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  • 1.
    Abdullaeva, Oliya
    et al.
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Sahalianov, Ihor
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Silverå Ejneby, Malin
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Jakesova, Marie
    Brno Univ Technol, Czech Republic.
    Zozoulenko, Igor
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Liin, Sara
    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. Brno Univ Technol, Czech Republic.
    Faradaic Pixels for Precise Hydrogen Peroxide Delivery to Control M-Type Voltage-Gated Potassium Channels2022In: Advanced Science, E-ISSN 2198-3844, Vol. 9, no 3, article id 2103132Article in journal (Refereed)
    Abstract [en]

    H2O2 plays a significant role in a range of physiological processes where it performs vital tasks in redox signaling. The sensitivity of many biological pathways to H2O2 opens up a unique direction in the development of bioelectronics devices to control levels of reactive-oxygen species (ROS). Here a microfabricated ROS modulation device that relies on controlled faradaic reactions is presented. A concentric pixel arrangement of a peroxide-evolving cathode surrounded by an anode ring which decomposes the peroxide, resulting in localized peroxide delivery is reported. The conducting polymer (poly(3,4-ethylenedioxythiophene) (PEDOT), is exploited as the cathode. PEDOT selectively catalyzes the oxygen reduction reaction resulting in the production of hydrogen peroxide (H2O2). Using electrochemical and optical assays, combined with modeling, the performance of the devices is benchmarked. The concentric pixels generate tunable gradients of peroxide and oxygen concentrations. The faradaic devices are prototyped by modulating human H2O2-sensitive Kv7.2/7.3 (M-type) channels expressed in a single-cell model (Xenopus laevis oocytes). The Kv7 ion channel family is responsible for regulating neuronal excitability in the heart, brain, and smooth muscles, making it an ideal platform for faradaic ROS stimulation. The results demonstrate the potential of PEDOT to act as an H2O2 delivery system, paving the way to ROS-based organic bioelectronics.

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  • 2.
    Ahl, Magnus
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Inst Postgrad Dent Educ, Sweden.
    Marcusson, Agneta
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit.
    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.
    Magnusson, Anders
    Inst Postgrad Dent Educ, Sweden; Jonkoping Univ, Sweden.
    Cardemil, Carina
    Karolinska Univ Hosp, Sweden; Univ Gothenburg, Sweden.
    Larsson, Pernilla
    Malmo Univ, Sweden; Folktandvarden Ostergotland, Sweden.
    Translation and validation of the English-language instrument Orthognathic Quality of Life Questionair into Swedish2021In: Acta Odontologica Scandinavica, ISSN 0001-6357, E-ISSN 1502-3850, Vol. 79, no 1, p. 19-24Article in journal (Refereed)
    Abstract [en]

    Introduction: In orthognathic surgery, understanding the patients motives for treatment is a key factor for postoperative patient satisfaction and treatment success. In countries/systems where orthognathic surgery is funded by public means, patients are referred mainly due to functional problems, although studies of quality of life related changes after treatment indicate that psychosocial and aesthetic reasons might be equal or more important for the patient. There is no available validated condition specific instruments in the Swedish language for quality of life evaluation of patients with dentofacial deformities. Aims/objectives: Cross cultural translation and adaptation of the English-language instrument Orthognathic Quality of Life Questionnaire (OQLQ) into Swedish. Methods: OQLQ was translated into Swedish. A total of 121 patients in four groups were recruited and the Swedish version of the OQLQ (OQLQ-S) was tested by psychometric methods. Reliability was assessed by internal consistency and test-retest reliability. Validity was evaluated by face, convergent and discriminant validity. Results/findings and conclusions: OQLQ-S is reliable and showed good construct validity and internal consistency and can be used in a Swedish speaking population as a complement to clinical variables to evaluate patients with dentofacial deformity.

  • 3.
    Ahmadpour, Doryaneh
    et al.
    Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala. Chalmers Univ Technol, Sweden.
    Kristoffersson, Anna
    Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Fredrikson, Mats
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences, Forum Östergötland.
    Link, Yumin
    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, Neurologiska kliniken i Linköping.
    Eriksson, Anne
    Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Iacobaeus, Ellen
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Landtblom, Anne-Marie
    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, Neurologiska kliniken i Linköping. Uppsala Univ, Sweden.
    Haghighi, Sara
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping. Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Inventory study of an early pandemic COVID-19 cohort in South-Eastern Sweden, focusing on neurological manifestations2023In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 1, article id e0280376Article in journal (Refereed)
    Abstract [en]

    BackgroundNeurological manifestations in patients with COVID-19 have been reported previously as outcomes of the infection.The purpose of current study was to investigate the occurrence of neurological signs and symptoms in COVID-19 patients, in the county of ostergotland in southeastern Sweden. MethodsThis is a retrospective, observational cohort study. Data were collected between March 2020 and June 2020. Information was extracted from medical records by a trained research assistant and physician and all data were validated by a senior neurologist. ResultsSeventy-four percent of patients developed at least one neurological symptom during the acute phase of the infection. Headache (43%) was the most common neurological symptom, followed by anosmia and/or ageusia (33%), confusion (28%), hallucinations (17%), dizziness (16%), sleep disorders in terms of insomnia and OSAS (Obstructive Sleep Apnea) (9%), myopathy and neuropathy (8%) and numbness and tingling (5%). Patients treated in the ICU had a higher male presentation (73%). Several risk factors in terms of co-morbidities, were identified. Hypertension (54.5%), depression and anxiety (51%), sleep disorders in terms of insomnia and OSAS (30%), cardiovascular morbidity (28%), autoimmune diseases (25%), chronic lung diseases (24%) and diabetes mellitus type 2 (23%) founded as possible risk factors. ConclusionNeurological symptoms were found in the vast majority (74%) of the patients. Accordingly, attention to neurological, mental and sleep disturbances is warranted with involvement of neurological expertise, in order to avoid further complications and long-term neurological effect of COVID-19. Furthermore, risk factors for more severe COVID-19, in terms of possible co-morbidities that identified in this study should get appropriate attention to optimizing treatment strategies in COVID-19 patients.

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  • 4.
    Al-Hawasi, Abbas
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Fagerholm, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Link, Yumin
    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, Neurologiska kliniken i Linköping.
    Longitudinal Optical Coherence Tomography Measurement of Retinal Ganglion Cell and Nerve Fiber Layer to Assess Benign Course in Multiple Sclerosis2023In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 12, no 6, article id 2240Article in journal (Refereed)
    Abstract [en]

    A benign form of multiple sclerosis (BMS) is not easily diagnosed, but changes of the retinal ganglion cell layer-inner plexiform layer (GCL-IPL) and retinal nerve fiber layer (RNFL) may be sensitive to the disease. The aim of this study was to use optical coherence tomography (OCT) to investigate longitudinal changes of GCL-IPL and RNFL in BMS. Eighteen patients with BMS and 22 healthy control (HC) subjects were included, with a mean follow-up period of 32.1 months in BMS and 34.3 months in HC. Mean disease duration in BMS was 23.3 years, with 14 patients left untreated. Unilateral optic neuritis (ON) was found in eight patients. Non-ON eyes showed thinner GCL-IPL layer in the BMS group relative to HC (p < 0.001). The thinning rate of GCL-IPL in non-ON BMS, however, was -0.19 +/- 0.15 mu m/year vs. 0 +/- 0.11 mu m/year for HC (p = 0.573, age-adjusted). Thinning rate of RNFL in non-ON BMS was -0.2 +/- 0.27 mu m/year vs. -0.05 +/- 0.3 mu m/year for HC (p = 0.454, age adjusted). Conclusions: Thinning rate of the GCL-IPL and RNFL in BMS is similar to the healthy population but differs from the thinning rate in relapsing-remitting MS, presenting a non-invasive OCT-based criterion for assessing a benign course in multiple sclerosis.

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  • 5.
    Ali, Tahir
    et al.
    Univ Calgary, Canada.
    Klein, Antonia N.
    Univ Calgary, Canada.
    McDonald, Keegan
    Univ Calgary, Canada.
    Johansson, Lovisa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Mukherjee, Priyanka Ganguli
    Univ Calgary, Canada.
    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.
    Doh-ura, Katsumi
    Tohoku Univ, Japan.
    Schatzl, Hermann M.
    Univ Calgary, Canada.
    Gilch, Sabine
    Univ Calgary, Canada.
    Cellulose ether treatment inhibits amyloid beta aggregation, neuroinflammation and cognitive deficits in transgenic mouse model of Alzheimers disease2023In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 20, no 1, article id 177Article in journal (Refereed)
    Abstract [en]

    Alzheimers disease (AD) is an incurable, progressive and devastating neurodegenerative disease. Pathogenesis of AD is associated with the aggregation and accumulation of amyloid beta (A & beta;), a major neurotoxic mediator that triggers neuroinflammation and memory impairment. Recently, we found that cellulose ether compounds (CEs) have beneficial effects against prion diseases by inhibiting protein misfolding and replication of prions, which share their replication mechanism with A & beta;. CEs are FDA-approved safe additives in foods and pharmaceuticals. Herein, for the first time we determined the therapeutic effects of the representative CE (TC-5RW) in AD using in vitro and in vivo models. Our in vitro studies showed that TC-5RW inhibits A & beta; aggregation, as well as neurotoxicity and immunoreactivity in A & beta;-exposed human and murine neuroblastoma cells. In in vivo studies, for the first time we observed that single and weekly TC-5RW administration, respectively, improved memory functions of transgenic 5XFAD mouse model of AD. We further demonstrate that TC-5RW treatment of 5XFAD mice significantly inhibited A & beta; oligomer and plaque burden and its associated neuroinflammation via regulating astrogliosis, microgliosis and proinflammatory mediator glial maturation factor beta (GMF & beta;). Additionally, we determined that TC-5RW reduced lipopolysaccharide-induced activated gliosis and GMF & beta; in vitro. In conclusion, our results demonstrate that CEs have therapeutic effects against A & beta; pathologies and cognitive impairments, and direct, potent anti-inflammatory activity to rescue neuroinflammation. Therefore, these FDA-approved compounds are effective candidates for developing therapeutics for AD and related neurodegenerative diseases associated with protein misfolding.

