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  • 1.
    Alping, P.
    et al.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Askling, J.
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Fink, K.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
    Fogdell-Hahn, A.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Gunnarsson, M.
    Department of Neurology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Langer-Gould, A.
    Clinical and Translational Neuroscience, Southern California Permanente Medical Group, Kaiser Permanente, Pasadena, CA, United States.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Nilsson, P.
    Department of Clinical Sciences/Neurology, Lund University, Lund, Sweden.
    Salzer, J.
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Svenningsson, A.
    Department of Clinical Sciences, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Vrethem, Magnus
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
    Frisell, T.
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Cancer Risk for Fingolimod, Natalizumab, and Rituximab in Multiple Sclerosis Patients2020In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 87, no 5, p. 688-699Article in journal (Refereed)
    Abstract [en]

    Objective: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking. Methods: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer. Results: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7–48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2–63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1–41.6). The general population IR was 31.0 (95% CI = 27.8–34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98–2.38) and rituximab (HR = 1.68, 95% CI = 1.00–2.84). Interpretation: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings. 

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  • 2.
    Andreasson, Ann-Charlotte
    et al.
    Univ Gothenburg, Sweden.
    Sigurdsson, Gudmundur V
    Univ Gothenburg, Sweden.
    Pegenius, Goran
    Univ Gothenburg, Sweden.
    Thordstein, Magnus
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Hallbook, Tove
    Univ Gothenburg, Sweden.
    Cortical excitability measured with transcranial magnetic stimulation in children with epilepsy before and after antiepileptic drugs2020In: Developmental Medicine & Child Neurology, ISSN 0012-1622, E-ISSN 1469-8749Article in journal (Refereed)
    Abstract [en]

    Aim To evaluate cortical excitability with transcranial magnetic stimulation (TMS) in children with new-onset epilepsy before and after antiepileptic drugs (AEDs). Method Fifty-five drug-naive patients (29 females, 26 males; 3-18y), with new-onset epilepsy were recruited from 1st May 2014 to 31st October 2017 at the Child Neurology Department, Queen Silvias Childrens Hospital, Gothenburg, Sweden. We performed TMS in 48 children (23 females, 25 males; mean [SD] age 10y [3y], range 4-15y) with epilepsy (27 generalized and 21 focal) before and after the introduction of AEDs. We used single- and paired-pulse TMS. We used single-pulse TMS to record resting motor thresholds (RMTs), stimulus-response curves, and cortical silent periods (CSPs). We used paired-pulse TMS to record intracortical inhibition and facilitation at short, long, and intermediate intervals. Results There were no differences in cortical excitability between children with generalized and focal epilepsy at baseline. After AED treatment, RMTs increased (p=0.001), especially in children receiving sodium valproate (p=0.005). CSPs decreased after sodium valproate was administered (p=0.050). As in previous studies, we noted a negative correlation between RMT and age in our study cohort. Paired-pulse TMS could not be performed in most children because high RMTs made suprathreshold stimulation impossible. Interpretation Cortical excitability as measured with RMT decreased after the introduction of AEDs. This was seen in children with both generalized and focal epilepsy who were treated with sodium valproate, although it was most prominent in children with generalized epilepsy. We suggest that TMS might be used as a prognostic tool to predict AED efficacy.

    The full text will be freely available from 2021-02-16 11:21
  • 3.
    Bistrom, Martin
    et al.
    Umea Univ, Sweden.
    Hultdin, Johan
    Umea Univ, Sweden.
    Andersen, Oluf
    Univ Gothenburg, Sweden.
    Alonso-Magdalena, Lucia
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Jons, Daniel
    Univ Gothenburg, Sweden.
    Gunnarsson, Martin
    Orebro Univ, Sweden.
    Vrethem, Magnus
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Sundstrom, Peter
    Umea Univ, Sweden.
    Leptin levels are associated with multiple sclerosis risk2020In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, article id 1352458520905033Article in journal (Refereed)
    Abstract [en]

    Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection. Objective: To determine if leptin and insulin are risk factors for relapsing-remitting multiple sclerosis (RRMS). Methods: In this nested case-control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z-scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A 1-unit leptin z-score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1-1.9) and in all men (OR = 1.4, 95% CI = 1.0-2.0). In contrast, for women aged 30-39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54-1.0) when adjusting for insulin levels. Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals.

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  • 4.
    Bohannon, Briana M.
    et al.
    Univ Miami, FL 33136 USA.
    de la Cruz, Alicia
    Univ Miami, FL 33136 USA.
    Wu, Xiaoan
    Univ Miami, FL 33136 USA.
    Jowais, Jessica J.
    Univ Miami, FL 33136 USA.
    Perez, Marta E.
    Univ Miami, FL 33136 USA.
    Liin, Sara
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, H. Peter
    Univ Miami, FL 33136 USA.
    Polyunsaturated fatty acid analogues differentially affect cardiac Na-V, Ca-V, and K-V channels through unique mechanisms2020In: eLIFE, E-ISSN 2050-084X, Vol. 9, article id e51453Article in journal (Refereed)
    Abstract [en]

    The cardiac ventricular action potential depends on several voltage-gated ion channels, including Na-V, Ca-V, and K-V channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating cardiac ion channels from all three families (Na-V, Ca-V, and K-V). In addition, a PUFA analogue selective for the cardiac IKs channel (Kv7.1/KCNE1) is effective in shortening the cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes. Our data suggest that PUFA analogues could potentially be developed as therapeutics for LQTS and cardiac arrhythmia.

