutations and thus OX2 receptor appears to have less strict requirements for ligand binding, likely explaining the lack of difference in affinity/potency between orexin-A and orexin-B on OX2 receptor.

    The other studies focus on orexin receptor signaling. OX1 receptors are shown to regulate adenylyl cyclase both in positive and negative manner, activate different MAP-kinases (ERK1/2 and p38) and induce cell death after long-lasting stimulation. Adenylyl cyclase regulation occurs likely through three different G-protein families, Gi, Gs and Gq. For ERK1/2, several downstream pathways, such as Ras, Src, PI3-kinase and protein kinase C (PKC) are implicated. OX1 receptor-mediated activation of ERK is suggested to be cytoprotective whereas p38 MAP-kinase induces programmed cell death.

    Three particularly interesting findings were made. Firstly, novel PKC δ (delta) is suggested to regulate adenylyl cyclase, whereas conventional and atypical PKCs are involved in activation of ERK. Secondly, adenylyl cyclase and ERK activation is fully dependent on extracellular Ca2+. Further experiments suggest that the previously discovered receptor-operated Ca2+ influx is not affecting the downstream effectors of orexin receptors but that it instead enables orexin receptors to couple to several signal cascades. Thirdly, upon inhibition of caspases, classical mediators of programmed cell death, OX1 receptor-mediated cell death is not reversed, but instead the pathways to death are altered so de novo gene transcription is no longer required for cell death.

    List of papers
    1. Distinct Recognition of OX1 and OX2 Receptors by Orexin Peptides
    Open this publication in new window or tab >>Distinct Recognition of OX1 and OX2 Receptors by Orexin Peptides
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    2003 (English)In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 305, no 2, 507-514 p.Article in journal (Refereed) Published
    Abstract [en]

    In this study, we have compared the abilities of orexin-A and orexin-B and variants of orexin-A to activate different Ca(2+) responses (influx and release) in human OX(1) and OX(2) receptor- expressing Chinese hamster ovary cells. Responses mediated by activation of both receptor subtypes with either orexin-A or -B were primarily dependent on extracellular Ca(2+), suggesting similar activation of Ca(2+) influx as we have previously shown for orexin-A and OX(1) receptors. Amino acid-wise truncation of orexin-A reduced its ability to activate OX(1) and OX(2) receptors, but the response mediated by the OX(2) receptor was more resistant to truncation than the response mediated by the OX(1) receptor. We also performed a sequential replacement of amino acids 14 to 26 with alanine in the truncated orexin-A variant orexin-A(14-33). Replacement of the same amino acids produced a fall in the potency for each receptor subtype, but the reduction was less prominent for the OX(2) receptor. The most marked reduction was produced by the replacement of Leu20, Asp25, and His26 with alanine. Interestingly, extracellular Ca(2+) dependence of responses to some of the mutated peptides was different from those of orexin-A and -B. The mutagenesis also suggests that although the determinants required from orexin-A for binding to and activation of the receptor are highly conserved between the orexin receptor subtypes, the OX(2) receptor requires fewer determinants. This might in part explain why orexin-B has the affinity and potency equal to orexin-A for this subtype, although it has 10- to 100-fold lower affinity and potency for the OX(1) receptor.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93307 (URN)10.1124/jpet.102.048025 (DOI)12606634 (PubMedID)
    Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2017-12-14Bibliographically approved
    2. OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms
    Open this publication in new window or tab >>OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms
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    2005 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 280, no 8, 6570-6579 p.Article in journal (Refereed) Published
    Abstract [en]

    In this study, the mechanism of OX(1) orexin receptors to regulate adenylyl cyclase activity when recombinantly expressed in Chinese hamster ovary cells was investigated. In intact cells, stimulation with orexin-A led to two responses, a weak (21%), high potency (EC(50) approximately 1 nm) inhibition and a strong (4-fold), low potency (EC(50) = approximately 300 nm) stimulation. The inhibition was reversed by pertussis toxin, suggesting the involvement of G(i/o) proteins. Orexin-B was, surprisingly, almost equally as potent as orexin-A in elevating cAMP (pEC(50) = approximately 500 nm). cAMP elevation was not caused by Ca(2+) elevation or by Gbetagamma. In contrast, it relied in part on a novel protein kinase C (PKC) isoform, PKCdelta, as determined using pharmacological inhibitors. Yet, PKC stimulation alone only very weakly stimulated cAMP production (1.1-fold). In the presence of G(s) activity, orexins still elevated cAMP; however, the potencies were greatly increased (EC(50) of orexin-A = approximately 10 nm and EC(50) of orexin-B = approximately 100 nm), and the response was fully dependent on PKCdelta. In permeabilized cells, only a PKC-independent low potency component was seen. This component was sensitive to anti-Galpha(s) antibodies. We conclude that OX(1) receptors stimulate adenylyl cyclase via a low potency G(s) coupling and a high potency phospholipase C --> PKC coupling. The former or some exogenous G activation is essentially required for the PKC to significantly activate adenylyl cyclase. The results also suggest that orexin-B-activated OX(1) receptors couple to G(s) almost as efficiently as the orexin-A-activated receptors, in contrast to Ca(2+) elevation and phospholipase C activation, for which orexin-A is 10-fold more potent.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93308 (URN)10.1074/jbc.M407397200 (DOI)15611118 (PubMedID)
    Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2017-12-14Bibliographically approved
    3. OX1 orexin receptors activate extracellular signal-regulated kinase in Chinese hamster ovary cells via multiple mechanisms: the role of Ca2+ influx in OX1 receptor signaling
    Open this publication in new window or tab >>OX1 orexin receptors activate extracellular signal-regulated kinase in Chinese hamster ovary cells via multiple mechanisms: the role of Ca2+ influx in OX1 receptor signaling
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    2006 (English)In: Molecular Endocrinology, ISSN 0888-8809, E-ISSN 1944-9917, Vol. 20, no 1, 80-99 p.Article in journal (Refereed) Published
    Abstract [en]