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  • 6.
    Almeida, Joana R.
    et al.
    Univ Porto, Portugal.
    Palmeira, Andreia
    Univ Porto, Portugal.
    Campos, Alexandre
    Univ Porto, Portugal.
    Cunha, Isabel
    Univ Porto, Portugal.
    Freitas, Micaela
    Univ Porto, Portugal; Univ Geneva, Switzerland.
    Felpeto, Aldo Barreiro
    Univ Porto, Portugal.
    Turkina, Maria V
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Vasconcelos, Vitor
    Univ Porto, Portugal.
    Pinto, Madalena
    Univ Porto, Portugal.
    Correia-da-Silva, Marta
    Univ Porto, Portugal.
    Sousa, Emilia
    Univ Porto, Portugal.
    Structure-Antifouling Activity Relationship and Molecular Targets of Bio-Inspired(thio)xanthones2020In: Biomolecules, E-ISSN 2218-273X, Vol. 10, no 8, article id 1126Article in journal (Refereed)
    Abstract [en]

    The development of alternative ecological and effective antifouling technologies is still challenging. Synthesis of nature-inspired compounds has been exploited, given the potential to assure commercial supplies of potential ecofriendly antifouling agents. In this direction, the antifouling activity of a series of nineteen synthetic small molecules, with chemical similarities with natural products, were exploited in this work. Six (4,5,7,10,15and17) of the tested xanthones showed in vivo activity toward the settlement ofMytilus galloprovincialislarvae (EC50: 3.53-28.60 mu M) and low toxicity to this macrofouling species (LC50> 500 mu M and LC50/EC50: 17.42-141.64), and two of them (7and10) showed no general marine ecotoxicity (Artemia salinamortality) after 48 h of exposure. Regarding the mechanism of action in mussel larvae, the best performance compounds4and5might be acting by the inhibition of acetylcholinesterase activity (in vitro and in silico studies), while7and10showed specific targets (proteomic studies) directly related with the mussel adhesive structure (byssal threads), given by the alterations in the expression ofMytiluscollagen proteins (PreCols) and proximal thread proteins (TMPs). A quantitative structure-activity relationship (QSAR) model was built with predictive capacity to enable speeding the design of new potential active compounds.

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  • 7.
    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, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i 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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  • 8.
    Ambati, Aditya
    et al.
    Stanford Univ, CA 94304 USA.
    Hillary, Ryan
    Stanford Univ, CA 94304 USA.
    Leu-Semenescu, Smaranda
    Sorbonne Univ, France.
    Ollila, Hanna M.
    Stanford Univ, CA 94304 USA.
    Lin, Ling
    Stanford Univ, CA 94304 USA.
    During, Emmanuel H.
    Stanford Univ, CA 94305 USA; Stanford Univ, CA 94305 USA.
    Farber, Neal
    Kleine Levin Syndrome Fdn, MA 02468 USA.
    Rico, Thomas J.
    Stanford Univ, CA 94304 USA.
    Faraco, Juliette
    Stanford Univ, CA 94304 USA.
    Leary, Eileen
    Stanford Univ, CA 94304 USA.
    Goldstein-Piekarski, Andrea N.
    Stanford Univ, CA 94305 USA; Vet Affairs Palo Alto Hlth Care Syst, CA 94304 USA.
    Huang, Yu-Shu
    Chang Gung Mem Hosp & Univ, Taiwan; Chang Gung Mem Hosp & Univ, Taiwan.
    Han, Fang
    Peking Univ Peoples Hosp, Peoples R China.
    Sivan, Yakov
    Tel Aviv Univ, Israel.
    Lecendreux, Michel
    Hosp Robert Debre, France; Hosp Robert Debre, France.
    Dodet, Pauline
    Sorbonne Univ, France.
    Honda, Makoto
    Tokyo Metropolitan Inst Med Sci, Japan.
    Gadoth, Natan
    Maynei Hayeshua Med Ctr, Israel; Tel Aviv Univ, Israel.
    Nevsimalova, Sona
    Charles Univ Prague, Czech Republic.
    Pizza, Fabio
    Univ Bologna, Italy; IRCCS, Italy.
    Kanbayashi, Takashi
    Univ Tsukuba, Japan.
    Peraita-Adrados, Rosa
    Univ Complutense Madrid, Spain; Univ Complutense Madrid, Spain.
    Leschziner, Guy D.
    Guys Hosp, England; Kings Coll London, England.
    Hasan, Rosa
    Univ Sao Paulo, Brazil.
    Canellas, Francesca
    Hosp Univ Son Espases, Spain.
    Kume, Kazuhiko
    Nagoya City Univ, Japan.
    Daniilidou, Makrina
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Uppsala Univ, Sweden.
    Bourgin, Patrice
    Hop Univ Strasbourg, France.
    Rye, David
    Emory Univ, GA 30322 USA.
    Vicario, Jose L.
    Blood Ctr Community Madrid, Spain.
    Hogl, Birgit
    Innsbruck Med Univ, Austria.
    Hong, Seung Chul
    Catholic Univ Korea, South Korea.
    Plazzi, Guiseppe
    Univ Bologna, Italy; IRCCS, Italy.
    Mayer, Geert
    Philipps Univ Marburg, Germany.
    Landtblom, Anne-Marie
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping. Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Uppsala Univ, Sweden.
    Dauvilliers, Yves
    Univ Montpellier, France; Univ Montpellier, France.
    Arnulf, Isabelle
    Sorbonne Univ, France.
    Mignot, Emmanuel Jean-Marie
    Stanford Univ, CA 94304 USA.
    Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci2021In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 12, article id e2005753118Article in journal (Refereed)
    Abstract [en]

    Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 x 10(-9)) within the 3region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R-2 = 0.15; P < 2.0 x 10(-22) at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

  • 9.
    Amendoeira, Isabel
    et al.
    Ctr Hosp Univ S Joao CHUSJ, Portugal; Ipatimup, Portugal.
    Arcidiacono, Paolo Giorgio
    IRCCS Osped San Raffaele Milano, Italy.
    Barizzi, Jessica
    Ist Cantonale Patol, Switzerland.
    Capitanio, Arrigo
    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.
    Cuatrecasas, Miriam
    Univ Barcelona, Spain.
    Matteo, Francesco Maria Di
    Fdn Policlin Univ Campus Biomed, Italy.
    Doglioni, Claudio
    Ist Sci San Raffaele, Italy.
    Fukushima, Noriyoshi
    Jichi Med Univ, Japan.
    Fulciniti, Franco
    Ist Cantonale Patol, Switzerland.
    Gines, Angels
    Hosp Clin Barcelona, Spain.
    Giovannini, Marc
    Paoli Calmettes Inst, France.
    Zaibo, Li
    Ohio State Univ, OH 43210 USA.
    Lopes, Joanne
    Ctr Hosp Univ S Joao CHUSJ, Portugal; Ipatimup, Portugal.
    Lujan, Giovanni
    Ohio State Univ, OH 43210 USA.
    Parisi, Alice
    Azienda Osped Univ Integrata Verona, Italy.
    Poizat, Flora
    Inst Paoli Calmettes, France.
    Bonetti, Luca Reggiani
    Univ Modena & Reggio Emilia, Italy.
    Stigliano, Serena
    Fdn Policlin Univ Campus Biomed, Italy.
    Taffon, Chiara
    Fdn Policlin Univ Campus Biomed, Italy.
    Verri, Martina
    Fdn Policlin Univ Campus Biomed, Italy.
    Crescenzi, Anna
    Fdn Policlin Univ Campus Biomed, Italy.
    New digital confocal laser microscopy may boost real-time evaluation of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) from solid pancreatic lesions: Data from an international multicenter study2022In: EBioMedicine, E-ISSN 2352-3964, Vol. 86, article id 104377Article in journal (Refereed)
    Abstract [en]

    Background Pancreatic cancer is an aggressive malignancy and a leading cause of cancer death worldwide; its lethality is partly linked to the difficulty of early diagnosis. Modern devices for endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) were recently developed to improve targeting and sampling of small lesions, but innovative technologies for microscopic assessment are still lacking. Ex vivo fluorescence confocal laser microscopy (FCM) is a new digital tool for real-time microscopic assessment of fresh unfixed biological specimens, avoiding conventional histological slide preparation and potentially being highly appealing for EUS-FNB specimens. Methods This study evaluated the possible role of FCM for immediate evaluation of pancreatic specimens from EUS-FNB. It involved comparison of the interobserver agreement between the new method and standard histological analysis during international multicenter sharing of digital images. Digital images from 25 cases of EUS-FNB obtained with real-time FCM technology and 25 paired digital whole-slide images from permanent conventional paraffin sections were observed by 10 pathologists from different Institutions in Europe, Japan, and the United States, in a blinded manner. The study evaluated 500 observations regarding adequacy, morphological clues, diagnostic categories, and final diagnosis. Findings Statistical analysis showed substantial equivalence in the interobserver agreement among pathologists using the two techniques. There was also good inter-test agreement in determining sample adequacy and when assigning a diagnostic category. Among morphological features, nuclear enlargement was the most reproducible clue, with very good inter-test agreement. Interpretation Findings in this study are from international multicenter digital sharing and are published here for the first time. Considering the advantages of FCM digital diagnostics in terms of reduced time and unaltered sample maintenance, the ex vivo confocal laser microscopy may effectively improve traditional EUS-FNB diagnostics, with significant implications for planning modern diagnostic workflow for pancreatic tumors. Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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  • 10.
    Ammendola, Serena
    et al.
    Univ Verona, Italy.
    Bariani, Elena
    Univ Verona, Italy.
    Eccher, Albino
    Univ & Hosp Trust Verona, Italy.
    Capitanio, Arrigo
    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.
    Ghimenton, Claudio
    Univ & Hosp Trust Verona, Italy.
    Pantanowitz, Liron
    Univ Michigan, MI 48109 USA.
    Parwani, Anil
    Ohio State Univ, OH 43210 USA.
    Girolami, Ilaria
    Cent Hosp Bolzano, Italy.
    Scarpa, Aldo
    Univ Verona, Italy; Univ & Hosp Trust Verona, Italy.
    Barresi, Valeria
    Univ Verona, Italy; Polyclin GB Rossi, Italy.
    The histopathological diagnosis of atypical meningioma: glass slide versus whole slide imaging for grading assessment2021In: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 478, p. 747-756Article in journal (Refereed)
    Abstract [en]

    Limited studies on whole slide imaging (WSI) in surgical neuropathology reported a perceived limitation in the recognition of mitoses. This study analyzed and compared the inter- and intra-observer concordance for atypical meningioma, using glass slides and WSI. Two neuropathologists and two residents assessed the histopathological features of 35 meningiomas-originally diagnosed as atypical-in a representative glass slide and corresponding WSI. For each histological parameter and final diagnosis, we calculated the inter- and intra-observer concordance in the two viewing modes and the predictive accuracy on recurrence. The concordance rates for atypical meningioma on glass slides and on WSI were 54% and 60% among four observers and 63% and 74% between two neuropathologists. The inter-observer agreement was higher using WSI than with glass slides for all parameters, with the exception of high mitotic index. For all histological features, we found median intra-observer concordance of >= 79% and similar predictive accuracy for recurrence between the two viewing modes. The higher concordance for atypical meningioma using WSI than with glass slides and the similar predictive accuracy for recurrence in the two modalities suggest that atypical meningioma may be safely diagnosed using WSI.

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  • 11.
    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 1469-8749, Vol. 62, no 7, p. 793-798Article 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.