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  • 5.
    Bohannon, Briana M.
    et al.
    Univ Miami, FL 33136 USA.
    Wu, Xiaoan
    Univ Miami, FL 33136 USA.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Perez, Marta E.
    Univ Miami, FL 33136 USA.
    Liin, Sara
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, H. Peter
    Univ Miami, FL 33136 USA.
    Polyunsaturated fatty acids produce a range of activators for heterogeneous I-Ks channel dysfunction2020In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 152, no 2, article id e201912396Article in journal (Refereed)
    Abstract [en]

    Repolarization and termination of the ventricular cardiac action potential is highly dependent on the activation of the slow delayed-rectifier potassium I-Ks channel. Disruption of the I-Ks current leads to the most common form of congenital long QT syndrome (LQTS), a disease that predisposes patients to ventricular arrhythmias and sudden cardiac death. We previously demonstrated that polyunsaturated fatty acid (PUFA) analogues increase outward K+ current in wild type and LQTS-causing mutant I-Ks channels. Our group has also demonstrated the necessity of a negatively charged PUFA head group for potent activation of the I-Ks channel through electrostatic interactions with the voltage-sensing and pore domains. Here, we test whether the efficacy of the PUFAs can be tuned by the presence of different functional groups in the PUFA head, thereby altering the electrostatic interactions of the PUFA head group with the voltage sensor or the pore. We show that PUFA analogues with taurine and cysteic head groups produced the most potent activation of I-Ks channels, largely by shifting the voltage dependence of activation. In comparison, the effect on voltage dependence of PUFA analogues with glycine and aspartate head groups was half that of the taurine and cysteic head groups, whereas the effect on maximal conductance was similar. Increasing the number of potentially negatively charged moieties did not enhance the effects of the PUFA on the I-Ks channel. Our results show that one can tune the efficacy of PUFAs on I-Ks channels by altering the pK(a) of the PUFA head group. Different PUFAs with different efficacy on I-Ks channels could be developed into more personalized treatments for LQTS patients with a varying degree of I-Ks channel dysfunction.

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  • 6.
    Eleftheriou, Andreas
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Blystad, Ida
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Tisell, Anders
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Gasslander, Johan
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Norrköping.
    Lundin, Fredrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Indication of Thalamo-Cortical Circuit Dysfunction in Idiopathic Normal Pressure Hydrocephalus: A Tensor Imaging Study2020In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 10, no 1Article in journal (Refereed)
    Abstract [en]

    Idiopathic normal pressure hydrocephalus (iNPH) is a disorder with unclear pathophysiology. The diagnosis of iNPH is challenging due to its radiological similarity with other neurodegenerative diseases and ischemic subcortical white matter changes. By using Diffusion Tensor Imaging (DTI) we explored differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in iNPH patients (before and after a shunt surgery) and healthy individuals (HI) and we correlated the clinical results with DTI parameters. Thirteen consecutive iNPH-patients underwent a pre- and post-operative clinical work-up: 10m walk time (w10mt) steps (w10ms), TUG-time (TUGt) and steps (TUGs); for cognitive function MMSE. Nine HI were included. DTI was performed before and 3 months after surgery, HI underwent DTI once. DTI differences analyzed by manually placing 12 regions-of-interest. In patients motor and balance function improved significantly after surgery (p=0.01, p=0.025). Higher nearly significant FA values found in the patients vs HI pre-operatively in the thalamus (p=0.07) accompanied by an almost significant lower ADC (p=0.08). Significantly FA and ADC-values were found between patients and HI in FWM (p=0.02, p=0.001) and almost significant (p=0.057) pre- vs postoperatively. Postoperatively we found a trend towards the HIs FA values and a strong significant negative correlation between FA changes vs. gait results in the FWM (r=-0.7, p=0.008). Our study gives a clear indication of an ongoing pathological process in the periventricular white matter, especially in the thalamus and in the frontal white matter supporting the hypothesis of a shunt reversible thalamo-cortical circuit dysfunction in iNPH.