    Activation of OX1 orexin receptors heterologously expressedin Chinese hamster ovary (CHO) cells led to a rapid, strong,and long-lasting increase in ERK phosphorylation (activation).Dissection of the signal pathways to ERK using multiple inhibitorsand dominant-negative constructs indicated involvement of Ras,protein kinase C, phosphoinositide-3-kinase, and Src. Most interestingly,Ca2+ influx appeared central for the ERK response in CHO cells,and the same was indicated in recombinant neuro-2a cells andcultured rat striatal neurons. Detailed investigations in CHOcells showed that inhibition of the receptor- and store-operatedCa2+ influx pathways could fully attenuate the response, whereasinhibition of the store-operated Ca2+ influx pathway alone orthe Ca2+ release was ineffective. If the receptor-operated pathwaywas blocked, an exogenously activated store-operated pathwaycould take its place and restore the coupling of OX1 receptorsto ERK. Further experiments suggested that Ca2+ influx, as such,may not be required for ERK phosphorylation, but that Ca2+,elevated via influx, acts as a switch enabling OX1 receptorsto couple to cascades leading to ERK phosphorylation, cAMP elevation,and phospholipase C activation. In conclusion, the data suggestthat the primary coupling of orexin receptors to Ca2+ influxallows them to couple to other signal pathways; in the absenceof coupling to Ca2+ influx, orexin receptors can act as signalintegrators by taking advantage of other Ca2+ influx pathways.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93309 (URN)10.1210/me.2004-0389 (DOI)16141359 (PubMedID)
    Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2017-12-14Bibliographically approved
    4. G-protein-coupled OX1 Orexin/hcrtr-1 Hypocretin Receptors Induce Caspase-dependent and -independent Cell Death through p38 Mitogen-/Stress-activated Protein Kinase
    Open this publication in new window or tab >>G-protein-coupled OX1 Orexin/hcrtr-1 Hypocretin Receptors Induce Caspase-dependent and -independent Cell Death through p38 Mitogen-/Stress-activated Protein Kinase
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    2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, 834-842 p.Article in journal (Refereed) Published
    Abstract [en]

    We have investigated the signaling of OX1 receptors to cell death using Chinese hamster ovary cells as a model system. OX1 receptor stimulation with orexin-A caused a delayed cell death independently of cytosolic Ca2+ elevation. The classical mitogen-activated protein kinase (MAPK) pathways, ERK and p38, were strongly activated by orexin-A. p38 was essential for induction of cell death, whereas the ERK pathway appeared protective. A pathway often implicated in the p38-mediated cell death, activation of p53, did not mediate the cell death, as there was no stabilization of p53 or increase in p53-dependent transcriptional activity, and dominant-negative p53 constructs did not inhibit cell demise. Under basal conditions, orexin-A-induced cell death was associated with compact chromatin condensation and it required de novo gene transcription and protein synthesis, the classical hallmarks of programmed (apoptotic) cell death. However, though the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)fluoromethyl ketone (Z-VAD-fmk) fully inhibited the caspase activity, it did not rescue the cells from orexin-A-induced death. In the presence of Z-VAD-fmk, orexin-A-induced cell death was still dependent on p38 and de novo protein synthesis, but it no longer required gene transcription. Thus, caspase inhibition causes activation of alternative, gene transcription-independent death pathway. In summary, the present study points out mechanisms for orexin receptor-mediated cell death and adds to our general understanding of the role of G-protein-coupled receptor signaling in cell death by suggesting a pathway from G-protein-coupled receptors to cell death via p38 mitogen-/stress-activated protein kinase independent of p53 and caspase activation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93310 (URN)10.1074/jbc.M508603200 (DOI)
    Available from: 2005-09-01 Created: 2005-09-01 Last updated: 2017-12-14Bibliographically approved
  • 22.
    Andell, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Tomson, Torbjorn
    Carlsson, Sofia
    Hellebro, Eva
    Andersson, Tomas
    Adelow, Cecilia
    Amark, Per
    The incidence of unprovoked seizures and occurrence of neurodevelopmental comorbidities in children at the time of their first epileptic seizure and during the subsequent six months2015In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 113, 140-150 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: To evaluate the incidence of unprovoked seizures in children and the prevalence of related neurodevelopmental comorbidities at the time of the presumed first seizure and six months thereafter. Methods: The medical records of all children (0-18 years of age) seeking medical attention as the result of a first unprovoked seizure between September 1, 2001 and December 31, 2006, and registered in the population-based Stockholm Incidence Registry of Epilepsy (SIRE) were reviewed. Neurodevelopmental comorbidities were evaluated on the basis of the medical records from this first visit and from other healthcare during the following six months. Results: The incidence of unprovoked seizures was between 30 and 204/100,000 person years (n=766) in the different age groups. It was highest among the youngest children and lowest among the 18-year-olds with small gender differences. The most common neurodevelopment comorbidities were developmental delay (22%, CI: 19-25%), speech/language and learning difficulties (23%, CI: 20-26%) and intellectual disability (16%, CI: 13-18%). The types of neurodevelopmental comorbidity varied by age at the time of seizure onset, with cerebral palsy being more common among the 0-5-year-olds, attention deficits among the 6-16-year-olds, and autism and psychiatric diagnosis among the older children. An associated neurodevelopmental comorbidity was more common among those experiencing recurrent than single seizures during follow-up six months from the index seizure (42% versus 66%). In 68% (CI: 64-71%) of the children there was no known or suspected neurodevelopmental comorbidity. Conclusion: The incidence of unprovoked, non-febrile seizures among 0-18-year-olds included in the SIRE was 67/100,000 person-years. Neurodevelopmental comorbidities were common already at the time of onset of the seizure disorder, indicating that neither seizure treatment nor seizures were the underlying cause of other neurodevelopmental symptoms in these patients during the period studied.

  • 23.
    Anderberg, Ulla Maria
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Fibromyalgia syndrome in women - a stress disorder?: Neurobiological and hormonal aspects1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The FMS is almost exclusively a female disorder, as 90% of the patients struck by it are women. About 7% of all women in modern society have this disorder.

    The studies in this thesis demonstrated that variations in the female sex hormones over the menstrual cycle and in different hormonal states are important with respect to the severity of pain and other symptoms, global functioning and well being of FMS patients. The hormonal state is also of importance in the inter-connection with the monoaminergic systems, stress systems and pain processing systems. Besides the symptoms, this also appears as perturbed levels of neuropeptide Y (NPY), nociceptin and oxytocin in plasma.

    The importance of estrogen to pain processing peptides was shown in an animal study. In that study it was revealed that estrogen increase reduces pain sensitivity, and that estrogen is also able to change the levels of pain processing peptides such as substance P (SP) and met-enkephalin-Arg-Phe (MEAP) in certain brain areas, spinal cord and serum. It is suggested that stress may elicit pain through several neuroendocrinological mechanisms.

    All FMS patients scored higher than healthy women on mood and tension related symptoms, which is interpreted as an increased sensitivity and reaction to stress. FMS patients at the time of menstruation, and older, postmenopausal FMS patients were the most sensitive to these changes.

    The increased sensitivity to stress was also demonstrated in a personality study using the Temperament and Character Inventory (TCI), which showed that many female FMS patients are more anxious and worried and therefore also become easily fatigued.