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  • 12.
    Andren, Kerstin
    et al.
    Univ Gothenburg, Sweden.
    Wikkelso, Carsten
    Univ Gothenburg, Sweden.
    Laurell, Katarina
    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, Neurologiska kliniken i Linköping.
    Kollen, Lena
    Univ Gothenburg, Sweden.
    Hellstrom, Per
    Univ Gothenburg, Sweden.
    Tullberg, Mats
    Univ Gothenburg, Sweden.
    Symptoms and signs did not predict outcome after surgery: a prospective study of 143 patients with idiopathic normal pressure hydrocephalus2024In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459Article in journal (Refereed)
    Abstract [en]

    ObjectiveTo determine the utility of symptoms, signs, comorbidities and background variables for the prediction of outcome of treatment in iNPH. MethodsA prospective observational study of consecutively included iNPH patients, who underwent neurological, physiotherapeutic and neuropsychological assessments before and after shunt surgery. The primary outcome measure was the total change on the iNPH scale, and patients were defined as improved postoperatively if they had improved by at least five points on that scale. Results143 iNPH patients were included, and 73% of those were improved after surgery. None of the examined symptoms or signs could predict which patients would improve after shunt surgery. A dominant subjective complaint of memory problems at baseline was predictive of non-improvement. The reported comorbidities, duration of symptoms and BMI were the same in improved and non-improved patients. Each of the symptom domains (gait, neuropsychology, balance, and continence) as well as the total iNPH scale score improved significantly (from median 53 to 69, p < 0.001). The proportions of patients with shuffling gait, broad-based gait, paratonic rigidity and retropulsion all decreased significantly. DiscussionThis study confirms that the recorded clinical signs, symptoms, and impairments in the adopted clinical tests are characteristic findings in iNPH, based on that most of them improved after shunt surgery. However, our clinical data did not enable predictions of whether patients would respond to shunt surgery, indicating that the phenotype is unrelated to the reversibility of the iNPH state and should mainly support diagnosis. Absence of specific signs should not be used to exclude patients from treatment.

  • 13.
    Angelini, Marina
    et al.
    Univ Calif Los Angeles, CA 90095 USA.
    Pezhouman, Arash
    Univ Calif Los Angeles, CA 90095 USA.
    Savalli, Nicoletta
    Univ Calif Los Angeles, CA 90095 USA.
    Chang, Marvin G.
    Harvard Med Sch, MA 02115 USA.
    Steccanella, Federica
    Univ Calif Los Angeles, CA 90095 USA.
    Scranton, Kyle
    Univ Calif Los Angeles, CA 90095 USA.
    Calmettes, Guillaume
    Univ Calif Los Angeles, CA 90095 USA.
    Ottolia, Michela
    Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA.
    Pantazis, Antonios
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Karagueuzian, Hrayr S.
    Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA.
    Weiss, James N.
    Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA.
    Olcese, Riccardo
    Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA.
    Suppression of ventricular arrhythmias by targeting late L-type Ca2+ current2021In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 153, no 12, article id e202012584Article in journal (Refereed)
    Abstract [en]

    Ventricular arrhythmias, a leading cause of sudden cardiac death, can be triggered by cardiomyocyte early afterdepolarizations (EADs). EADs can result from an abnormal late activation of L-type Ca2+ channels (LTCCs). Current LTCC blockers (class IV antiarrhythmics), while effective at suppressing EADs, block both early and late components of I-Ca,I-L, compromising inotropy. However, computational studies have recently demonstrated that selective reduction of late I-Ca,I-L (Ca2+ influx during late phases of the action potential) is sufficient to potently suppress EADs, suggesting that effective antiarrhythmic action can be achieved without blocking the early peak I-Ca,I-L, which is essential for proper excitation-contraction coupling. We tested this new strategy using a purine analogue, roscovitine, which reduces late I-Ca,I-L with minimal effect on peak current. Scaling our investigation from a human Ca(V)1.2 channel clone to rabbit ventricular myocytes and rat and rabbit perfused hearts, we demonstrate that (1) roscovitine selectively reduces I-Ca,I-L noninactivating component in a human Ca(V)1.2 channel clone and in ventricular myocytes native current, (2) the pharmacological reduction of late I-Ca,I-L suppresses EADs and EATs (early after Ca2+ transients) induced by oxidative stress and hypokalemia in isolated myocytes, largely preserving cell shortening and normal Ca2+ transient, and (3) late I-Ca,I-L reduction prevents/suppresses ventricular tachycardia/fibrillation in ex vivo rabbit and rat hearts subjected to hypokalemia and/or oxidative stress. These results support the value of an antiarrhythmic strategy based on the selective reduction of late I-Ca,I-L to suppress EAD-mediated arrhythmias. Antiarrhythmic therapies based on this idea would modify the gating properties of Ca(V)1.2 channels rather than blocking their pore, largely preserving contractility.

  • 14.
    Araujo, Mario Jorge
    et al.
    Univ Porto, Portugal.
    Sousa, Maria Ligia
    Univ Porto, Portugal.
    Felpeto, Aldo Barreiro
    Univ Porto, Portugal.
    Turkina, Maria V
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Fonseca, Elza
    Univ Porto, Portugal.
    Martins, Jose Carlos
    Univ Porto, Portugal.
    Vasconcelos, Vitor
    Univ Porto, Portugal; Univ Porto, Portugal.
    Campos, Alexandre
    Univ Porto, Portugal.
    Comparison of Sample Preparation Methods for Shotgun Proteomic Studies in Aquaculture Species2021In: Proteomes, ISSN 2227-7382, Vol. 9, no 4, article id 46Article in journal (Refereed)
    Abstract [en]

    Proteomics has been recently introduced in aquaculture research, and more methodological studies are needed to improve the quality of proteomics studies. Therefore, this work aims to compare three sample preparation methods for shotgun LC-MS/MS proteomics using tissues of two aquaculture species: liver of turbot Scophthalmus maximus and hepatopancreas of Mediterranean mussel Mytilus galloprovincialis. We compared the three most common sample preparation workflows for shotgun analysis: filter-aided sample preparation (FASP), suspension-trapping (S-Trap), and solid-phase-enhanced sample preparations (SP3). FASP showed the highest number of protein identifications for turbot samples, and S-Trap outperformed other methods for mussel samples. Subsequent functional analysis revealed a large number of Gene Ontology (GO) terms in turbot liver proteins (nearly 300 GO terms), while fewer GOs were found in mussel proteins (nearly 150 GO terms for FASP and S-Trap and 107 for SP3). This result may reflect the poor annotation of the genomic information in this specific group of animals. FASP was confirmed as the most consistent method for shotgun proteomic studies; however, the use of the other two methods might be important in specific experimental conditions (e.g., when samples have a very low amount of protein).

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  • 15.
    Arifin, Maria I.
    et al.
    Univ Calgary, Canada; Univ Calgary, Canada.
    Kaczmarczyk, Lech
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Zeng, Doris
    Univ Calgary, Canada; Univ Calgary, Canada.
    Hannaoui, Samia
    Univ Calgary, Canada; Univ Calgary, Canada.
    Lee, Chi
    Univ Calgary, Canada; Univ Calgary, Canada.
    Chang, Sheng Chun
    Univ Calgary, Canada; Univ Calgary, Canada.
    Mitchell, Gordon
    Canadian Food Inspection Agcy, Canada.
    McKenzie, Debbie
    Univ Alberta, Canada.
    Beekes, Michael
    Robert Koch Inst, Germany.
    Jackson, Walker
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Gilch, Sabine
    Univ Calgary, Canada; Univ Calgary, Canada.
    Heterozygosity for cervid S138N polymorphism results in subclinical CWD in gene-targeted mice and progressive inhibition of prion conversion2023In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, no 15, article id e2221060120Article in journal (Refereed)
    Abstract [en]

    Prions are proteinaceous infectious particles that replicate by structural conversion of the host-encoded cellular prion protein (PrPC), causing fatal neurodegenerative diseases in mammals. Species-specific amino acid substitutions (AAS) arising from single nucleotide polymorphisms within the prion protein gene (Prnp) modulate prion disease patho-genesis, and, in several instances, reduce susceptibility of homo-or heterozygous AAS carriers to prion infection. However, a mechanistic understanding of their protective effects against clinical disease is missing. We generated gene-targeted mouse infection models of chronic wasting disease (CWD), a highly contagious prion disease of cervids. These mice express wild-type deer or PrPC harboring the S138N substitution homo-or heterozygously, a polymorphism found exclusively in reindeer (Rangifer tarandus spp.) and fallow deer (Dama dama). The wild-type deer PrP-expressing model recapitulated CWD pathogenesis including fecal shedding. Encoding at least one 138N allele pre-vented clinical CWD, accumulation of protease-resistant PrP (PrPres) and abnormal PrP deposits in the brain tissue. However, prion seeding activity was detected in spleens, brains, and feces of these mice, suggesting subclinical infection accompanied by prion shedding. 138N-PrPC was less efficiently converted to PrPres in vitro than wild-type deer (138SS) PrPC. Heterozygous coexpression of wild-type deer and 138N-PrPC resulted in dominant-negative inhibition and progressively diminished prion conversion over serial rounds of protein misfolding cyclic amplification. Our study indicates that heterozy-gosity at a polymorphic Prnp codon can confer the highest protection against clinical CWD and highlights the potential role of subclinical carriers in CWD transmission.

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  • 16.
    Arnfred, Benjamin
    et al.
    Copenhagen Univ Hosp, Denmark.
    Bang, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Copenhagen Univ Hosp, Denmark.
    Hjorthoj, Carsten
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Christensen, Clas Winding
    Copenhagen Univ Hosp, Denmark.
    Moeller, Kirsten Stengaard
    Copenhagen Univ Hosp, Denmark.
    Hvenegaard, Morten
    Copenhagen Univ Hosp, Denmark.
    Agerskov, Lone
    Copenhagen Univ Hosp, Denmark.
    Gausboel, Ulrik Krog
    Copenhagen Univ Hosp, Denmark.
    Soe, Ditte
    Copenhagen Univ Hosp, Denmark.
    Wiborg, Peter
    Copenhagen Univ Hosp, Denmark.
    Smith, Christopher Ian Scholer
    Copenhagen Univ Hosp, Denmark.
    Rosenberg, Nicole
    Copenhagen Univ Hosp, Denmark.
    Nordentoft, Merete
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Group cognitive behavioural therapy with virtual reality exposure versus group cognitive behavioural therapy with in vivo exposure for social anxiety disorder and agoraphobia: a protocol for a randomised clinical trial2022In: BMJ Open, E-ISSN 2044-6055, Vol. 12, no 2, article id e051147Article in journal (Refereed)
    Abstract [en]

    Introduction Anxiety disorders have a high lifetime prevalence, early-onset and long duration or chronicity. Exposure therapy is considered one of the most effective elements in cognitive behavioural therapy (CBT) for anxiety, but in vivo exposure can be challenging to access and control, and is sometimes rejected by patients because they consider it too aversive. Virtual reality allows flexible and controlled exposure to challenging situations in an immersive and protected environment. Aim The SoREAL-trial aims to investigate the effect of group cognitive behavioural therapy (CBT-in vivo) versus group CBT with virtual reality exposure (CBT-in virtuo) for patients diagnosed with social anxiety disorder and/or agoraphobia, in mixed groups. Methods and analysis The design is an investigator-initiated randomised, assessor-blinded, parallel-group and superiority-designed clinical trial. Three hundred two patients diagnosed with social anxiety disorder and/or agoraphobia will be included from the regional mental health centres of Copenhagen and North Sealand and the Northern Region of Denmark. All patients will be offered a manual-based 14-week cognitive behavioural group treatment programme, including eight sessions with exposure therapy. Therapy groups will be centrally randomised with concealed allocation sequence to either CBT-in virtuo or CBT-in vivo. Patients will be assessed at baseline, post-treatment and 1-year follow-up by treatment blinded researchers and research assistants. The primary outcome will be diagnosis-specific symptoms measured with the Liebowitz Social Anxiety Scale for patients with social anxiety disorder and the Mobility Inventory for Agoraphobia for patients with agoraphobia. Secondary outcome measures will include depression symptoms, social functioning and patient satisfaction. Exploratory outcomes will be substance and alcohol use, working alliance and quality of life. Ethics and dissemination The trial has been approved by the research ethics committee in the Capital Region of Denmark. All results, positive, negative as well as inconclusive, will be published as quickly as possible and still in concordance with Danish law on the protection of confidentially and personal information. Results will be presented at national and international scientific conferences. The trial has obtained approval by the Regional Ethics Committee of Zealand (H-6-2013-015) and the Danish Data Protection Agency (RHP-2014-009-02670). The trial is registered at ClinicalTrial.gov as NCT03845101. The patients will receive information on the trial both verbally and in written form. Written informed consent will be obtained from each patient before inclusion in the trial. The consent form will be scanned and stored in the database system and the physical copy will be destroyed. It is emphasised that participation in the trial is voluntary and that the patient can withdraw his or her consent at any time without consequences for further and continued treatment.