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  • 7.
    Eskilsson, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Inflammatory Signaling Across the Blood-Brain Barrier and the Generation of Fever2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fever is a cardinal sign of inflammation and is evolutionary conserved. Fever is known to be beneficial during acute inflammation, but over time and if very high it can be detrimental. The signaling pathways by which fever is initiated by the brain and the peripheral mechanisms through which the temperature increase is generated were studied from several point of views. Fever is known to be dependent on prostaglandin E2 (PGE2) binding to its receptors in the median preoptic nucleus of the hypothalamus, which signals to the brainstem and through sympathetic nerves to heat conserving and heat producing effector organs. This thesis focuses on identifying the cells that produce the PGE2 critical for the fever response; showing where in the brain the critical PGE2 production takes place; demonstrating how peripheral inflammation activates these cells to produce PGE2; and finally, identifying the effector mechanisms behind the temperature elevation in fever. By using a newly developed specific antibody we showed that the enzyme responsible for the terminal step in the production of PGE2, microsomal prostaglandin E-synthase 1 (mPGES-1), is expressed in endothelial cells of brain blood vessels in mice where it is co-expressed with the enzyme cyclooxygenase-2 (Cox-2), which is known to be induced in these cells and to be rate limiting for the PGE2 production. The mPGES-1 enzyme was also expressed in several other cell types and structures which however did not express Cox-2, such as capillary-associated pericytes, astroglial cells, leptomeninges, and the choroid plexus. The role of the mPGES-1 in these other cells/structures remains unknown. Next, by using mice with selective deletion of Cox-2 in brain endothelial cells, we showed that local PGE2 production in deep brain areas, such as the hypothalamus, is critical for the febrile response to peripheral inflammation. In contrast, PGE2 production in other brain areas and the overall PGE2 level in the brain were not critical for the febrile response. Partly restoring the PGE2 synthesizing capacity in the anterior hypothalamus of mice lacking such capacity with a lentiviral vector resulted in a temperature elevation in response to an intraperitoneal injection of bacterial wall lipopolysaccharide (LPS). The data show that the febrile response is dependent on the local release of PGE2 onto its target neurons, possibly by a paracrine mechanism. Deletion of the receptor for the pyrogenic cytokine IL-6 on brain endothelial cells, but not on neurons or peripheral nerves, strongly attenuated the febrile response to LPS and reduced the induction of the Cox-2 expression in the hypothalamus. Furthermore, mice deficient of the IL- 6Rα gene in the brain endothelial cells showed a reduced SOCS3 mRNA induction, whereas IκB mRNA-levels were unaffected, suggesting that the IL-6 signaling occurs via STAT3 activation and not signaling through the transcription factor NF-κB. This idea was confirmed by the observation of attenuated fever in mice deficient of STAT3 in brain endothelial cells. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R on brain endothelial cells to induce prostaglandin synthesis in these cells. Finally, we demonstrate that mice with genetic deletion of uncoupling protein-1 (UCP-1), hence lacking functional brown adipose tissue, had a normal fever response to LPS, and that LPS caused no activation of brown adipose tissue in wild type mice. However, blocking peripheral cutaneous vasoconstriction resulted in a blunted fever response to LPS, suggesting that heat conservation, possibly together with shivering or non-shivering thermogenesis in the musculature, is responsible for the generation of immune-induced fever, whereas brown adipose tissue thermogenesis is not involved.  

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  • 8.
    Eskilsson, Anna
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Shionoya, Kiseko
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Enerback, Sven
    Univ Gothenburg, Sweden.
    Engblom, David
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    The generation of immune-induced fever and emotional stress-induced hyperthermia in mice does not involve brown adipose tissue thermogenesis2020In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 34, no 4, p. 5863-5876Article in journal (Refereed)
    Abstract [en]

    We examined the role of brown adipose tissue (BAT) for fever and emotional stress-induced hyperthermia. Wild-type and uncoupling protein-1 (UCP-1) knockout mice were injected with lipopolysaccharide intraperitoneally or intravenously, or subjected to cage exchange, and body temperature monitored by telemetry. Both genotypes showed similar febrile responses to immune challenge and both displayed hyperthermia to emotional stress. Neither procedure resulted in the activation of BAT, such as the induction of UCP-1 or peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) mRNA, or reduced BAT weight and triglyceride content. In contrast, in mice injected with a beta (3) agonist, UCP-1 and PGC-1 alpha were strongly induced, and BAT weight and triglyceride content reduced. Both lipopolysaccharide and the beta (3) agonist, and emotional stress, induced UCP-3 mRNA in skeletal muscle. A beta (3) antagonist did not attenuate lipopolysaccharide-induced fever, but augmented body temperature decrease and inhibited BAT activation when mice were exposed to cold. An alpha (1)/alpha (2b) antagonist or a 5HT(1A) agonist, which inhibit vasoconstriction, abolished lipopolysaccharide-induced fever, but had no effect on emotional stress-induced hyperthermia. These findings demonstrate that in mice, UCP-1-mediated BAT thermogenesis does not take part in inflammation-induced fever, which is dependent on peripheral vasoconstriction, nor in stress-induced hyperthermia. However, both phenomena may involve UCP-3-mediated muscle thermogenesis.

  • 9.
    Håkansson, Irene
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Ernerudh, Jan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Vrethem, Magnus
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ekdahl, Kristina N.
    Centre of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden ; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Complement activation in cerebrospinal fluid in clinically isolated syndrome and early stages of relapsing remitting multiple sclerosis2020In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 340, article id 577147Article in journal (Refereed)
    Abstract [en]

    To assess if markers of complement activation are associated with disease activity, C1q, C3, C3a and sC5b-9 levels in plasma and cerebrospinal fluid (CSF) were determined in 41 patients with clinically isolated syndrome (CIS) or remitting multiple sclerosis (RRMS), in a prospective longitudinal four-year cohort study. C1q in CSF (CSF-C1q) was significantly higher in patients than in controls. Baseline CSF-C1q and CSF-C3a correlated with several neuroinflammatory markers and neurofilament light chain levels. Baseline CSF-C3a correlated with the number of T2 lesions at baseline and new T2 lesions during follow-up. Baseline CSF-C3a was also significantly higher in patients with (n = 21) than in patients without (n = 20) signs of disease activity according to the NEDA-3 concept during one year of follow-up (p ≀ .01) Study results support that complement activation is involved in MS pathophysiology and that CSF-C3a carries prognostic information.

  • 10.
    Larsson, Johan
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology.
    Molecular mechanisms of modulation of KV7 channels by polyunsaturated fatty acids and their analogues2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ion channels are membrane proteins that regulate the permeability of ions across the cell membrane. The sequential opening of different types of ion channels produces action potentials in excitable cells. Action potentials are a way for the body to, for example, transmit signals quickly over a long distance.

    The KV7 family is an important group of voltage-gated potassium channels. Mutations that cause dysfunction in members of the KV7 family are associated with several forms of disease. Compounds that can activate KV7 channels have previously been shown to work as medical treatments. However, the previously available antiepileptic drug retigabine, has been withdrawn due to adverse effects. Thus, there is a need for further development of compounds that target these channels. PUFA and PUFA analogs have previously been demonstrated to activate KV7.1 through an electrostatic mechanism. This thesis investigates new aspects of the interaction between KV7 channels and PUFA-related compounds.