    It is likely that development of the FMS is due to numerous biological events occurring in response to long-term stress. Women with stressful life experiences and anxious personality traits are probably more prone to develop this disorder, although various and sufficient stressful events of different origins can most likely lead to this disorder in any woman over the long run.

  • 24.
    Andreou, Dimitrios
    et al.
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden..
    Soderman, Erik
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden..
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sedvall, Goran C.
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden..
    Terenius, Lars
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden..
    Agartz, Ingrid
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden.;Univ Oslo, Inst Clin Med, NORMENT, Oslo, Norway.;Diakonhjemmet Hosp, Dept Psychiat Res, Oslo, Norway..
    Jonsson, Erik G.
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden..
    Associations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis2016In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 619, 126-130 p.Article in journal (Refereed)
    Abstract [en]

    Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder. We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls. We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia.

  • 25.
    Antonodimitrakis, Pantelis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Streptozocin and 5-FU for the treatment of Pancreatic Neuroendocrine Tumors: Efficacy, Prognostic Factors and Toxicity2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, no 3-4, 345-353 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In our center, the combination of streptozocin (STZ) and 5-fluorouracil (5-FU) has been used as the first-line treatment in the majority of patients with pancreatic neuroendocrine tumors (pNETs) over the past few decades. The objective of the current study was to assess the efficacy, prognostic factors and safety of the combination of STZ and 5-FU.

    PATIENTS AND METHODS: Medical records and radiological reports of 133 patients with pNETs who received the combination of STZ and 5-FU during the period 1981-2014 were retrospectively evaluated.

    RESULTS: Median survival from start of treatment was 51.9 months in the whole group. In the radiologically evaluable patients (n = 100) progression-free survival was 23 months. Complete response was reached in 3 patients (3%), partial response in 25 patients (25%), 64 patients (64%) had stable disease and 8 patients (8%) had progressive disease. In a multivariate analysis, surgery of the primary tumor and having a G3 tumor were significant positive and negative prognostic factors of survival from start of treatment, respectively. Having either a G3 tumor or stage IV tumor were significant prognostic factors for shorter progression-free survival. Chemotherapy had to be discontinued in 29 patients due to side-effects, of which kidney toxicity (mainly grade 1-2) was the most frequent.

    CONCLUSION: As shown in recent reports, the combination of STZ and 5-FU is effective in the treatment of pNETs in terms of survival and radiological response, and has an acceptable toxicity profile.

  • 26.
    Appelros, Peter
    et al.
    Örebro Univ Hosp.
    Farahmand, Bahman
    Alzheimer Dis Res Ctr, Epiconsultant Formerly Karolinska Inst, Stockholm, Sweden..
    Terént, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Åsberg, Signild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    To Treat or Not to Treat: Anticoagulants as Secondary Preventives to the Oldest Old With Atrial Fibrillation2017In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 48, no 6, 1617-1622 p.Article in journal (Refereed)
    Abstract [en]

    Background and Purpose-Anticoagulant treatment is effective for preventing recurrent ischemic strokes in patients who have atrial fibrillation. This benefit is paid by a small increase of hemorrhages. Anticoagulant-related hemorrhages seem to increase with age, but there are few studies showing whether the benefits of treatment persist in old age.

    Methods-For this observational study, 4 different registers were used, among them Riksstroke, the Swedish Stroke Register. Patients who have had a recent ischemic stroke, were 80 to 100 years of age, and had atrial fibrillation, were included from 2006 through 2013. The patients were stratified into 3 age groups: 80 to 84, 85 to 89, and ?90 years of age. Information on stroke severity, risk factors, drugs, and comorbidities was gathered from the registers. The patients were followed with respect to ischemic or hemorrhagic stroke, other hemorrhages, or death.

    Results-Of all 23 356 patients with atrial fibrillation, 6361 (27%) used anticoagulants after an ischemic stroke. Anticoagulant treatment was associated with less recurrent ischemic stroke in all age groups. Hemorrhages increased most in the >= 90-year age group, but this did not offset the overall beneficial effect of the anticoagulant. Apart from age, no other cardiovascular risk factor or comorbidity was identified that influenced the risk of anticoagulant-associated hemorrhage. Drugs other than anticoagulants did not influence the incidence of major hemorrhage.

    Conclusions-Given the patient characteristics in this study, there is room for more patients to be treated with anticoagulants, without hemorrhages to prevail. In nonagenarians, hemorrhages increased somewhat more, but this did not affect the overall outcome in this age stratum.

  • 27.
    Aquilonius, Sten-Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Development of new levodopa treatment strategies in Parkinson’s disease – from bedside to bench to bedside2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 2, 71-77 p.Article, review/survey (Refereed)
    Abstract [en]

    This review will illustrate the process of moving from an idea through preclinical research and Galenic developments into clinical investigations and finally to approval by regulatory agencies within the European Union. The two new treatment strategies described, levodopa/carbidopa intestinal gel and levodopa/carbidopa microtablets, for advanced Parkinson's disease, have been developed in collaborative research within departments at Uppsala University. With this historical approach, reference priority is given to reports considered to be of special importance for this more than two decades long process from bedside to bench to bedside'.

  • 28.
    Arnardottir, E. S.
    et al.
    Landspitali, Reykjavik, Iceland.;Univ Iceland, Reykjavik, Iceland..
    Bjornsdottir, E.
    Landspitali, Reykjavik, Iceland..
    Emilsson, Össur Ingi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Landspitali, Reykjavik, Iceland.;Univ Iceland, Reykjavik, Iceland..
    Benediktsdottir, B.
    Landspitali, Reykjavik, Iceland.;Univ Iceland, Reykjavik, Iceland..
    Gislason, T.
    Landspitali, Reykjavik, Iceland.;Univ Iceland, Reykjavik, Iceland..
    Sleepiness is more related to snoring than obstructive sleep apnea in the general population2016In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 25, 332-332 p.Article in journal (Other academic)
  • 29.
    Arnberg, Filip K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, National Center for Disaster Psychiatry. Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden..
    Lekander, Mats
    Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden.;Karolinska Inst, Osher Ctr Integrat Med, Stockholm, Sweden..
    Morey, Jennifer N.
    Univ Kentucky, Dept Psychol, 125 Kastle Hall, Lexington, KY 40506 USA..
    Segerstrom, Suzanne C.
    Univ Kentucky, Dept Psychol, 125 Kastle Hall, Lexington, KY 40506 USA..
    Self-rated health and interleukin-6: Longitudinal relationships in older adults2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 54, 226-232 p.Article in journal (Refereed)
    Abstract [en]