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  • 17.
    Arvidsson, Ida
    et al.
    Lund Univ, Sweden.
    Overgaard, Niels Christian
    Lund Univ, Sweden.
    Astrom, Kalle
    Lund Univ, Sweden.
    Heyden, Anders
    Lund Univ, Sweden.
    Figueroa, Miguel Ochoa
    Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Frias Rose, Miguel Jeronimo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Davidsson, Anette
    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, Heart Center, Department of Clinical Physiology in Linköping.
    Prediction of Obstructive Coronary Artery Disease from Myocardial Perfusion Scintigraphy using Deep Neural Networks2021In: 2020 25TH INTERNATIONAL CONFERENCE ON PATTERN RECOGNITION (ICPR), IEEE COMPUTER SOC , 2021, p. 4442-4449Conference paper (Refereed)
    Abstract [en]

    For diagnosis and risk assessment in patients with stable ischemic heart disease, myocardial perfusion scintigraphy is one of the most common cardiological examinations performed today. There are however many motivations for why an artificial intelligence algorithm would provide useful input to this task. For example to reduce the subjectiveness and save time for the nuclear medicine physicians working with this time consuming task. In this work we have developed a deep learning algorithm for multi-label classification based on a convolutional neural network to estimate the probability of obstructive coronary artery disease in the left anterior artery, left circumflex artery and right coronary artery. The prediction is based on data from myocardial perfusion scintigraphy studies conducted in a dedicated Cadmium-Zinc-Telluride cardio camera (D-SPECT Spectrum Dynamics). Data from 588 patients was available, with stress images in both upright and supine position, as well as a number of auxiliary parameters such as angina symptoms and age. The data was used to train and evaluate the algorithm using 5-fold cross-validation. We achieve state-of-the-art results for this task with an area under the receiver operating characteristics curve of 0.89 as average on per-vessel level and 0.95 on per-patient level.

  • 18.
    Arvidsson, Ida
    et al.
    Lund Univ, Sweden.
    Overgaard, Niels Christian
    Lund Univ, Sweden.
    Davidsson, Anette
    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, Heart Center, Department of Clinical Physiology in Linköping.
    Frias Rose, Miguel Jeronimo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Astrom, Kalle
    Lund Univ, Sweden.
    Figueroa, Miguel Ochoa
    Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping. Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Heyden, Anders
    Lund Univ, Sweden.
    Detection of left bundle branch block and obstructive coronary artery disease from myocardial perfusion scintigraphy using deep neural networks2021In: MEDICAL IMAGING 2021: COMPUTER-AIDED DIAGNOSIS, SPIE-INT SOC OPTICAL ENGINEERING , 2021, Vol. 11597, article id 115970NConference paper (Refereed)
    Abstract [en]

    Myocardial perfusion scintigraphy, which is a non-invasive imaging technique, is one of the most common cardiological examinations performed today, and is used for diagnosis of coronary artery disease. Currently the analysis is performed visually by physicians, but this is both a very time consuming and a subjective approach. These are two of the motivations for why an automatic tool to support the decisions would be useful. We have developed a deep neural network which predicts the occurrence of obstructive coronary artery disease in each of the three major arteries as well as left bundle branch block. Since multiple, or none, of these could have a defect, this is treated as a multi-label classification problem. Due to the highly imbalanced labels, the training loss is weighted accordingly. The prediction is based on two polar maps, captured during stress in upright and supine position, together with additional information such as BMI and angina symptoms. The polar maps are constructed from myocardial perfusion scintigraphy examinations conducted in a dedicated Cadmium-Zinc-Telluride cardio camera (D-SPECT Spectrum Dynamics). The study includes data from 759 patients. Using 5-fold cross-validation we achieve an area under the receiver operating characteristics curve of 0.89 as average on per-vessel level for the three major arteries, 0.94 on per-patient level and 0.82 for left bundle branch block.

  • 19.
    Azevedo, Carla
    et al.
    Lund Univ, Sweden.
    Teku, Gabriel
    Lund Univ, Sweden.
    Pomeshchik, Yuriy
    Lund Univ, Sweden.
    Reyes, Juan F.
    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.
    Chumarina, Margarita
    Lund Univ, Sweden.
    Russ, Kaspar
    H Lundbeck & Co AS, Denmark; Lund Univ, Sweden.
    Savchenko, Ekaterina
    Lund Univ, Sweden.
    Hammarberg, Anna
    Lund Univ, Sweden.
    Lamas, Nuno Jorge
    Univ Minho, Portugal; PT Govt Associate Lab, Portugal; Ctr Hosp & Univ Porto, Portugal.
    Collin, Anna
    Reg Skane Off Med Serv, Sweden.
    Gouras, Gunnar K.
    Lund Univ, Sweden.
    Klementieva, Oxana
    Lund Univ, Sweden.
    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.
    Taipa, Ricardo
    Ctr Hosp Univ Porto, Portugal.
    Vihinen, Mauno
    Lund Univ, Sweden.
    Roybon, Laurent
    Lund Univ, Sweden.
    Parkinsons disease and multiple system atrophy patient iPSC-derived oligodendrocytes exhibit alpha-synuclein-induced changes in maturation and immune reactive properties2022In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, no 12, article id e2111405119Article in journal (Refereed)
    Abstract [en]

    Limited evidence has shed light on how aSYN proteins affect the oligodendrocyte phenotype and pathogenesis in synucleinopathies that include Parkinsons disease (PD) and multiple system atrophy (MSA). Here, we investigated early transcriptomic changes within PD and MSA O4(+) oligodendrocyte lineage cells (OLCs) generated from patient-induced pluripotent stem cells (iPSCs). We found impaired maturation of PD and MSA O4(+) OLCs compared to controls. This phenotype was associated with changes in the human leukocyte antigen (HLA) genes, the immunoproteasome subunit PSMB9, and the complement component C4b for aSYN p.A53T and MSA O4(+) OLCs, but not in SNCA(trip) O4(+) OLCs despite high levels of aSYN assembly formation. Moreover, SNCA overexpression resulted in the development of O4(+) OLCs, whereas exogenous treatment with aSYN species led to significant toxicity. Notably, transcriptome profiling of genes encoding proteins forming Lewy bodies and glial cytoplasmic inclusions revealed clustering of PD aSYN p.A53T O4(+) OLCs with MSA O4(+) OLCs. Our work identifies early phenotypic and pathogenic changes within human PD and MSA O4(+) OLCs.

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  • 20.
    Balata, Dilan
    et al.
    Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Mellergård, Johan
    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, Neurologiska kliniken i Linköping.
    Ekqvist, David
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Infectious Diseases.
    Baranowski, Jacek
    Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping.
    Garcia, Isidro Albert
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Volosyraki, Marina
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Broqvist, Mats
    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, Heart Center, Department of Cardiology in Linköping.
    Non-Bacterial Thrombotic Endocarditis: A Presentation of COVID-192020In: European journal of case reports in internal medicine, ISSN 2284-2594, Vol. 7, no 8Article in journal (Refereed)
    Abstract [en]

    The SARS-CoV-2 virus is a newly emergent pathogen first identified in Wuhan, China, and responsible for the COVID-19 global pandemic. In this case report we describe a manifestation of non-bacterial thrombotic endocarditis with continuous peripheral embolization in a COVID-19-positive patient. The patient responded well to high-dose LMWH treatment with cessation of the embolic process.

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  • 21.
    Bang, Peter
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Igelström, Kajsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience.
    Modality-specific associations between sensory differences and autistic traits2023In: Autism, ISSN 1362-3613, E-ISSN 1461-7005, Vol. 27, no 7, p. 2158-2172Article in journal (Refereed)
    Abstract [en]

    Sensory processing differences measured by self- or parent-report co-segregate with quantitative autistic traits and have potential endophenotypic properties. It is not known to what extent this reflects generalized sensory dysfunction versus more specific associations involving individual senses or autistic trait domains. We combined Bayesian variable selection with dominance analysis to obtain a more nuanced understanding of modality-specific associations. We recruited two independent samples of adults to complete the Broad Autism Phenotype Questionnaire and the Glasgow Sensory Questionnaire. For each domain of autistic traits (social interaction, communication, cognitive rigidity), we performed stochastic search variable selection using Glasgow Sensory Questionnaire modality subscales as predictors while controlling for uncertainty in other variables. Dominance analysis was applied to the reduced models to evaluate the relative importance of predictors. Only auditory scores reliably predicted all three autistic traits when other modalities were accounted for. The proprioceptive scale, which included motor and interoceptive deficits, predicted communicative autistic traits more than other trait domains. The tactile scale appeared most specific for social autistic traits. Although the findings must be interpreted in light of the limitations of the questionnaires, the study suggests that auditory differences may be more likely than differences in other senses to be a robust sensory endophenotype relevant to autism. Lay abstract Sensory symptoms are a major source of distress for many autistic people, causing anxiety, stress, and avoidance. Sensory problems are thought to be passed on genetically together with other autistic characteristics, such as social preferences. This means that people who report cognitive rigidity and autistic-like social function are more likely to suffer from sensory issues. We do not know what role the individual senses, such as vision, hearing, smell, or touch, play in this relationship, because sensory processing is generally measured with questionnaires that target general, multisensory issues. This study aimed to investigate the individual importance of the different senses (vision, hearing, touch, smell, taste, balance, and proprioception) in the correlation with autistic traits. To ensure the results were replicable, we repeated the experiment in two large groups of adults. The first group contained 40% autistic participants, whereas the second group resembled the general population. We found that problems with auditory processing were more strongly predictive of general autistic characteristics than were problems with the other senses. Problems with touch were specifically related to differences in social interaction, such as avoiding social settings. We also found a specific relationship between proprioceptive differences and autistic-like communication preferences. The sensory questionnaire had limited reliability, so our results may underestimate the contribution of some senses. With that reservation in mind, we conclude that auditory differences are dominant over other modalities in predicting genetically based autistic traits and may therefore be of special interest for further genetic and neurobiological studies.