    The data in this thesis are from human KV7 channels expressed in Xenopus laevis oocytes. The currents produced by the channels expressed in the oocytes have been studied using twoelectrode voltage clamp. Our aim was to study the mechanism for the activation of KV7 channels by PUFA and PUFA analogs. More specifically, we intended to study why the beta subunit KCNE1 abolishes the activating effect of PUFA on KV7.1 and how PUFAs activate KV7.2 and KV7.3. Additionally, we wanted to study aspects that may affect whether these compounds are viable as medical treatments. For instance, whether these compounds can activate channels containing disease-causing mutations and whether we can improve compound selectivity towards certain KV7 channels.

    In Paper I, we introduce disease-causing mutations found in patients into KV7.1 and KCNE1. The characterization showed that these channels had altered biophysical properties compared to wild type channels. A PUFA analog was found to activate and, to a large degree, restore wild type-like biophysical properties in the mutated channels regardless of the localization of the mutation in the channel.

    In Paper II, we demonstrate why PUFA is unable to activate KV7.1 co-expressed with beta subunit KCNE1. KCNE1 induces a conformational change of KV7.1 that moves the S5-Phelix loop closer to the PUFA binding site. This causes negative charges of the loop to attract protons that reduce local pH at the PUFA binding site. The decreased local pH leads to protonation of PUFA and the PUFAs therefore lose their negative charge. Thus, PUFA cannot activate KV7.1 when it is co-expressed with KCNE1.

    In Paper III, we study a group of PUFA-related substances, endocannabinoids, on KV7 channels. One endocannabinoid, Arachidonoyl-L-Serine (ARA-S), was identified as a potent activator of the neuronal M-channel, comprising KV7.2 and KV7.3 heteromers. We study the activating mechanism of ARA-S in KV7.2 and KV7.3, demonstrating how the activating effect is linked to two parts of the channel protein, one in the voltage sensor domain and the other in the pore domain. ARA-S was also found to activate KV7.1 and KV7.5 but not KV7.4, which instead was inhibited. Retigabine, a compound that activates the M-channel but has a different KV7 subtype selectivity compared to ARA-S, was used in combination with ARA-S to maintain a potent effect on the M-channel while limiting the activation of other KV7 channels.

    In conclusion, the activating effect of PUFA analogs on KV7 channels may be helpful in the development of future drug candidates for diseases such as arrhythmia and epilepsy.

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  • 11.
    Larsson, Johan
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Urban
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Liin, Sara
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology.
    Combining endocannabinoids with retigabine for enhanced M-channel effect and improved KV7 subtype selectivity2020In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 152, no 8Article in journal (Refereed)
    Abstract [en]

    Retigabine is unique among anticonvulsant drugs by targeting the neuronal M-channel, which is composed of KV7.2/KV7.3 and contributes to the negative neuronal resting membrane potential. Unfortunately, retigabine causes adverse effects, which limits its clinical use. Adverse effects may be reduced by developing M-channel activators with improved KV7 subtype selectivity. The aim of this study was to evaluate the prospect of endocannabinoids as M-channel activators, either in isolation or combined with retigabine. Human KV7 channels were expressed in Xenopus laevis oocytes. The effect of extracellular application of compounds with different properties was studied using two-electrode voltage clamp electrophysiology. Site-directed mutagenesis was used to construct channels with mutated residues to aid in the mechanistic understanding of these effects. We find that arachidonoyl-L-serine (ARA-S), a weak endocannabinoid, potently activates the human M-channel expressed in Xenopus oocytes. Importantly, we show that ARA-S activates the M-channel via a different mechanism and displays a different KV7 subtype selectivity compared with retigabine. We demonstrate that coapplication of ARA-S and retigabine at low concentrations retains the effect on the M-channel while limiting effects on other KV7 subtypes. Our findings suggest that improved KV7 subtype selectivity of M-channel activators can be achieved through strategically combining compounds with different subtype selectivity.

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  • 12.
    Lin, Chung-Ying
    et al.
    Hong Kong Polytech Univ, Peoples R China.
    Cheng, Andy S. K.
    Hong Kong Polytech Univ, Peoples R China.
    Nejati, Babak
    Tabriz Univ Med Sci, Iran.
    Imani, Vida
    Tabriz Univ Med Sci, Iran.
    Ulander, Martin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology.
    Browall, Maria
    Jonkoping Univ, Sweden.
    Griffiths, Mark D.
    Nottingham Trent Univ, England.
    Broström, Anders
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology. Jonkoping Univ, Sweden.
    Pakpour, Amir H.
    Jonkoping Univ, Sweden; Qazvin Univ Med Sci, Iran.
    A thorough psychometric comparison between Athens Insomnia Scale and Insomnia Severity Index among patients with advanced cancer2020In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 29, no 1, article id e12891Article in journal (Refereed)
    Abstract [en]