    Background: Both self-rated health (SRH) and inflammation are implicated in chronic diseases and premature mortality. Better SRH is associated with lower proinflammatory cytokines, but there is little evidence about whether this relationship is more stable or dynamic. Objective: To study the between- and within-person associations between SRH and IL-6. Methods: Older adults (N = 131; M-age = 75 years) rated their health and provided blood samples for analysis of IL-6 at separate occasions every 6 months over a period up to 5 years. Age, sex, BMI, neuroticism, and statin use were examined as covariates in multilevel models. Results: In bivariate models, better SRH, lower BMI, younger age, and female sex correlated with lower IL-6. In multilevel models, stable SRH (between-person differences; p < .001) but not dynamic SRH (within-person changes; p = .93) correlated with IL-6. The stable relationship persisted with demographic and health covariates in the model. Conclusions: Better stable SRH but not dynamic SRH was robustly associated with lower IL-6 among older adults, lending support to previous cross-sectional findings on the relation between inflammatory markers and SRH. The findings suggest that trait-like mechanisms, rather than changes over a time scale of 6-month waves, govern this association. To further investigate the mechanisms behind the SRH-IL-6 association, studies with different measurement frequencies, higher within-person variability, and experimental approaches are warranted.

  • 30. Asklund, T
    et al.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Henriksson, R
    PET response and tumor stabilization under erlotinib and bevacizumab treatment of an intracranial lesion non-invasively diagnosed as likely chordoma2011In: Clinical Neuropathology, ISSN 0722-5091, Vol. 30, no 5, 242-246 p.Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Chordoma is a rare and a slow-growing tumor originating from the notochord and commonly localized in the skull base. Surgery and occasionally radiotherapy have emerged as the treatments of choice. In the relapsed situations available treatment options are strictly limited; however, recently molecularly targeted agents have been proposed to be of potential beneficial value.

    THE CASE: A 63-year-old male presenting with seizures and an extradural mass in the left brain hemisphere. An attempt to resect the tumor was followed by severe bradycardia when manipulating with the dura and therefore discontinued. It was considered too hazardous even to take a biopsy specimen. The tumor was considered radiologically and macroscopically as a chordoma. As the tumor progressed after radiotherapy, chemotherapy with erlotinib in combination with cetuximab was initiated. This treatment was interrupted due to progressive disease and toxicity. However, combination treatment with erlotinib and bevacizumab normalized the uptake of [11C]methionine PET signal and resulted in a slight tumor shrinkage on MRI. The patient is still (March 2011) free of symptoms, without cranial nerve deficits or seizures.

    DISCUSSION: This report shows that erlotinib and bevacizumab in combination may completely quench the transport of the essential amino acid methionine to a treatment refractory intracranial tumor bearing radiological and clinical characteristics of a chordoma. Further studies are necessary to establish this strategy as a treatment option for this indication.

  • 31.
    Askmark, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Haggård, L
    Nygren, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Punga, Anna Rostedt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Vitamin D deficiency in patients with myasthenia gravis and improvement of fatigue after supplementation of vitamin D3: a pilot study2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no 12, 1554-1560 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder. Vitamin D has important roles both in the autoimmune response and in skeletal muscles. We determined the levels of 25-hydroxy vitamin D [25(OH)D] in patients with MG and in healthy subjects to determine whether vitamin D deficiency is present in MG and whether vitamin D supplementation has beneficial effects on fatigue. METHODS: Plasma levels of 25(OH)D were analyzed in 33 patients with MG (22 males; mean age, 58 years) and in 50 healthy age- and sex-matched blood donors, without vitamin D3 medication. MG composite score (MGC) assessed fatigue. 13 patients with MG without previous vitamin D3 supplementation were started on vitamin D3 supplementation (cholecalciferol) 800 IU/day, with a follow-up examination after 2.5-10 months (mean, 6 months). RESULTS: Patients with MG without pre-existing vitamin D3 supplementation (N = 16) had a mean MGC of 4.5 and lower plasma 25(OH)D levels (mean, 51 ± 19 nM) than healthy controls (69 ± 21 nM) (P = 0.017). Seventeen patients had pre-existing vitamin D3 supplementation, because of corticosteroid treatment, and their mean 25(OH)D was 79 ± 22 nM and mean MGC was 5.5. In the 13 patients who received cholecalciferol, 25(OH)D was overall increased at follow-up with 22% (P = 0.033) and MGC score improved with 38% (P = 0.05). CONCLUSIONS: Plasma 25(OH)D levels are significantly lower in patients with MG compared with healthy controls. As vitamin D has beneficial effects on the autoimmune response and on fatigue score in patients with MG, we suggest monitoring this parameter in patients with MG and supplementation with vitamin D3 when 25(OH)D levels are low.

  • 32.
    Asser, Andres
    et al.
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Koks, Sulev
    Univ Tartu, Dept Pathophysiol, Tartu, Estonia..
    Snellman, Anniina
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Haaparanta-Solin, Merja
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Arponen, Eveliina
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Gronroos, Tove
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Nairismagi, Jaak
    Tallinn Univ Technol, Inst Gene Technol, Tallinn, Estonia..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Soomets, Ursel
    Univ Tartu, Dept Biochem, Tartu, Estonia..
    Piip, Piret
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Eltermaa, Mall
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Sauk, Martin
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Lindmae, Hanna
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Rinne, Juha O.
    Univ Turku, Turku PET Ctr, Turku, Finland.;Turku Univ Hosp, Dept Neurol, Turku, Finland..
    Taba, Pille
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Increased striatal VMAT2 binding in mice after chronic administration of methcathinone and manganese2016In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1652, 97-102 p.Article in journal (Refereed)
    Abstract [en]

    Intravenous use of a psychostimulant drug containing methcathinone (ephedrone) and manganese causes an irreversible extrapyramidal syndrome in drug abusers. We aimed to reproduce the syndrome in mice to evaluate dopaminergic damage. C57/B6 mice were intraperitoneally injected once a day with the study drug or saline for a period of 27 weeks. Motor activity was recorded in an automated motility-box. After 13 and 27 weeks of treatment, ex vivo digital autoradiography was performed using [C-11]dihydrotetrabenazine ([C-11]DTBZ). After 27 weeks of treatment [C-11]DTBZ autoradiography demonstrated a significant increase in the striatum to -cerebellum binding ratio compared with saline treated controls. At the same time point, there was no evident change in motor activity. Increased [C-11]DTBZ binding may indicate vesicular monoamine transporter type 2 (VMAT2) function is altered. The lack of extrapyramidal symptoms in animals could be attributed to low dosing regimen or high metabolic rate.