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  • 22.
    Bang, Peter
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Igelström, Kajsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Modality-specific associations of sensory deficits with autistic traitsManuscript (preprint) (Other academic)
    Abstract [en]

    Background

    Atypical sensory processing measured by self- or parent-report co-segregates with quantitative autistic traits (QAT) and has potential endophenotypic properties relevant to the mechanisms of autism. However, it is not known whether this association reflects a generalized sensory dysfunction or combinations of modality-specific mechanisms. Collinearity between QAT and modality-specific sensory scales limits the use of multiple regression to determine relative importance. Therefore, we combined a Bayesian variable selection method with dominance analysis to obtain a more nuanced understanding of potential modality-specific associations.

    Methods

    We recruited two independent cohorts of adults online to complete the Broad Autism Phenotype Questionnaire and the Glasgow Sensory Questionnaire (N = 592 in total). Subscale scores were derived for social, communicative, and rigid QAT and for the visual, auditory, tactile, olfactory, gustatory, proprioceptive, and vestibular sensory modalities. For each QAT, we performed a stochastic search variable selection (SSVS) procedure on the sensory modality subscales to test which sensory modalities predicted QAT while controlling for uncertainty in the other variables. Dominance analysis was then applied to the models identified by the SSVS to evaluate the relative importance of sensory modalities in predicting QAT.

    Results

    Only auditory scores reliably predicted all three QAT. The proprioceptive scale, which included motor and interoceptive deficits, specifically predicted communicative QAT. The tactile scale, which included touch sensitivity and atypical pain/temperature processing, specifically predicted social QAT.

    Limitations

    The findings must be interpreted in light of limitations of the Glasgow Sensory Questionnaire. For example, associations between QAT and visual, olfactory, gustatory, or vestibular modalities might appear if measured in a different way. The study relied on self-report by anonymous participants, which precluded clinical evaluation of sensory difficulties. It is also important to note that the modalities found to lack associations with QAT are nevertheless known to be clinically significant in autism.

    Conclusions

    Auditory processing deficits, such as noise sensitivity, strongly predicted all QAT, whereas other sensory modalities did not. Thus, auditory processing could be further studied as a potential sensory endophenotype for autism. The results also indicate potential roles for tactile dysfunction in atypical social interaction and proprioceptive/motor dysfunction in pragmatic language. 

  • 23.
    Bang, Peter
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Igelström, Kajsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Relationships between autistic trait dimensions and speech understanding, affective sound intolerance, and general auditory perceptionManuscript (preprint) (Other academic)
    Abstract [en]

    Sound intolerance is a transdiagnostic phenomenon with high clinical relevance in autism. It appears to cosegregate with quantitative autistic traits (QATs) and can be measured dimensionally. Auditory subscales of commonly used instruments tend to pool speech perception difficulties with autonomic and limbic reactions to sound. We evaluated associations between QATs and auditory difficulties using more specific self-report measures of affective reactions to sounds, speech perception and non-social auditory function. We found that both social and non-social QATs linearly predicted autonomic and limbic reactions to sounds. Communicative QATs specifically predicted difficulties with speech perception, but also with spatial perception and auditory stream segregation. We discuss possible mechanisms and suggest that transdiagnostic studies are especially suitable for research on autistic auditory perception.

  • 24.
    Bang, Peter
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Kidane Andemichael, Danait
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Pieslinger, Johan
    Igelström, Kajsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Sensory symptoms associated with autistic traits and anxiety levels in children aged 6–11 yearsManuscript (preprint) (Other academic)
    Abstract [en]

    Autism spectrum conditions (ASC) and quantitative autistic traits (QATs) are associated with sensory symptoms, which may contribute to anxiety and adversely affect social and cognitive development. Although sensory symptoms can occur across all senses, the relative roles of specific sensory modalities as contributors to the autistic phenotype and to anxiety are not well understood. The objective of this study was to examine which sensory symptoms were most predictive of high anxiety. We recruited 257 female primary caregivers of children aged 6 to 11 years (49 % girls) to a questionnaire study comprising parent-report measures for classical QATs (social, communicative, and rigid), autism-related sensorimotor symptoms (visual, auditory, tactile, olfactory, gustatory, vestibular, proprioceptive, and motor), and anxiety symptoms. First, Bayesian stochastic search variable selection (SSVS) was used to identify the most probable sensorimotor predictors of specific QATs as well as diagnosed ASC. Then, the selected predictors were used in another SSVS, using anxiety symptoms as a dependent variable, to identify which of the autism-relevant sensorimotor symptoms were most robustly predictive of anxiety. Finally, the effect sizes of anxiety-related sensory symptoms were estimated with linear regressions. We found that auditory symptoms and motor difficulties were most predictive of ASC diagnosis. Developmental motor difficulties were also strongly related to all individual QATs, whereas auditory symptoms were more selectively predictive of rigid traits. Tactile symptoms robustly predicted social interaction QATs, and proprioceptive symptoms predicted communicative QATs. Anxiety outcomes were most predicted by difficulties with auditory and olfactory processing. The results support the clinical importance of being alert to complaints about sounds and hearing in neurodevelopmental populations, and that auditory processing difficulties may be evaluated as an early marker of poor mental health in children with and without diagnosed autism. Olfactory processing differences appeared to be an anxiety marker less strongly associated with ASC or QATs, while motor difficulties were highly autism-relevant but not equally strongly associated with anxiety outcomes. We suggest that future studies may focus on the mechanisms and consequences of neurodevelopmental central auditory processing dysfunction and its potential relationship to anxiety disorders.

  • 25.
    Bang, Peter
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Strömberg, Maria
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology.
    Meera, Shoba S.
    Department of Speech Pathology and Audiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India.
    Igelström, Kajsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Brief Report: The Broad Autism Phenotype in Swedish Parentsof Children With and Without Autism Spectrum Conditions2022In: Journal of autism and developmental disorders, ISSN 0162-3257, E-ISSN 1573-3432, Vol. 52, no 10, p. 4575-4582Article in journal (Refereed)
    Abstract [en]

    The broad autism phenotype (BAP) is a set of characteristics often observed in typically developing people with a genetic load for autism, such as parents of autistic children. The Broad Autism Phenotypic Questionnaire (BAPQ) is a 36-item questionnaire developed to identify the BAP in first-degree relatives of autistic people. We translated the BAPQ into Swedish and examined its psychometric properties in a Swedish sample consisting of 45 parents of children with ASC and 74 parents of non-autistic children. We found support for the original 3-factor structure (aloof, pragmatic language and rigid), good internal consistency and convergent validity with the Autism Quotient. Thus, the Swedish BAPQ exhibits acceptable psychometric properties and may be useful for assessing the BAP in non-clinical populations.

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  • 26.
    Bartek, Jiri
    et al.
    Karolinska universitetssjukhuset, Stockholm, Sweden.
    Nittby-Redebrandt, Henrietta
    Skånes universitetssjukhus Lund, Sweden.
    Sjöberg, Rickard
    Norrlands universitetssjukhus, Umeå, Sweden.
    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.
    Hesselager, Göran
    Akademiska sjukhuset, Uppsala, Sweden.
    Jakola, Asgeir
    Sahlgrenska universitetssjukhuset, Sweden.
    Neurokirurgin alltjämt kärnan i behandlingen av hjärntumörer: [Neurosurgery still pivotal in the diagnostics and treatment of brain tumor patients]2023In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 120Article, review/survey (Refereed)
    Abstract [en]

    Treatment of adult patients with brain tumors is a multi-disciplinary effort involving several medical disciplines: neurosurgery, oncology, neurology, neuropathology, neuroradiology, and rehabilitation medicine. While the brain tumor field has gone through vast diagnostical changes during the last decade, the hopes of similar achievements in the systemic treatment of these patients with new methods have so far not been fulfilled. As such, neurosurgery still has a pivotal role in the diagnostics and treatment of brain tumor patients. Improved preoperative evaluation of the tumor and adjacent anatomical and functional brain areas, together with advanced microsurgical techniques, intraoperative mapping and monitoring, as well as new minimally invasive techniques, makes brain tumor surgery safer. Indeed, it is now possible to safely operate patients previously considered to have too unfavorable risk-benefit ratio. This article aims at presenting an overview of current neurosurgical treatments of brain tumors.

  • 27. Order onlineBuy this publication >>
    Bauer, Susanne
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Cell type-specific translatome analysis of mouse models of three genetic neurodegenerative diseases2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The burden neurodegenerative diseases place on patients, their loved ones, and the healthcare system is significant, and despite extensive research efforts, there is currently no cure. Since degenerative changes in the brain can begin years before symptoms appear, early intervention is critical. Additionally, neurodegenerative diseases target certain brain regions and neuron types early on. A more comprehensive understanding of the affected cells during the presymptomatic phase is therefore crucial for an effective and targeted intervention. 

    Herein, we isolated, sequenced, and analyzed translatome samples from six neuronal cell types in knock-in mouse models of three monogenic neurodegenerative diseases at a presymptomatic stage: genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Huntington’s disease (HD). To obtain the translatome samples, we used RiboTag to immunoprecipitate HA-tagged ribosomes with their translating mRNAs from targeted cell types. We analyzed six cell types across two brain regions: cerebral and cerebellar glutamatergic and GABAergic neurons, and cerebral parvalbumin (PV) and somatostatin (SST)-expressing neurons. 

    In the first paper, we focused our analysis on the prion diseases, gCJD (E200K) and FFI (D178N). Here observed a similar response of SST+ neurons, a cell type not previously reported as affected, in both disease models. This was characterized by upregulation of ribosomeassociated genes, and downregulation of cytoskeleton and synapse-associated genes in FFI. Weighted gene co-expression network analysis of SST+ neurons pointed towards the downregulation of mTOR inhibition as a potential mechanism underlying the observed gene expression changes. 

    In the second paper, we analyzed a 129S4-HdhQ200 knock-in mouse model of HD. Histological and behavioral assessment revealed pathological changes in the striatum and cerebellum at 9 months and a later, mild behavioral phenotype. Translatome analysis indicated a surprisingly strong response in reportedly resistant glutamatergic neurons of the cerebellum, marked by upregulation of cell cycle regulators Ccnd1 and chromobox protein genes. 

    In the third paper, we aimed to compare disease-specific responses of PV+ neurons across the three disease models. This analysis revealed a milder response in HD compared to prion disease at comparable disease stages. Functional analysis further indicated PV+ neurons may respond differently in the investigated diseases, showing upregulation of immune response-associated pathways in gCJD, neurodegenerative-disease pathways in FFI, and autophagy in HD. 

    Lastly, the generation of mouse models such as were used in papers I-III requires stable and predictable transgene expression without interfering with the expression of endogenous genes. In the fourth paper, we conducted a pilot study to compare three potential loci, Rpl6, Rpl7, and Eef1a1, as potential safe harbors for transgene integration. Preliminary results indicated that the Rpl6 locus may be best suited for our purposes. 