    For patients with cancer, sleep disturbance is commonplace. Using classical test theory and Rasch analyses, the present study compared two commonly used psychometric instruments for insomnia - Athens Insomnia Scale and Insomnia Severity Index - among patients with advanced cancer. Through convenience sampling, patients with cancer at stage III or IV (n = 573; 326 males; mean age = 61.3 years; SD = 10.7) from eight oncology units of university hospitals in Iran participated in the study. All the participants completed the Athens Insomnia Scale, Insomnia Severity Index, Edmonton Symptom Assessment Scale, Hospital Anxiety and Depression Scale, General Health Questionnaire-12, Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index. Additionally, 433 participants wore an Actigraph device for two continuous weekdays. Classical test theory and Rasch analysis both supported the construct validity for Athens Insomnia Scale (factor loadings from confirmatory factor analysis = 0.61-0.87; test-retest reliability = 0.72-0.82; infit mean square = 0.81-1.17; outfit MnSq = 0.79-1.14) and for Insomnia Severity Index (factor loadings from confirmatory factor analysis = 0.61-0.81; test-retest reliability = 0.72-0.82; infit mean square = 0.72-1.14; outfit mean square = 0.76-1.11). Both Athens Insomnia Scale and Insomnia Severity Index had significant associations with Edmonton Symptom Assessment Scale, Hospital Anxiety and Depression Scale, General Health Questionnaire-12, Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index, as well as having good sensitivity and specificity. Significant differences in the actigraphy measure were found between insomniacs and non-insomniacs based on Athens Insomnia Scale or Insomnia Severity Index score. With promising results, healthcare providers can use either Athens Insomnia Scale or Insomnia Severity Index to understand the insomnia of patients with advanced cancer.

  • 13.
    Luna, Gustavo
    et al.
    Karolinska Inst, Sweden.
    Alping, Peter
    Karolinska Inst, Sweden.
    Burman, Joachim
    Uppsala Univ, Sweden.
    Fink, Katharina
    Karolinska Inst, Sweden.
    Fogdell-Hahn, Anna
    Karolinska Inst, Sweden.
    Gunnarsson, Martin
    Orebro Univ, Sweden.
    Hillert, Jan
    Karolinska Inst, Sweden.
    Langer-Gould, Annette
    Kaiser Permanente, CA USA.
    Lycke, Jan
    Univ Gothenburg, Sweden.
    Nilsson, Petra
    Lund Univ, Sweden.
    Salzer, Jonatan
    Umea Univ, Sweden.
    Svenningsson, Anders
    Karolinska Inst, Sweden.
    Vrethem, Magnus
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Olsson, Tomas
    Karolinska Inst, Sweden.
    Piehl, Fredrik
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Acad Specialist Ctr, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies2020In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 77, no 2, p. 184-191Article in journal (Refereed)
    Abstract [en]

    Question What is the risk of infections in association with different disease-modifying treatments for multiple sclerosis? Findings This nationwide cohort study found that patients with multiple sclerosis are at a generally increased risk of infections, and this risk is partly dependent on the choice of treatment. The rate of infections was lowest with injectable therapies; among newer treatments, use of rituximab was associated with the highest rate of serious infections but less use of herpes antiviral medications compared with fingolimod and natalizumab. Meaning Per the results of this study, physicians and patients should be aware of infection risks associated with newer multiple sclerosis treatments and perhaps particularly anti-CD20 therapies. This registry-based cohort study examines the risk of serious infections associated with disease-modifying treatments for multiple sclerosis in Sweden. Importance Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden. Objective To examine the risk of serious infections associated with disease-modifying treatments for MS. Design, Setting, and Participants This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included. Exposures Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA. Main Outcomes and Measures Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions. Results A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 amp; x202f;645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]). Conclusions and Relevance Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.

  • 14.
    Majd, Nilofar Rajabi
    et al.
    Qazvin Univ Med Sci, Iran.
    Broström, Anders
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology. Jonkoping Univ, Sweden.
    Ulander, Martin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology. Linköping University, Faculty of Medicine and Health Sciences.
    Lin, Chung-Ying
    Hong Kong Polytech Univ, Peoples R China.
    Griffiths, Mark D.
    Nottingham Trent Univ, England.
    Imani, Vida
    Tabriz Univ Med Sci, Iran.
    Ahorsu, Daniel Kwasi
    Hong Kong Polytech Univ, Peoples R China.
    Ohayon, Maurice M.
    Stanford Univ, CA 94304 USA.
    Pakpour, Amir H.
    Qazvin Univ Med Sci, Iran; Jonkoping Univ, Sweden.
    Efficacy of a Theory-Based Cognitive Behavioral Technique App-Based Intervention for Patients With Insomnia: Randomized Controlled Trial2020In: Journal of Medical Internet Research, ISSN 1438-8871, E-ISSN 1438-8871, Vol. 22, no 4, article id e15841Article in journal (Refereed)
    Abstract [en]

    Background: Sleep hygiene is important for maintaining good sleep and reducing insomnia. Objective: This study examined the long-term efficacy of a theory-based app (including cognitive behavioral therapy [CBT], theory of planned behavior [TPB], health action process approach [HAPA], and control theory [CT]) on sleep hygiene among insomnia patients. Methods: The study was a 2-arm single-blind parallel-group randomized controlled trial (RCT). Insomnia patients were randomly assigned to a treatment group that used an app for 6 weeks (ie, CBT for insomnia [CBT-I], n=156) or a control group that received only patient education (PE, n=156) through the app. Outcomes were assessed at baseline and 1 month, 3 months, and 6 months postintervention. Primary outcomes were sleep hygiene, insomnia, and sleep quality. Secondary outcomes included attitudes toward sleep hygiene behavior, perceived behavioral control, behavioral intention, action and coping planning, self-monitoring, behavioral automaticity, and anxiety and depression. Linear mixed models were used to evaluate the magnitude of changes in outcomes between the two groups and across time. Results: Sleep hygiene was improved in the CBT-I group compared with the PE group (P=.02 at 1 month, P=.04 at 3 months, and P=.02 at 6 months) as were sleep quality and severity of insomnia. Mediation analyses suggested that perceived behavioral control on sleep hygiene as specified by TPB along with self-regulatory processes from HAPA and CT mediated the effect of the intervention on outcomes. Conclusions: Health care providers might consider using a CBT-I app to improve sleep among insomnia patients.