  • 33.
    Atesok, Kivanc
    et al.
    University of Alabama at Birmingham, Birmingham, USA.
    Tanaka, Nobuhiro
    Hiroshima University, Hiroshima, Japan.
    O'Brien, Andrew
    Royal Victoria Hospital and Royal Belfast Hospital for Sick Children, Belfast, UK.
    Robinson, Yohan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pang, Dachling
    University of California, Davis, USA; Kaiser Permanente Hospitals, Oakland, USA; Great Ormond Street Hospital For Children, London, UK.
    Deinlein, Donald
    University of Alabama at Birmingham, Birmingham, USA.
    Manoharan, Sakthivel Rajaram
    University of Alabama at Birmingham, Birmingham, USA.
    Pittman, Jason
    University of Alabama at Birmingham, Birmingham, USA.
    Theiss, Steven
    University of Alabama at Birmingham, Birmingham, USA.
    Posttraumatic Spinal Cord Injury without Radiographic Abnormality2018In: Advances in Orthopedics, ISSN 2090-3464, E-ISSN 2090-3472, Vol. 2018, 7060654Article, review/survey (Refereed)
    Abstract [en]

    “Spinal Cord Injury without Radiographic Abnormality” (SCIWORA) is a term that denotes objective clinical signs of posttraumatic spinal cord injury without evidence of fracture or malalignment on plain radiographs and computed tomography (CT) of the spine. SCIWORA is most commonly seen in children with a predilection for the cervical spinal cord due to the increased mobility of the cervical spine, the inherent ligamentous laxity, and the large head-to-body ratio during childhood. However, SCIWORA can also be seen in adults and, in rare cases, the thoracolumbar spinal cord can be affected too. Magnetic resonance imaging (MRI) has become a valuable diagnostic tool in patients with SCIWORA because of its superior ability to identify soft tissue lesions such as cord edema, hematomas and transections, and discoligamentous injuries that may not be visualized in plain radiographs and CT. The mainstay of treatment in patients with SCIWORA is nonoperative management including steroid therapy, immobilization, and avoidance of activities that may increase the risk of exacerbation or recurrent injury. Although the role of operative treatment in SCIWORA can be controversial, surgical alternatives such as decompression and fusion should be considered in selected patients with clinical and MRI evidence of persistent spinal cord compression and instability.

  • 34.
    Axelson, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Muscle Thixotropy: Implications for Human Motor Control2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human skeletal muscles possess thixotropic, i.e. history-dependent mechanical properties. This means that the degree of passive muscle stiffness and resting tension is dependent on the immediately preceding history of contractions and length changes. Athletes, for instance, reduce passive muscle stiffness by various types of ‘limbering-up’ procedures, whereas muscle stiffness gradually increases during inactivity.

    Passive resistance of antagonistic muscles may significantly add to the total load during voluntary muscle contractions. This resistance may vary from one moment to another, depending on immediately preceding events. This research was conducted to determine whether history-dependent variations in passive muscular forces influence motor control of voluntary joint movements and steady maintenance of joint positions in healthy subjects.

    In study I, the EMG signal revealed motor compensations for history-dependent variations in passive stiffness of the antagonists during slow voluntary wrist joint movements. Studies II and III demonstrated that the voluntary muscle activity required to maintain a certain wrist joint position was highly influenced by previous changes in forearm muscle length and contractions. Study IV showed that rapid voluntary movements varied in speed and onset time depending on the prevailing degree of muscle resistance, and in addition that the central nervous reaction time required to execute rapid movements was highly influenced by immediately preceding muscle-conditioning procedures.

    History-dependent variations in passive muscular forces seem to be effectively compensated by the motor control system. Presumably, voluntary motor commands to the muscles are automatically adjusted in strength to history-dependent changes in passive muscular forces. Such adjustments occur within the central nervous system, which receives information about the mechanical state of the muscles. Several issues in connection with muscle thixotropy remain unaddressed. For instance, do alterations in the normal thixotropic mechanical behaviour of the muscles impose a particular problem in patients with certain neuromuscular diseases?

    List of papers
    1. Human motor control consequences of thixotropic changes in muscular short-range stiffness
    Open this publication in new window or tab >>Human motor control consequences of thixotropic changes in muscular short-range stiffness
    2001 In: J Physiol, Vol. Aug 15, no 535, 279-88 p.Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93032 (URN)
    Available from: 2005-05-09 Created: 2005-05-09Bibliographically approved
    2. Human motor compensations for thixotropy-dependent changes in resting wrist joint position after large joint movements
    Open this publication in new window or tab >>Human motor compensations for thixotropy-dependent changes in resting wrist joint position after large joint movements
    2003 In: Acta Physiol Scand., Vol. Dec, no 179(4), 389-98 p.Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93033 (URN)
    Available from: 2005-05-09 Created: 2005-05-09Bibliographically approved
    3. Human motor compensations for thixotropy-dependent changes in muscular resting tension after moderate joint movements
    Open this publication in new window or tab >>Human motor compensations for thixotropy-dependent changes in muscular resting tension after moderate joint movements
    2004 In: Acta Physiol Scand, Vol. Nov, no 182(3), 295-304 p.Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93034 (URN)
    Available from: 2005-05-09 Created: 2005-05-09Bibliographically approved
    4. Signs of muscle thixotropy during human ballistic wrist joint movements
    Open this publication in new window or tab >>Signs of muscle thixotropy during human ballistic wrist joint movements
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-93035 (URN)
    Available from: 2005-05-09 Created: 2005-05-09Bibliographically approved
  • 35.
    Axelson, Hans W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Isberg, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Amandusson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Trigeminal Nerve Stimulation Does Not Acutely Affect Cortical Excitability in Healthy Subjects2014In: Brain Stimulation, ISSN 1935-861X, E-ISSN 1876-4754, Vol. 7, no 4, 613-617 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Trigeminal nerve stimulation (TNS) has recently emerged as a new therapeutic option for patients with drug-resistant epilepsy but its potential mechanisms of action are not known. Since other antiepileptic treatments have been shown to alter cortical excitability, thereby reducing the liability to seizures, it has been suggested that cranial nerve stimulation such as TNS may act in the same way.

    OBJECTIVE: To study whether TNS has the potential to alter cortical excitability in healthy subjects.

    METHODS: An adaptive paired-pulse transcranial magnetic stimulation protocol stimulating the dominant hand motor area was used to measure resting motor threshold (rMT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and long-interval intracortical inhibition (LICI) before, during, and after 40 min of 120 Hz bilateral external continuous trigeminal nerve stimulation. Neuronavigation was used for guidance.