    Furthermore, this work generated a novel dataset consisting of translatome profiles of six cell types in three neurodegenerative disease models. This provides gene expression data at a previously unavailable level of cellular resolution, especially in prion disease. We believe that this data will serve as a valuable resource for future research and help expand our understanding of the early molecular mechanisms in neurodegenerative disease beyond the scope of this thesis. 

    List of papers
    1. Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons
    Open this publication in new window or tab >>Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons
    Show others...
    2022 (English)In: Life Science Alliance, E-ISSN 2575-1077, Vol. 5, no 11, article id e202201530Article in journal (Refereed) Published
    Abstract [en]

    Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, in-cluding fatal familial insomnia (FFI) and Creutzfeldt-Jakob dis-ease (CJD), different mutations in the Prnp gene manifest as clinically and neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased in 21 mo old knock-in mice modeling FFI and CJD and that sleep is mildy affected in FFI mice. To define affected cell types, we analyzed cell type-specific translatomes from six neuron types of 9 mo old FFI and CJD mice. Somatostatin (SST) neurons responded the strongest in both diseases, with unex-pectedly high overlap in genes and pathways. Functional analyses revealed up-regulation of neurodegenerative disease pathways and ribosome and mitochondria biogenesis, and down-regulation of synaptic function and small GTPase-mediated signaling in FFI, implicating down-regulation of mTOR signaling as the root of these changes. In contrast, responses in glutamatergic cerebellar neurons were disease-specific. The high similarity in SST neurons of FFI and CJD mice suggests that a common therapy may be beneficial for multiple genetic prion diseases.

    Place, publisher, year, edition, pages
    Life Science Allience, 2022
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:liu:diva-189755 (URN)10.26508/lsa.202201530 (DOI)000870440200001 ()36192034 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [2018-05973]; Swedish Bioinformatics Advisory Program - National Bioinformatics Infrastructure Sweden (NBIS); Knut and Alice Wallenberg foundation; German Center for Neurodegenerative Diseases (DZNE)

    Available from: 2022-11-07 Created: 2022-11-07 Last updated: 2023-04-28
    2. Cerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntingtons disease mice
    Open this publication in new window or tab >>Cerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntingtons disease mice
    Show others...
    2023 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 11, no 1, article id 17Article in journal (Refereed) Published
    Abstract [en]

    Although Huntingtons disease (HD) is classically defined by the selective vulnerability of striatal projection neurons, there is increasing evidence that cerebellar degeneration modulates clinical symptoms. However, little is known about cell type-specific responses of cerebellar neurons in HD. To dissect early disease mechanisms in the cerebellum and cerebrum, we analyzed translatomes of neuronal cell types from both regions in a new HD mouse model. For this, HdhQ200 knock-in mice were backcrossed with the calm 129S4 strain, to constrain experimental noise caused by variable hyperactivity of mice in a C57BL/6 background. Behavioral and neuropathological characterization showed that these S4-HdhQ200 mice had very mild behavioral abnormalities starting around 12 months of age that remained mild up to 18 months. By 9 months, we observed abundant Huntingtin-positive neuronal intranuclear inclusions (NIIs) in the striatum and cerebellum. The translatome analysis of GABAergic cells of the cerebrum further confirmed changes typical of HD-induced striatal pathology. Surprisingly, we observed the strongest response with 626 differentially expressed genes in glutamatergic neurons of the cerebellum, a population consisting primarily of granule cells, commonly considered disease resistant. Our findings suggest vesicular fusion and exocytosis, as well as differentiation-related pathways are affected in these neurons. Furthermore, increased expression of cyclin D1 (Ccnd1) in the granular layer and upregulated expression of polycomb group complex protein genes and cell cycle regulators Cbx2, Cbx4 and Cbx8 point to a putative role of aberrant cell cycle regulation in cerebellar granule cells in early disease.

    Place, publisher, year, edition, pages
    BMC, 2023
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:liu:diva-191739 (URN)10.1186/s40478-022-01500-x (DOI)000918127100001 ()36670467 (PubMedID)
    Note

    Funding Agencies|Linkoeping University; German Center for Neurodegenerative Diseases; Wallenberg Center for Molecular Medicine at Linkoeping University; Knut and Alice Wallenberg Foundation [KAW 2019-0047]; Swedish Research Council [2018-05973]

    Available from: 2023-02-13 Created: 2023-02-13 Last updated: 2023-04-28
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  • 28.
    Bauer, Susanne
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Chen, Chwen-Yu
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Jonson, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Kaczmarczyk, Lech
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. German Ctr Neurodegenerat Dis, Germany.
    Magadi, Srivathsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Jackson, Walker
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. German Ctr Neurodegenerat Dis, Germany.
    Cerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntingtons disease mice2023In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 11, no 1, article id 17Article in journal (Refereed)
    Abstract [en]

    Although Huntingtons disease (HD) is classically defined by the selective vulnerability of striatal projection neurons, there is increasing evidence that cerebellar degeneration modulates clinical symptoms. However, little is known about cell type-specific responses of cerebellar neurons in HD. To dissect early disease mechanisms in the cerebellum and cerebrum, we analyzed translatomes of neuronal cell types from both regions in a new HD mouse model. For this, HdhQ200 knock-in mice were backcrossed with the calm 129S4 strain, to constrain experimental noise caused by variable hyperactivity of mice in a C57BL/6 background. Behavioral and neuropathological characterization showed that these S4-HdhQ200 mice had very mild behavioral abnormalities starting around 12 months of age that remained mild up to 18 months. By 9 months, we observed abundant Huntingtin-positive neuronal intranuclear inclusions (NIIs) in the striatum and cerebellum. The translatome analysis of GABAergic cells of the cerebrum further confirmed changes typical of HD-induced striatal pathology. Surprisingly, we observed the strongest response with 626 differentially expressed genes in glutamatergic neurons of the cerebellum, a population consisting primarily of granule cells, commonly considered disease resistant. Our findings suggest vesicular fusion and exocytosis, as well as differentiation-related pathways are affected in these neurons. Furthermore, increased expression of cyclin D1 (Ccnd1) in the granular layer and upregulated expression of polycomb group complex protein genes and cell cycle regulators Cbx2, Cbx4 and Cbx8 point to a putative role of aberrant cell cycle regulation in cerebellar granule cells in early disease.

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  • 29.
    Bauer, Susanne
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Dittrich, Lars
    German Ctr Neurodegenerat Dis, Germany.
    Kaczmarczyk, Lech
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. German Ctr Neurodegenerat Dis, Germany.
    Schleif, Melvin
    German Ctr Neurodegenerat Dis, Germany.
    Benfeitas, Rui
    Stockholm Univ, Sweden.
    Jackson, Walker
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. German Ctr Neurodegenerat Dis, Germany.
    Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons2022In: Life Science Alliance, E-ISSN 2575-1077, Vol. 5, no 11, article id e202201530Article in journal (Refereed)
    Abstract [en]

    Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, in-cluding fatal familial insomnia (FFI) and Creutzfeldt-Jakob dis-ease (CJD), different mutations in the Prnp gene manifest as clinically and neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased in 21 mo old knock-in mice modeling FFI and CJD and that sleep is mildy affected in FFI mice. To define affected cell types, we analyzed cell type-specific translatomes from six neuron types of 9 mo old FFI and CJD mice. Somatostatin (SST) neurons responded the strongest in both diseases, with unex-pectedly high overlap in genes and pathways. Functional analyses revealed up-regulation of neurodegenerative disease pathways and ribosome and mitochondria biogenesis, and down-regulation of synaptic function and small GTPase-mediated signaling in FFI, implicating down-regulation of mTOR signaling as the root of these changes. In contrast, responses in glutamatergic cerebellar neurons were disease-specific. The high similarity in SST neurons of FFI and CJD mice suggests that a common therapy may be beneficial for multiple genetic prion diseases.

    Download full text (pdf)
    fulltext
  • 30.
    Bauza-Thorbrügge, Marco
    et al.
    Univ Gothenburg, Sweden.
    Banke, Elin
    Univ Gothenburg, Sweden.
    Chanclon, Belen
    Univ Gothenburg, Sweden.
    Peris, Eduard
    Univ Gothenburg, Sweden.
    Wu, Yanling
    Univ Gothenburg, Sweden.
    Musovic, Saliha
    Univ Gothenburg, Sweden.
    Jönsson, Cecilia
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Rorsman, Patrik
    Univ Gothenburg, Sweden; Univ Oxford, England.
    Olofsson, Charlotta S.
    Univ Gothenburg, Sweden.
    Asterholm, Ingrid Wernstedt
    Univ Gothenburg, Sweden.
    Adipocyte-specific ablation of the Ca2+pump SERCA2 impairs whole-body metabolic function and reveals the diverse metabolic flexibility of white and brown adipose tissue2022In: Molecular Metabolism, ISSN 2212-8778, Vol. 63, article id 101535Article in journal (Refereed)
    Abstract [en]

    Objective: Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) transports Ca2+ from the cytosol into the endoplasmic retitculum (ER) and is essential for appropriate regulation of intracellular Ca2+ homeostasis. The objective of this study was to test the hypothesis that SERCA pumps are involved in the regulation of white adipocyte hormone secretion and other aspects of adipose tissue function and that this control is disturbed in obesity-induced type-2 diabetes. Methods: SERCA expression was measured in isolated human and mouse adipocytes as well as in whole mouse adipose tissue by Western blot and RT-qPCR. To test the significance of SERCA2 in adipocyte functionality and whole-body metabolism, we generated adipocyte-specific SERCA2 knockout mice. The mice were metabolically phenotyped by glucose tolerance and tracer studies, histological analyses, measurements of glucose-stimulated insulin release in isolated islets, and gene/protein expression analyses. We also tested the effect of pharmacological SERCA inhibition and genetic SERCA2 ablation in cultured adipocytes. Intracellular and mitochondrial Ca2+ levels were recorded with dualwavelength ratio imaging and mitochondrial function was assessed by Seahorse technology. Results: We demonstrate that SERCA2 is downregulated in white adipocytes from patients with obesity and type-2 diabetes as well as in adipocytes from diet-induced obese mice. SERCA2-ablated adipocytes display disturbed Ca2+ homeostasis associated with upregulated ER stress markers and impaired hormone release. These adipocyte alterations are linked to mild lipodystrophy, reduced adiponectin levels, and impaired glucose tolerance. Interestingly, adipocyte-specific SERCA2 ablation leads to increased glucose uptake in white adipose tissue while the glucose uptake is reduced in brown adipose tissue. This dichotomous effect on glucose uptake is due to differently regulated mitochondrial function. In white adipocytes, SERCA2 deficiency triggers an adaptive increase in fibroblast growth factor 21 (FGF21), increased mitochondrial uncoupling protein 1 (UCP1) levels, and increased oxygen consumption rate (OCR). In contrast, brown SERCA2 null adipocytes display reduced OCR despite increased mitochondrial content and UCP1 levels compared to wild type controls. Conclusions: Our data suggest causal links between reduced white adipocyte SERCA2 levels, deranged adipocyte Ca2+ homeostasis, adipose tissue dysfunction and type-2 diabetes. (c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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  • 31.
    Bergquist, Filip
    et al.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Ehrnebo, Mats
    Uppsala Univ, Sweden; Pharm Assist Sweden AB, Sweden.
    Nyholm, Dag
    Uppsala Univ, Sweden.
    Johansson, Anders
    Karolinska Inst, Sweden.
    Lundin, Fredrik
    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, Neurologiska kliniken i Linköping.
    Odin, Per
    Lund Univ, Sweden.
    Svenningsson, Per
    Karolinska Inst, Sweden.
    Hansson, Fredrik
    CTC Clin Trial Consultants AB, Sweden.
    Bring, Leif
    Dizlin Pharmaceut, Sweden.
    Eriksson, Elias
    Univ Gothenburg, Sweden.
    Dizdar Segrell, Nil
    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, Neurologiska kliniken i Linköping.
    Pharmacokinetics of Intravenously (DIZ101), Subcutaneously (DIZ102), and Intestinally (LCIG) Infused Levodopa in Advanced Parkinson Disease2022In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 99, no 10, p. E965-E976Article in journal (Refereed)
    Abstract [en]

    Background and Objectives Intestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson disease. The primary objective of this trial was to investigate whether continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady-state plasma concentrations of levodopa that are equivalent in magnitude, and noninferior in variability, to those obtained with LCIG in patients with advanced Parkinson disease. Methods A concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved LCIG in a randomized, 3-period crossover, open-label, multicenter trial. Formulations were infused for 16 hours to patients with Parkinson disease who were using LCIG as their regular treatment. Patients were recruited from several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and noninferior variability of DIZ101 and DIZ102 vs LCIG with respect to levodopa plasma concentrations. Results With dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits compared with LCIG in the 18 participants who received all treatments. Although the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Owing to poor uptake of LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n = 20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient. Discussion It is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa-containing solution.