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  • 15.
    Malmström, Annika
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Lysiak, Malgorzata
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Åkesson, Lisa
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Jakobsen, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Mudaisi, Munila
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Milos, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Hallbeck, Martin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Fomichov Casaballe, Victoria
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Business support and Development, Regional Cancer Center.
    Broholm, Helle
    Copenhagen Univ Hosp, Denmark.
    Grunnet, Kirsten
    Copenhagen Univ Hosp, Denmark.
    Poulsen, Hans Skovgaard
    Copenhagen Univ Hosp, Denmark; Copenhagen Univ Hosp, Denmark.
    Bratthall, Charlotte
    Cty Hosp, Sweden.
    Strandeus, Michael
    Ryhov Hosp, Sweden.
    Papagiannopoulou, Angeliki
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Stenmark-Askmalm, Marie
    Lund Univ, Sweden.
    Green, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    ABCB1 single-nucleotide variants and survival in patients with glioblastoma treated with radiotherapy concomitant with temozolomide2020In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 20, no 2, p. 213-219Article in journal (Refereed)
    Abstract [en]

    Standard treatment for glioblastoma (GBM) patients is surgery and radiochemotherapy (RCT) with temozolomide (TMZ). TMZ is a substrate for ABCB1, a transmembrane drug transporter. It has been suggested that survival for GBM patients receiving TMZ is influenced by different single-nucleotide variants (SNV) of ABCB1. We therefore examined SNV:s of ABCB1, namely 1199Gamp;gt;A, 1236Camp;gt;T, 2677Gamp;gt;T/A, and 3435Camp;gt;T and correlated to survival for GBM patients receiving RCT. In a pilot cohort (97 patients) a significant correlation to survival was found for SNV 1199Gamp;gt;A, with median OS for variant G/G patients being 18.2 months versus 11.5 months for A/G (p = 0.012). We found no correlation to survival for the other SNV:s. We then expanded the cohort to 179 patients (expanded cohort) and also included a confirmatory cohort (49 patients) focusing on SNV 1199Gamp;gt;A. Median OS for G/G versus A/G plus A/A was 15.7 and 11.5 months, respectively (p = 0.085) for the expanded cohort and 13.8 versus 16.8 months (p = 0.19) for the confirmatory. In conclusion, in patients with GBM receiving RCT with TMZ, no correlation with survival was found for the SNV:s 1236Camp;gt;T, 2677Gamp;gt;T/A, and 3435Camp;gt;T of ABCB1. Although the SNV 1199Gamp;gt;A might have some impact, a clinically significant role could not be confirmed.

  • 16.
    Mayo, Leah
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Asratian, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Lindé, Johan
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Morena, Maria
    Cummings Scool Med, Canada; Univ Calgary, Canada; Univ Calgary, Canada.
    Haataja, Roosa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Hammar, Valter
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Augier, Gaëlle
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Hill, Matthew N.
    Cummings Scool Med, Canada; Cummings Scool Med, Canada; Univ Calgary, Canada; Univ Calgary, Canada.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Psykiatriska kliniken inkl beroendekliniken.
    Elevated Anandamide, Enhanced Recall of Fear Extinction, and Attenuated Stress Responses Following Inhibition of Fatty Acid Amide Hydrolase: A Randomized, Controlled Experimental Medicine Trial2020In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 87, no 6, p. 538-547Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Posttraumatic stress disorder, an area of large unmet medical needs, is characterized by persistence of fear memories and maladaptive stress responses. In rodents, elevation of the endocannabinoid anandamide due to inhibition of fatty acid amide hydrolase (FAAH) facilitates fear extinction and protects against the anxiogenic effects of stress. We recently reported that elevated anandamide levels in people homozygous for a loss-of-function FAAH mutation are associated with a similar phenotype, suggesting a translational validity of the preclinical findings. METHODS: In this double-blind, placebo-controlled experimental medicine study, healthy adults were randomized to an FAAH inhibitor (PF-04457845, 4 mg orally, once daily; n = 16) or placebo (n = 29) for 10 days. On days 9 and 10, participants completed a task battery assessing psychophysiological indices of fear learning, stress reactivity, and stress-induced affective responses. RESULTS: FAAH inhibition produced a 10-fold increase in baseline anandamide. This was associated with potentiated recall of fear extinction memory when tested 24 hours after extinction training. FAAH inhibition also attenuated autonomic stress reactivity, assessed via electrodermal activity, and protected against stress-induced negative affect, measured via facial electromyography. CONCLUSIONS: Our data provide preliminary human evidence that FAAH inhibition can improve the recall of fear extinction memories and attenuate the anxiogenic effects of stress, in a direct translation of rodent findings. The beneficial effects of FAAH inhibition on fear extinction, as well as stress- and affect-related behaviors, provide a strong rationale for developing this drug class as a treatment for posttraumatic stress disorder.