    RESULTS: TNS was well tolerated by all subjects. No significant changes were seen in the parameters studied.

    CONCLUSION: Unlike for example anti-epileptic drugs and the ketogenic diet, trigeminal nerve stimulation does not seem to alter cortical excitability in healthy subjects. This is the first study on cortical excitability in relation to continuous trigeminal nerve stimulation. It still remains to be proven that TNS has the prerequisites to effectively counteract epileptic events in humans.

  • 36.
    Axelson, Hans W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Microdialysis and electromyography of experimental muscle fatigue in healthy volunteers and patients with mitochondrial myopathy2002In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 26, no 4, 520-526 p.Article in journal (Refereed)
    Abstract [en]

    Consecutive 60-min microdialysis samples were taken from the tibial anterior muscle in 11 healthy subjects and 4 patients with mitochondrial myopathy before (2-3 samples) and after (3-4 samples, 2 controls and 1 patient excluded) sustained isometric foot dorsiflexions. Before exercise, mean concentrations of lactate, pyruvate, hypoxanthine, urate, aspartate, and glutamate did not significantly differ between controls and patients. After exercise, the controls showed significantly increased concentrations of lactate, pyruvate, and urate, decreased hypoxanthine, and no change in aspartate and glutamate. Similar findings were observed in the patients. Plasma lactate was unchanged. Exercise-induced increase in integrated electromyogram amplitude and rated subjective fatigue were correlated to increased post-exercise lactate concentrations, with no obvious difference between the groups. Microdialysis of skeletal muscle allows the detection and monitoring of biochemical changes in the interstitial space. With the exercise protocol used, however, it was not possible to demonstrate any biochemical difference between healthy controls and patients with mitochondrial myopathy.

  • 37.
    Axelson, Hans W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Öberg, Gunnar
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Successful repeated treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP2009In: BMJ case reports, ISSN 1757-790XArticle in journal (Refereed)
    Abstract [en]

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterised by the occurrence of symmetrical weakness and sensory impairment in arms and legs. The course is relapsing or chronic and progressing. CIDP is considered to be an autoimmune disease, which is supported by the beneficial response to immunomodulating therapies in most patients. We report on a patient with CIDP who has been in remission for more than 3 years after treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP on two occasions.

  • 38.
    Backryd, Emmanuel
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, Pain & Rehabil Ctr, Linkoping, Sweden..
    Tanum, Lars
    Akershus Univ Hosp, Dept R&D Mental Hlth, Lorenskog, Norway..
    Lind, Anne-Li
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma2017In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 10Article in journal (Refereed)
    Abstract [en]

    In addition to central hyperexcitability and impaired top-down modulation, chronic inflammation probably plays a role in the pathophysiology of fibromyalgia (FM). Indeed, on the basis of both animal experiments and human studies involving the analysis of cytokines and other inflammation-related proteins in different body fluids, neuroinflammatory mechanisms are considered to be central to the pathophysiology of many chronic pain conditions. However, concerning FM, previous human plasma/serum and/or cerebrospinal fluid (CSF) cytokine studies have looked only at a few predetermined cytokine candidates. Instead of analyzing only a few substances at a time, we used a new multiplex protein panel enabling simultaneous analysis of 92 inflammation-related proteins. Hence, we investigated the CSF and plasma inflammatory profiles of 40 FM patients compared with CSF from healthy controls (n= 10) and plasma from blood donor controls (n= 46). Using multivariate data analysis by projection, we found evidence of both neuroinflammation (as assessed in CSF) and chronic systemic inflammation (as assessed in plasma). Two groups of proteins (one for CSF and one for plasma) highly discriminating between patients and controls are presented. Notably, we found high levels of CSF chemokine CX3CL1 (also known as fractalkine). In addition, previous findings concerning IL-8 in FM were replicated, in both CSF and plasma. This is the first time that such an extensive inflammatory profile has been described for FM patients. Hence, FM seems to be characterized by objective biochemical alterations, and the lingering characterization of its mechanisms as essentially idiopathic or even psychogenic should be seen as definitively outdated.

  • 39.
    Badoud, Simon
    et al.
    Univ Hosp Geneva, Neurol Unit, Dept Clin Neurosci, Geneva, Switzerland.;Univ Fribourg CH, Neurophysiol Unit, Dept Med, Fribourg, Switzerland.;Univ Geneva, Fac Med, Geneva, Switzerland..
    Nicastro, Nicolas
    Univ Hosp Geneva, Neurol Unit, Dept Clin Neurosci, Geneva, Switzerland.;Univ Geneva, Fac Med, Geneva, Switzerland..
    Garibotto, Valentina
    Univ Geneva, Fac Med, Geneva, Switzerland.;Geneva Univ Hosp, Nucl Med & Mol Imaging Unit, Dept Med Imaging, Geneva, Switzerland..
    Burkhard, Pierre R.
    Univ Hosp Geneva, Neurol Unit, Dept Clin Neurosci, Geneva, Switzerland.;Univ Geneva, Fac Med, Geneva, Switzerland..
    Haller, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Geneva, Fac Med, Geneva, Switzerland.;Ctr Diagnost Radiolog Carouge, Geneva, Switzerland.;Univ Hosp Freiburg, Dept Neuroradiol, Freiburg, Germany..
    Distinct spatiotemporal patterns for disease duration and stage in Parkinson's disease2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, no 3, 509-516 p.Article in journal (Refereed)
    Abstract [en]

    Purpose To assess correlations between the degree of dopaminergic depletion measured using single-photon emission computed tomography (SPECT) and different clinical parameters of disease progression in Parkinson's disease (PD). Methods This retrospective study included 970 consecutive patients undergoing I-123-ioflupane SPECT scans in our institution between 2003 and 2013, from which we selected a study population of 411 patients according to their clinical diagnosis: 301 patients with PD (69.4 +/- 11.0 years, of age, 163 men) and 110 patients with nondegenerative conditions included as controls (72.7 +/- 8.0 years of age, 55 men). Comprehensive and operator-independent data analysis included spatial normalization into standard space, estimation of the mean uptake values in the striatum (caudate nucleus + putamen) and voxel-wise correlation between SPECT signal intensity and disease stage as well as disease duration in order to investigate the spatiotemporal pattern of the dopaminergic nigrostriatal degeneration. To compensate for potential interactions between disease stage and disease duration, one parameter was used as nonexplanatory coregressor for the other. Results Increasing disease stage was associated with an exponential decrease in I-123-ioflupane uptake (R (2) = 0.1501) particularly in the head of the ipsilateral caudate nucleus (p < 0.0001), whereas increasing disease duration was associated with a linear decrease in I-123-ioflupane uptake (p < 0.0001; R (2) = 0.1532) particularly in the contralateral anterior putamen (p < 0.0001). Conclusion We observed two distinct spatiotemporal patterns of posterior to anterior dopaminergic depletion associated with disease stage and disease duration in patients with PD. The developed operator-independent reference database of 411 I-123-ioflupane SPECT scans can be used for clinical and research applications.