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  • 32.
    Bergquist, Filip
    et al.
    Sahlgrenska Academy, Göteborg, Sweden .
    Johansson, Anders
    Karolinska Universitetssjukhuset, Stockholm, Sweden.
    Dizdar Segrell, Nil
    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, Neurologiska kliniken i Linköping.
    Widner, Håkan
    Lunds universitet Medicinska fakulteten, Lund, Sweden .
    Nyholm, Dag
    Akademiska sjukhuset, Uppsala, Sweden .
    Odin, Per
    Lunds universitet Medicinska fakulteten, Lund, Sweden.
    Svenningsson, Per
    Karolinska Universitetssjukhuset, Tema Neuro Stockholm, Sweden .
    Parkinsons sjukdom [Parkinsons disease]: heterogen och komplex i sitt kliniska uttryck [heterogeneous and complex in its clinical presentation]2020In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 117Article in journal (Refereed)
    Abstract [en]

    Parkinsons disease is the second most common neurodegenerative disease. Lewy bodies with alpha-synuclein as the major component and loss of dopaminergic nerve cells in substantia nigra are neuropathological features. The diagnosis of Parkinsons disease is based on the occurrence of bradykinesia, rigidity and resting tremor. The disease is also associated with several non-motor symptoms. The therapy is mainly based on pharmacological treatment to increase dopamine signaling and neurosurgical deep brain stimulation. The symptoms and signs of the progressive disease change over time, requiring treatment adjustments. Patients should be followed by a physician, nurse and a multidisciplinary team with expertise in Parkinsons disease.

  • 33.
    Berntsson, Shala Ghaderi
    et al.
    Uppsala Univ, Sweden.
    Matsson, Hans
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Kristoffersson, Anna
    Uppsala Univ, Sweden.
    Niemela, Valter
    Uppsala Univ, Sweden.
    van Duyvenvoorde, Hermine A.
    Leiden Univ, Netherlands.
    Richel-van Assenbergh, Cindy
    Leiden Univ, Netherlands.
    van der Klift, Heleen M.
    Leiden Univ, Netherlands.
    Casar-Borota, Olivera
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Frykholm, Carina
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Landtblom, Anne-Marie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Uppsala Univ, Sweden.
    Case report: a novel deep intronic splice-altering variant in DMD as a cause of Becker muscular dystrophy2023In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 14, article id 1226766Article in journal (Refereed)
    Abstract [en]

    We present the case of a male patient who was ultimately diagnosed with Becker muscular dystrophy (BMD; MIM# 300376) after the onset of muscle weakness in his teens progressively led to significant walking difficulties in his twenties. A genetic diagnosis was pursued but initial investigation revealed no aberrations in the dystrophin gene (DMD), although immunohistochemistry and Western blot analysis suggested the diagnosis of dystrophinopathy. Eventually, after more than 10 years, an RNA analysis captured abnormal splicing where 154 nucleotides from intron 43 were inserted between exon 43 and 44 resulting in a frameshift and a premature stop codon. Normal splicing of the DMD gene was also observed. Additionally, a novel variant c.6291-13537A>G in DMD was confirmed in the genomic DNA of the patient. The predicted function of the variant aligns with the mRNA results. To conclude, we here demonstrate that mRNA analysis can guide the diagnosis of non-coding genetic variants in DMD.

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  • 34.
    Biskou, Olga
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Jauregi-Miguel, Amaia
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology.
    Measuring intestinal permeability in celiac disease ex vivo, using Ussing chambers2023In: Methods in Cell Biology, ISSN 0091-679X, Vol. 179, p. 21-38Article in journal (Refereed)
    Abstract [en]

    Multicellular organisms need epithelial barriers to remain compartmentalized and protected from external influences. Although much progress has been made in understanding barrier integrity disruption in Celiac disease (CD), the regulatory and genetic mechanisms underlying the increased intestinal epithelial flux are still unknown. As we learn more about the regulation of permeability in homeostasis and pathogenesis, we will be able to develop strategies to strengthen the epithelial barrier function in intestinal disorders, including CD. For this purpose, Ussing chambers are increasingly used in native tissue, such as gut mucosa or cell monolayers, to assess the integrity of the barrier. In particular, the Ussing chambers allow the measurement of paracellular and transcellular parameters of CD small intestinal biopsies under physiologically specific conditions. In diverse types of diseases, this method is commonly used to determine epithelial barrier defects, but its application to CD has not yet been widely expanded. To provide a great model of barrier ex vivo studies in CD, we facilitate a standard protocol to measure paracellular and transcellular permeability using the Ussing chamber.

  • 35.
    Bistrom, M.
    et al.
    Umea Univ, Sweden.
    Jons, D.
    Univ Gothenburg, Sweden.
    Engdahl, E.
    Karolinska Inst, Sweden; Ctr Mol Med, Sweden.
    Gustafsson, R.
    Karolinska Inst, Sweden; Ctr Mol Med, Sweden.
    Huang, J.
    Karolinska Inst, Sweden; Ctr Mol Med, Sweden.
    Brenner, N.
    German Canc Res Ctr, Germany.
    Butt, J.
    German Canc Res Ctr, Germany.
    Alonso-Magdalena, L.
    Lund Univ, Sweden; Lund Univ, Sweden.
    Gunnarsson, M.
    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, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping.
    Bender, N.
    German Canc Res Ctr, Germany.
    Waterboer, T.
    German Canc Res Ctr, Germany.
    Granasen, G.
    Umea Univ, Sweden.
    Olsson, T.
    Karolinska Inst, Sweden; Ctr Mol Med, Sweden.
    Kockum, I.
    Karolinska Inst, Sweden; Ctr Mol Med, Sweden.
    Andersen, O.
    Univ Gothenburg, Sweden.
    Fogdell-Hahn, A.
    Karolinska Inst, Sweden; Ctr Mol Med, Sweden.
    Sundstrom, Peter
    Umea Univ, Sweden.
    Epstein-Barr virus infection after adolescence and human herpesvirus 6A as risk factors for multiple sclerosis2021In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 28, no 2, p. 579-586Article in journal (Refereed)
    Abstract [en]

    Background and purpose Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. Methods In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Results Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). Conclusions This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS.

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  • 36.
    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, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping.
    Sundstrom, Peter
    Umea Univ, Sweden.
    Leptin levels are associated with multiple sclerosis risk2021In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 27, no 1, p. 19-27Article 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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  • 37.
    Bivik Stadler, Caroline
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lindvall, Martin
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering. Sectra AB, Tekn Ringen 20, SE-58330 Linkoping, Sweden.
    Lundström, Claes
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV). Sectra AB, Tekn Ringen 20, SE-58330 Linkoping, Sweden.
    Boden, Anna
    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. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lindman, Karin
    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.
    Rose, Jeronimo
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Treanor, Darren
    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, Clinical pathology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Leeds Teaching Hosp NHS Trust, England; Univ Leeds, England.
    Blomma, Johan
    Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Stacke, Karin
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering. Sectra AB, Tekn Ringen 20, SE-58330 Linkoping, Sweden.
    Pinchaud, Nicolas
    ContextVision AB, Sweden.
    Hedlund, Martin
    ContextVision AB, Sweden.
    Landgren, Filip
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Woisetschläger, Mischa
    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. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Forsberg, Daniel
    Sectra AB, Tekn Ringen 20, SE-58330 Linkoping, Sweden.
    Proactive Construction of an Annotated Imaging Database for Artificial Intelligence Training2021In: Journal of digital imaging, ISSN 0897-1889, E-ISSN 1618-727X, Vol. 34, p. 105-115Article in journal (Refereed)
    Abstract [en]

    Artificial intelligence (AI) holds much promise for enabling highly desired imaging diagnostics improvements. One of the most limiting bottlenecks for the development of useful clinical-grade AI models is the lack of training data. One aspect is the large amount of cases needed and another is the necessity of high-quality ground truth annotation. The aim of the project was to establish and describe the construction of a database with substantial amounts of detail-annotated oncology imaging data from pathology and radiology. A specific objective was to be proactive, that is, to support undefined subsequent AI training across a wide range of tasks, such as detection, quantification, segmentation, and classification, which puts particular focus on the quality and generality of the annotations. The main outcome of this project was the database as such, with a collection of labeled image data from breast, ovary, skin, colon, skeleton, and liver. In addition, this effort also served as an exploration of best practices for further scalability of high-quality image collections, and a main contribution of the study was generic lessons learned regarding how to successfully organize efforts to construct medical imaging databases for AI training, summarized as eight guiding principles covering team, process, and execution aspects.