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  • 17.
    Oliveira, Flavio
    et al.
    Univ Porto, Portugal.
    Diez-Quijada, Leticia
    Univ Seville, Spain.
    Turkina, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Morais, Joao
    Univ Porto, Portugal.
    Felpeto, Aldo Barreiro
    Univ Porto, Portugal.
    Azevedo, Joana
    Univ Porto, Portugal.
    Jos, Angeles
    Univ Seville, Spain.
    Camean, Ana M.
    Univ Seville, Spain.
    Vasconcelos, Vitor
    Univ Porto, Portugal; Univ Porto, Portugal.
    Martins, Jose Carlos
    Univ Porto, Portugal.
    Campos, Alexandre
    Univ Porto, Portugal.
    Physiological and Metabolic Responses of Marine Mussels Exposed to Toxic Cyanobacteria Microcystis aeruginosa and Chrysosporum ovalisporum2020In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, TOXINS, Vol. 12, no 3, article id 196Article in journal (Refereed)
    Abstract [en]

    Toxic cyanobacterial blooms are a major contaminant in inland aquatic ecosystems. Furthermore, toxic blooms are carried downstream by rivers and waterways to estuarine and coastal ecosystems. Concerning marine and estuarine animal species, very little is known about how these species are affected by the exposure to freshwater cyanobacteria and cyanotoxins. So far, most of the knowledge has been gathered from freshwater bivalve molluscs. This work aimed to infer the sensitivity of the marine mussel Mytilus galloprovincialis to single as well as mixed toxic cyanobacterial cultures and the underlying molecular responses mediated by toxic cyanobacteria. For this purpose, a mussel exposure experiment was outlined with two toxic cyanobacteria species, Microcystis aeruginosa and Chrysosporum ovalisporum at 1 x 10(5) cells/mL, resembling a natural cyanobacteria bloom. The estimated amount of toxins produced by M. aeruginosa and C. ovalisporum were respectively 0.023 pg/cell of microcystin-LR (MC-LR) and 7.854 pg/cell of cylindrospermopsin (CYN). After 15 days of exposure to single and mixed cyanobacteria, a depuration phase followed, during which mussels were fed only non-toxic microalga Parachlorella kessleri. The results showed that the marine mussel is able to filter toxic cyanobacteria at a rate equal or higher than the non-toxic microalga P. kessleri. Filtration rates observed after 15 days of feeding toxic microalgae were 1773.04 mL/ind.h (for M. aeruginosa), 2151.83 mL/ind.h (for C. ovalisporum), 1673.29 mL/ind.h (for the mixture of the 2 cyanobacteria) and 2539.25 mL/ind.h (for the non-toxic P. kessleri). Filtering toxic microalgae in combination resulted in the accumulation of 14.17 ng/g dw MC-LR and 92.08 ng/g dw CYN. Other physiological and biochemical endpoints (dry weight, byssus production, total protein and glycogen) measured in this work did not change significantly in the groups exposed to toxic cyanobacteria with regard to control group, suggesting that mussels were not affected with the toxic microalgae. Nevertheless, proteomics revealed changes in metabolism of mussels related to diet, specially evident in those fed on combined cyanobacteria. Changes in metabolic pathways related with protein folding and stabilization, cytoskeleton structure, and gene transcription/translation were observed after exposure and feeding toxic cyanobacteria. These changes occur in vital metabolic processes and may contribute to protect mussels from toxic effects of the toxins MC-LR and CYN.

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  • 18.
    Petkovic, Filip
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Lazzarino, Gisela
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    IL-6R expressed on CNS vascular endothelial cells contributes to the development of experimental autoimmune encephalomyelitis in mice2020In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 342, article id 577211Article in journal (Refereed)
    Abstract [en]

    Experimental autoimmune encephalomyelitis (EAE) is the most common model for studying the molecular mechanisms of multiple sclerosis (MS). Here, we examined the CNS-restricted effects of classical interleukin (IL)6 signaling on the development of EAE, using mice with cell-type specific deletion of the IL-6 receptor (IL-6R). We found that IL-6R deletion in CNS vascular endothelial cells, but not in microglia, ameliorated symptoms of EAE. The milder clinical symptoms in the gene-deleted mice were associated with less demyelination and immune cell infiltration/activation, and lower mRNA levels of the cytokines IL-17 and IL-1 beta, as well as the cell adhesion molecules VCAM-1, ICAM-1 and ICAM-2 than what was seen in WT mice. These findings demonstrate that classical IL-6 signaling via endothelial cells of the CNS contributes substantially to the development of MS-like pathology, which should be taken into consideration when conceptualizing future therapeutic approaches.

  • 19.
    Pipan, Eva
    et al.
    Univ Med Ctr Ljubljana, Slovenia.
    Apostolou, Alexandros
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Bograkou, Maria
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Brooks, Petra
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Vigren, Patrick
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology.
    Gauffin, Helena
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Vagal Nerve Stimulation in Epilepsy: Experiences of Participants with Cognitive Deficits2020In: NEUROPSYCHIATRIC DISEASE AND TREATMENT, Vol. 16, p. 1181-1188Article in journal (Refereed)
    Abstract [en]

    Introduction: The purpose of this study was to examine patients experiences of vagal nerve stimulation (VNS) with a special interest in patients with cognitive deficit (CD). Materials and Methods: An open, retrospective study was conducted on 82 patients with pharmacoresistant epilepsy, who were treated with VNS for at least 10 months. Based on the inability to live independently, they were divided into two groups: patients with cognitive deficit (CD group) and patients without cognitive deficit (non-CD group). A specially designed questionnaire was used for semi-structured interviews about patients experiences of VNS treatment. Results: Approximately one-third described a continuous reduction of seizure frequency of 50% or more and were regarded as responders. Fewer subjects in the CD group were responders than in the non-CD group. Approximately one-third of all subjects had no positive effect of VNS treatment. More CD patients described additional improvements and the most common were milder seizures and improved alertness. The most commonly reported adverse effect was hoarseness. Discussion: VNS treatment in patients without CD had better effect on seizure frequency reduction than in patients with CD, but many patients with CD reported other benefits from the treatment.