  • 40.
    Bagchi, Sonchita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hellsten, Sofie Victora
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hägglund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Arapi, Vasiliki
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Löfqvist, Erik
    Gridlund, Viktoria
    Karlsson, Edvin
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Characterization of a unique amino acid transporter, SNAT10, in the Golgi apparatus2016Article in journal (Refereed)
  • 41.
    Bakalkin, Georgy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Stålhandske, Lada
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    TBI induced spinal cord plasticity: The endogenous opioid system mediates trauma effects on motor reflexes2016In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 30, no 5-6, 712-712 p.Article in journal (Other academic)
  • 42. Barr, Travis P.
    et al.
    Hrnjic, Alen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Khodorova, Alla
    Sprague, Jared M.
    Strichartz, Gary R.
    Sensitization of cutaneous neuronal purinergic receptors contributes to endothelin-1-induced mechanical hypersensitivity2014In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 155, no 6, 1091-1101 p.Article in journal (Refereed)
    Abstract [en]

    Endothelin (ET-1), an endogenous peptide with a prominent role in cutaneous pain, causes mechanical hypersensitivity in the rat hind paw, partly through mechanisms involving local release of algogenic molecules in the skin. The present study investigated involvement of cutaneous ATP, which contributes to pain in numerous animal models. Pre-exposure of ND7/104 immortalized sensory neurons to ET-1 (30 nM) for 10 min increased the proportion of cells responding to ATP (2 mu M) with an increase in intracellular calcium, an effect prevented by the ETA receptor-selective antagonist BQ-123. ET-1 (3 nM) pre-exposure also increased the proportion of isolated mouse dorsal root ganglion neurons responding to ATP (0.2-0.4 mu M). Blocking ET-1-evoked increases in intracellular calcium with the IP3 receptor antagonist 2-APB did not inhibit sensitization to ATP, indicating a mechanism independent of ET-1-mediated intracellular calcium increases. ET-1-sensitized ATP calcium responses were largely abolished in the absence of extracellular calcium, implicating ionotropic P2X receptors. Experiments using quantitative polymerase chain reaction and receptor-selective ligands in ND7/104 showed that ET-1-induced sensitization most likely involves the P2X4 receptor subtype. ET-1-sensitized calcium responses to ATP were strongly inhibited by broad-spectrum (TNP-ATP) and P2X4-selective (5-BDBD) antagonists, but not antagonists for other P2X subtypes. TNP-ATP and 5-BDBD also significantly inhibited ET-1-induced mechanical sensitization in the rat hind paw, supporting a role for purinergic receptor sensitization in vivo. These data provide evidence that mechanical hypersensitivity caused by cutaneous ET-1 involves an increase in the neuronal sensitivity to ATP in the skin, possibly due to sensitization of P2X4 receptors.

  • 43.
    Bejerot, Susanne
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Obsessive-compulsive disorders: Personality traits and disorders, autistic traits and biochemical findings2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Obsessive-compulsive disorder (OCD) is a common disabling mental disorder.Personality disorders are frequent in OCD. Asperger syndrome and high-functioning autism share similarities with obsessive-compulsive and schizoid personality disorders and may be referred to as "odd" personality traits. Also compulsions are common in autism. The present study aims at investigating personality disorders and dimensions in OCD and their relationship to autistic traits Sixty-four subjects suffering from OCD participated. The Karolinska Scales of Personality (KSP), the Temperament and Character Inventory (TCI), self-report questionnaires for personality disorders and an instrument to identify autistic traits were used. Nicotine use and its relation to personality traits were investigated in 193 subjects with OCD. In addition, we looked for serotonergic response predictors in, therapy with SRIs, by investigating serotonin levels in whole blood repeatedly during treatment with SRIs in 36 patients with OCD. Finally,one patient that needed high dose treatmentwith SRIs is presented.

    Results: In 61% of the 64 subjects with OCD, personality disorders were identified. More-over, subjects with OCD had significantly higher scores in KSP scales measuring Anxiety, Muscular tension, Psychasthenia, Indirect aggression, Irritability, Suspicion and Guilt, whereas Socialization and Social desirability were lower. The TCI scale measuring Harm avoidance was higher among subjects with OCD and Self-directedness and Cooperativeness were lower. In addition we found obvious autistic traits in 20 % of the subjects. Subjects with autistic traits fulfilled significantly more personality disorder criteria. In addition, subjects with autistic traits scored significantly higher on KSP scales measuring Muscular tension, Psychasthenia and Inhibition of aggression whereas Socialization was lower as compared to OCD subjects without autistic traits. However, subjects with most conspicuous autistic traits lacked insight, and identified less of those traits in themselves. Smoking was rare among subjects with OCD,especially among those with an obsessive-compulsive personality disorder. Smokers with OCD did not differ from the normal population as regard to personality disorders and traits, and none had autistic traits. Autistic traits predicted non-response to SRI treatment. Those subjects who responded to SRI treatmenthad significantly less reduction of whole-blood serotonin after one week as compared to non-responders. Occasionally, high doses of SRIs may be needed.

    Conclusions: In OCD, autistic traits are common whereas smoking is race. Subjects with OCD and autistic traits may be identical to those OCD subjects often referred to as "odd" or schizotypal. OCD with autistic traits is suggested to constitute a distinct phenotype within the neuropsychiatric spectrum. A possible response predictor in pharmacotherapy of OCD is suggested.