  • 20.
    Pohl, Petra
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Activity and Health.
    Wressle, Ewa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Lundin, Fredrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Enthoven, Paul
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Dizdar Segrell, Nil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Group-based music intervention in Parkinsons disease: findings from a mixed-methods study2020In: Clinical Rehabilitation, ISSN 0269-2155, E-ISSN 1477-0873, article id 0269215520907669Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate a group-based music intervention in patients with Parkinsons disease. Design: Parallel group randomized controlled trial with qualitative triangulation. Setting: Neurorehabilitation in primary care. Subjects: Forty-six patients with Parkinsons disease were randomized into intervention group (n = 26), which received training with the music-based intervention, and control group (n = 20) without training. Interventions: The intervention was delivered twice weekly for 12 weeks. Main measures: Primary outcome was Timed-Up-and-Go subtracting serial 7s (dual-task ability). Secondary outcomes were cognition, balance, concerns about falling, freezing of gait, and quality of life. All outcomes were evaluated at baseline, post-intervention, and three months post-intervention. Focus groups and individual interviews were conducted with the intervention group and with the delivering physiotherapists. Results: No between-group differences were observed for dual-task ability. Between-group differences were observed for Falls Efficacy Scale (mean difference (MD) = 6.5 points; 95% confidence interval (CI) = 3.0 to 10.0, P = 0.001) and for Parkinson Disease Questionnaire-39 items (MD = 8.3; 95% CI = 2.7 to 13.8, P = 0.005) when compared to the control group post-intervention, but these were not maintained at three months post-intervention. Three themes were derived from the interviews: Expectations versus Results, Perspectives on Treatment Contents, and Key Factors for Success. Conclusion: Patient-reported outcomes and interviews suggest that the group-based music intervention adds value to mood, alertness, and quality of life in patients with Parkinsons disease. The study does not support the efficacy in producing immediate or lasting gains in dual-tasking, cognition, balance, or freezing of gait.

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  • 21.
    Silverå Ejneby, Malin
    et al.
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Migliaccio, Ludovico
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Gicevicius, Mindaugas
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering. Vilnius Univ, Lithuania.
    Derek, Vedran
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Jakesova, Marie
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Elinder, Fredrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Glowacki, Eric
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering. Warsaw Univ Technol, Poland.
    Extracellular Photovoltage Clamp Using Conducting Polymer-Modified Organic Photocapacitors2020In: ADVANCED MATERIALS TECHNOLOGIES, ISSN 2365-709X, article id 1900860Article in journal (Refereed)
    Abstract [en]

    Optoelectronic control of physiological processes accounts for new possibilities ranging from fundamental research to treatment of disease. Among nongenetic light-driven approaches, organic semiconductor-based device platforms such as the organic electrolytic photocapacitor (OEPC) offer the possibility of localized and wireless stimulation with a minimal mechanical footprint. Optimization of efficiency hinges on increasing effective capacitive charge delivery. Herein, a simple strategy to significantly enhance the photostimulation performance of OEPC devices by employing coatings of the conducting polymer formulation poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate), or PEDOT:PSS is reported. This modification increases the charge density of the stimulating photoelectrodes by a factor of 2-3 and simultaneously decreases the interfacial impedance. The electrophysiological effects of PEDOT:PSS-derivatized OEPCs on Xenopus laevis oocyte cells on membrane potential are measured and voltage-clamp techniques are used, finding an at-least twofold increase in capacitive coupling. The large electrolytic capacitance of PEDOT:PSS allows the OEPC to locally alter the extracellular voltage and keep it constant for long periods of time, effectively enabling a unique type of light-controlled membrane depolarization for measurements of ion channel opening. The finding that PEDOT:PSS-coated OEPCs can remain stable after a 50-day accelerated ageing test demonstrates that PEDOT:PSS modification can be applied for fabricating reliable and efficient optoelectronic stimulation devices.

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  • 22.
    Zsigmond, Peter
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Optical Measurements during Asleep Deep Brain Stimulation Surgery along Vim-Zi Trajectories2020In: Stereotactic and Functional Neurosurgery, ISSN 1011-6125, E-ISSN 1423-0372, Vol. 98, no 1, p. 55-61Article in journal (Refereed)
    Abstract [en]

    Background: Optics can be used for guidance in deep brain stimulation (DBS) surgery. The aim was to use laser Doppler flowmetry (LDF) to investigate the intraoperative optical trajectory along the ventral intermediate nucleus (VIM) and zona incerta (Zi) regions in patients with essential tremor during asleep DBS surgery, and whether the Zi region could be identified. Methods: A forward-looking LDF guide was used for creation of the trajectory for the DBS lead, and the microcirculation and tissue greyness, i.e., total light intensity (TLI) was measured along 13 trajectories. TLI trajectories and the number of high-perfusion spots were investigated at 0.5-mm resolution in the last 25 mm from the targets. Results: All implantations were done without complications and with significant improvement of tremor (p < 0.01). Out of 798 measurements, 12 tissue spots showed high blood flow. The blood flow was significantly higher in VIM than in Zi (p < 0.001). The normalized mean TLI curve showed a significant (p < 0.001) lower TLI in the VIM region than in the Zi region. Conclusion: Zi DBS performed asleep appears to be safe and effective. LDF monitoring provides direct in vivomeasurement of the microvascular blood flow in front of the probe, which can help reduce the risk of hemorrhage. LDF can differentiate between the grey substance in the thalamus and the transmission border entering the posterior subthalamic area where the tissue consists of more white matter tracts.

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