  • 44. Belalov, V. V.
    et al.
    Dyagileva, Yu. O.
    Pavlenko, V. B.
    Kochukhova, Olga M.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Neurophysiological Analysis of Speech Perception in 2.5 to 3.5-Year-Old Orphans and Children Raised in a Family2014In: Neurophysiology (New York), ISSN 0090-2977, E-ISSN 1573-9007, Vol. 46, no 1, 79-87 p.Article in journal (Refereed)
    Abstract [en]

    In 2.5-3.5-year-old orphans (n = 41) and children raised in a family (n = 50), we examined specificities of speech perception-related changes in the spectral power density (SPD) of the EEG rhythms. Changes in the SPDs of the theta-, alpha-, beta-, and gamma-rhythms in 16 EEG leads where estimated at presentation of a meaningful speech fragment record (short poem) and of a reversed record of the same signal (direct and reversed speech, respectively). The Bayley Scales of Infant and Toddler Development III demonstrated the existence of noticeable delays in the development of speech in orphans. Comparison of background EEGs and EEGs in the course of listening for direct speech showed that the alpha-rhythm is desynchronized, while the theta-, beta-, and, especially, gamma-oscillations are synchronized upon perception of the above stimulus. In this case, children raised in a family demonstrated significant increases in the gamma-rhythm SPD in 13 leads of both hemispheres; in orphans, this was observed only in 8 loci localized mostly in the left hemisphere. In children of both groups, listening for reversed speech induced mostly desynchronization of all EEG rhythms with the greatest drops in the gamma SPD mostly in the frontal and left temporal leads. Comparison of SPDs of the EEG components (rhythms) at listening for direct and reversed speech demonstrated that powers of theta-, beta-, and gamma-oscillations increased at presentation of a direct (comprehended) speech in children of both groups. In children raised in families, greater SPDs of the gamma-rhythm were observed in 13 leads (differences were most significant in the frontal parts of the left hemisphere). In institutionalized children, the number of leads with significant increments of the gamma-rhythm power was significantly smaller (only 9). It is supposed that smaller increases in the SPD of of gamma-range oscillations in orphans are related to deviations in the processing of a semantic component of speech perception. This can result from insufficient development of cerebral neuronal networks responsible for processing of verbal information.

  • 45.
    Benediktsdottir, B.
    et al.
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali, Dept Resp Med & Sleep, Reykjavik, Iceland.;Primary Hlth Care Ctr, Gardabaer, Iceland..
    Arnardottir, E. S.
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali, Dept Resp Med & Sleep, Reykjavik, Iceland..
    Schlunssen, V.
    Aarhus Univ, Dept Publ Hlth, Aarhus, Denmark..
    Real, F. Gomez
    Univ Bergen, Dept Gynecol & Obstet, Bergen, Norway..
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Gislason, T.
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali, Dept Resp Med & Sleep, Reykjavik, Iceland..
    Bjornsdottir, E.
    Landspitali, Dept Resp Med & Sleep, Reykjavik, Iceland..
    The prevalence of insomnia, excessive daytime sleepiness and snoring across two generations - Results from RHINE and RHINESSA, multinational general population studies2016In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 25, 304-304 p.Article in journal (Other academic)
  • 46.
    Bengtsson, Caroline
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Jonsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Holmstrom, M.
    Svensson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Impact of nasal obstruction on sleep quality - a community based study of women2014In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 23, 149-149 p.Article in journal (Other academic)
  • 47.
    Bengtsson, Henrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Bone Morphogenetic Protein Receptors in the Nervous System: Neurotrophic Functions with Emphasis on Catecholaminergic Neurons2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Members of the transforming growth factor-β (TGF-β) superfamily exhibit a range of effects on a host of different cell types. They signal through heteromeric complexes of serine/threonine kinase receptors of type I and type II. Gene targeted mutations of both factors and receptors have revealed that many of them are involved in early embryonic development. This thesis examines the receptors for this superfamily in the nervous system, especially bone morphogenetic protein receptor type II (BMPR-II). It was cloned from chicken nervous tissue, and its and other receptors’ expression in peripheral ganglia, spinal cord and brain of chicken, rat and mouse were examined. BMPR-II, ActR-II and ActR-IA were abundantly expressed throughout development in the nervous system, however with temporal regulation. One ligand of BMPR-II, BMP-7, was found to act synergistically with NT-3 and GDNF on subsets of peripheral neurons to promote survival and neurite outgrowth. A knock-in mouse was generated, encoding a truncated form of BMPR-II coupled to the endogenous tyrosine hydroxylase (TH) gene with an internal ribosome entry site (IRES). For ES-cell selection, a neomycin resistance gene was incorporated into the construct. Homozygous mice carrying the knock-in allele exhibited a small, hypokinetic phenotype. Levels of dopamine, noradrenaline and serotonin were measured, and the catecholamines were found to be lowered, dopamine as much as 97% in the caudate nucleus. The low catecholamine levels may not be an effect of the truncated BMPR-II, but rather a consequence of the knock-in construct reducing TH transcriptional rate. The TH hypomorphic mouse strain generated could find use as a model for catecholamine impaired systems, as seen in Parkinson’s disease.

  • 48.
    Bergdahl, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Berman, Anne H.
    Karolinska Institutet, Institutionen för klinisk neurovetenskap.
    Haglund, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Patients’ experience of auricular acupuncture during protracted withdrawal2014In: Journal of Psychiatric and Mental Health Nursing, ISSN 1351-0126, E-ISSN 1365-2850, Vol. 21, no 2, 163-169 p.Article in journal (Refereed)
    Abstract [en]

    Over the last decades interest in using auricular acupuncture for substance dependence care has increased. The specific auricular acupuncture protocol used follows the National Acupuncture Detoxification Association (NADA) definition. This paper describes patients’ experiences of receiving auricular acupuncture during protracted withdrawal. Interviews were conducted with fifteen patients treated at an outpatient clinic for substance dependence. Content analysis was used to analyze the interviews. The analysis resulted in eight categories of positive experiences and five categories of negative experiences. The positive experiences were: Relaxation and wellbeing, Peacefulness and harmony, New behaviours, Positive physical impact, Importance of context, Anxiety reduction and Reduced drug- and alcohol consumption. The negative experiences were: Nothing negative, Disturbing context, Short term effect, Depending on someone else, Time consuming, Physical distrations and Remaining cravings. The conclusion of this study is that all respondents appreciated NADA treatment. This study supports further research on using NADA in addiction treatment to reduce suffering during protracted withdrawal and in other contexts.

  • 49.
    Bergdahl, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Berman, A. H.
    Karolinska Inst, Ctr Psychiat Res, Clin Neurosci, Stockholm, Sweden..
    Haglund, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    von Knorring, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Markström, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    A randomised controlled trial of auricular acupuncture and cognitive behavioural therapy for insomnia: a short-term self-assessment2016In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 25, 213-213 p.Article in journal (Other academic)
  • 50.
    Bergdahl, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Berman, A. H.
    Karolinska Inst, Ctr Psychiat Res, Clin Neurosci, Stockholm, Sweden..
    Haglund, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    von Knorring, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Markström, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Auricular acupuncture and cognitive behavioural therapy for insomnia - a randomised controlled study2016In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 25, 214-214 p.Article in journal (Other academic)
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Output format
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  • asciidoc
  • rtf