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  • 38.
    Bjork, Maria
    et al.
    Jonkoping Univ, Sweden.
    Knutsson, Susanne
    Linnaeus Univ, Sweden.
    Odzakovic, Elzana
    Jonkoping Univ, Sweden.
    Hellstrom, Amanda
    Linnaeus Univ, Sweden.
    Sandlund, Christina
    Karolinska Inst, Sweden; Acad Primary Hlth Care Ctr, Sweden.
    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.
    Lind, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Pakpour, Amir H.
    Jonkoping Univ, Sweden.
    Broström, Anders
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology. Jonkoping Univ, Sweden; Western Norway Univ Appl Sci, Norway.
    Members of, Jonkoping Univ JU Sleep Well Res Grp
    Validation of two brief instruments (the SURE and CollaboRATE) to measure shared decision-making in patients with restless legs syndrome2023In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869Article in journal (Refereed)
    Abstract [en]

    Restless legs syndrome (RLS) is a common neurological disorder characterised by an urge to move arms and legs, usually associated with discomfort, pain, motor restlessness, and sleep disturbance. An individually adapted treatment is needed but difficult to optimise, which makes shared decision-making (SDM) important. However, brief validated instruments on how patients with RLS perceive their involvement in treatment decisions are lacking. Therefore, the aim was to validate two instruments, SURE (Sure of myself, Understand information, Risk-benefit ratio, Encouragement, i.e., to assess decisional conflict) and CollaboRATE (brief patient survey focused on SDM, i.e., to assess SDM), in patients with RLS. A cross-sectional design, including 788 participants with RLS (65% females, mean [SD] age 70.8 [11.4] years) from a national patient organisation for RLS, was used. A postal survey was sent out to collect data regarding weight, height, comorbidities, demographics, and RLS-related treatment data. The following instruments were included: the SURE, CollaboRATE, Restless Legs Syndrome-6 Scale, and eHealth Literacy Scale. Confirmatory factor analysis and Rasch models were used to assess the validity and reliability of the SURE and CollaboRATE. Measurement invariance, unidimensionality, and differential item functioning (DIF) across age, gender, and medication groups were assessed. The SURE and CollaboRATE were both identified as unidimensional instruments with satisfactory internal consistency. No DIF across age and gender was identified, while significant DIF was observed for both the SURE and CollaboRATE regarding medication use categories. However, both the SURE and CollaboRATE are potential instruments to be used in research, but also as reflection tools by healthcare professionals, patients, and students to explore and assess SDM, and support its development in clinical care.

  • 39.
    Bjorvatn, Bjorn
    et al.
    Univ Bergen, Norway; Haukeland Hosp, Norway.
    Merikanto, Ilona
    Univ Helsinki, Finland; Orton Orthopaed Hosp, Finland.
    Reis, Catia
    Univ Catolica Portuguesa, Portugal; Fac Med Lisbon, Portugal.
    Korman, Maria
    Ariel Univ, Israel.
    Bjelajac, Adrijana Koscec
    Inst Med Res & Occupat Hlth, Croatia.
    Holzinger, Brigitte
    Med Univ Vienna, Austria.
    De Gennaro, Luigi
    Sapienza Univ Rome, Italy; IRCCS Fdn Santa Lucia, Italy.
    Wing, Yun Kwok
    Chinese Univ Hong Kong, Peoples R China.
    Morin, Charles M.
    Univ Laval, Canada.
    Espie, Colin A.
    Univ Oxford, England.
    Benedict, Christian
    Uppsala Univ, Sweden.
    Landtblom, Anne-Marie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping. Uppsala Univ, Sweden.
    Matsui, Kentaro
    Natl Ctr Hosp, Japan.
    Hrubos-Strom, Harald
    Akershus Univ Hosp, Norway; Univ Oslo, Norway.
    Mota-Rolim, Sergio
    Univ Fed Rio Grande do Norte, Brazil; Univ Fed Rio Grande do Norte, Brazil.
    Nadorff, Michael R.
    Mississippi State Univ, MS USA.
    Plazzi, Giuseppe
    IRCCS Ist Sci Neurol Bologna, Italy; Univ Modena & Reggio Emilia, Italy.
    Chan, Rachel Ngan Yin
    Chinese Univ Hong Kong, Peoples R China.
    Partinen, Markku
    Univ Helsinki, Finland; Helsinki Sleep Clin, Finland.
    Dauvilliers, Yves
    Univ Montpellier, France.
    Chung, Frances
    Univ Hlth Network, Canada.
    Forthun, Ingeborg
    Univ Bergen, Norway; Haukeland Hosp, Norway.
    Shift workers are at increased risk of severe COVID-19 compared with day workers: Results from the international COVID sleep study (ICOSS) of 7141 workers2023In: Chronobiology International, ISSN 0742-0528, E-ISSN 1525-6073, Vol. 40, no 2, p. 114-122Article in journal (Refereed)
    Abstract [en]

    The present study had two main aims. First, to investigate whether shift/night workers had a higher prevalence and severity of COVID-19 compared with day workers. Second, to investigate whether people regularly working in face-to-face settings during the pandemic exhibited a higher prevalence and severity of COVID-19 compared with those having no need to be in close contact with others at work. Data consisted of 7141 workers from 15 countries and four continents who participated in the International COVID Sleep Study-II (ICOSS-II) between May and December 2021. The associations between work status and a positive COVID-19 test and several indications of disease severity were tested with chi-square tests and logistic regressions adjusted for relevant confounders. In addition, statistical analyses were conducted for the associations between face-to-face work and COVID-19 status. Results showed that shift/night work was not associated with an increased risk of COVID-19 compared to day work. Still, shift/night workers reported higher odds for moderate to life-threatening COVID-19 (adjusted odds ratio (aOR) = 2.71, 95%-confidence interval = 1.23-5.95) and need for hospital care (aOR = 5.66, 1.89-16.95). Face-to-face work was associated with an increased risk of COVID-19 (aOR = 1.55, 1.12-2.14) but not with higher disease severity. In conclusion, shift/night work was not associated with an increased risk of COVID-19, but when infected, shift/night workers reported more severe disease. Impaired sleep and circadian disruption commonly seen among shift/night workers may be mediating factors. Working face-to-face increased the risk of COVID-19, likely due to increased exposure to the virus. However, face-to-face work was not associated with increased disease severity.

  • 40.
    Blockhuys, Stephanie
    et al.
    Chalmers Univ Technol, Sweden.
    Hildesjö, Camilla
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Regional Cancer Center.
    Olsson, Hans
    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.
    Vahdat, Linda
    Mem Sloan Kettering Canc Ctr, NY 10065 USA.
    Wittung-Stafshede, Pernilla
    Chalmers Univ Technol, Sweden.
    Evaluation of ATOX1 as a Potential Predictive Biomarker for Tetrathiomolybdate Treatment of Breast Cancer Patients with High Risk of Recurrence2021In: Biomedicines, E-ISSN 2227-9059, Vol. 9, no 12, article id 1887Article in journal (Refereed)
    Abstract [en]

    Copper plays a key role in cancer metastasis, which is the most common cause of cancer death. Copper depletion treatment with tetrathiomolybdate (TM) improved disease-free survival in breast cancer patients with high risk of recurrence in a phase II clinical trial. Because the copper metallochaperone ATOX1 was recently reported to drive breast cancer cell migration and breast cancer migration is a critical factor in metastasis, we tested if ATOX1 expression levels in primary tumor tissue could predict the TM treatment outcome of breast cancer patients at high risk of recurrence. We performed ATOX1 immunohistochemical staining of breast tumor material (before TM treatment) of 47 patients enrolled in the phase II TM clinical trial and evaluated ATOX1 expression levels in relation with patient outcome after TM treatment. Our results show that higher ATOX1 levels in the tumor cell cytoplasm correlate with a trend towards better event-free survival after TM treatment for triple-negative breast cancer patients and patients at stage III of disease. In conclusion, ATOX1 may be a potential predictive biomarker for TM treatment of breast cancer patients at high risk of recurrence and should be tested in a larger cohort of patients.

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  • 41.
    Blomqvist, Anders
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology.
    Pain and temperature, and human awareness: The legacy of Bud Craig2023In: Temperature (Austin, Tex.), ISSN 2332-8940, Vol. 10, no 4, p. 395-401Article in journal (Other academic)
  • 42.
    Blomqvist, Anders
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Prostaglandin E-2 Production by Brain Endothelial Cells and the Generation of Fever2023In: DNA and Cell Biology, ISSN 1044-5498, E-ISSN 1557-7430, Vol. 42, no 3, p. 107-112Article in journal (Refereed)
    Abstract [en]

    We recently demonstrated that prostaglandin production in brain endothelial cells is both necessary and sufficient for the generation of fever during systemic immune challenge. I here discuss this finding in light of the previous literature and point to some unresolved issues.

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  • 43.
    Blomqvist, Anders
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Evrard, Henry C.
    Chinese Acad Sci, Peoples R China; Karl Eberhard Univ Tubingen, Germany; Max Planck Inst Biol Cybernet, Germany.
    The thalamic projection of pain sensations to the posterior dorsal fundus in the insula: comment on Mandonnet et al2024In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 165, no 3, p. E15-E16Article in journal (Other academic)
  • 44.
    Blomqvist, Anders
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Evrard, Henry C.
    Chinese Acad Sci, Peoples R China; Nathan S Kline Inst Psychiat Res, NY 10962 USA; Univ Tubingen, Germany; Max Planck Inst Biol Cybernet, Germany.
    Dostrovsky, Jonathan O.
    Univ Toronto, Canada.
    Strigo, Irina A.
    San Francisco Vet Affairs Hlth Care Ctr, CA USA; Univ Calif San Francisco, CA USA.
    Jaenig, Wilfrid
    Christian Albrechts Univ Kiel, Germany.
    OBITUARY: A. D. (Bud) Craig, Jr. (1951-2023)2023In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 26, p. 1835-1836Article in journal (Other academic)
    Abstract [en]

    Bud Craig, an outstanding neuroscientist, died on 15 July 2023 at age 71. Bud made unique contributions to the fields of pain and interoception, challenging major dogmas and offering powerful explanations for various phenomena including central pain and the subjective awareness of feelings, with great implications for our understanding of consciousness.

  • 45.
    Blomstrand, Hakon
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Olsson, Hans
    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.
    Green, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Dept Forens Genet & Forens Toxicol, Natl Board Forens Med, Linkoping, Sweden.
    Björnsson, Bergthor
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Elander, Nils
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Clatterbridge Canc Ctr NHS FT, England.
    Impact of resection margins and para-aortic lymph node metastases on recurrence patterns and prognosis in resectable pancreatic cancer - a long-term population-based cohort study2023In: HPB, ISSN 1365-182X, E-ISSN 1477-2574, Vol. 25, no 12, p. 1531-1544Article in journal (Refereed)
    Abstract [en]

    Background: Pancreatic cancer remains a leading cause of cancer-related death. To individualise management and improve survival, more accurate prognostic models are needed.Methods: All patients resected for pancreatic ductal adenocarcinoma in a tertiary Swedish centre during 2009-2019 were thoroughly analysed with regards to pathological and clinical parameters including tumour grade, resection margin status, para-aortic lymph node engagement (node station 16), and systemic treatment.Results: The study cohort included 275 patients. Overall median survival was 21.2 months (95% CI 17.5-24.8). Year of resection, margin status (R1 subdivided into R1(1mm)/R1(ink)), perineural invasion, differentiation grade, TNM stage, and adjuvant therapy were independent factors with significant impact on survival. Margin status also significantly affected recurrence-free survival and relapse patterns, with local and peritoneal relapses being associated with R1-status (p < 0.001 and p = 0.007). Presence of paraaortic lymph node metastases was associated with shorter recurrence-free survival as compared to N1 status only.Conclusion: Survival in resected pancreatic cancer is improving over time. Resection margin status is a key factor affecting recurrence patterns and prognosis. Given the poor recurrence-free survival in node station 16 metastasised patients, the rational for resection remains in doubt, and improved treatment strategies for this patient group is necessary.

  • 46.
    Bodén, Anna
    et al.
    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.
    Molin, Jesper
    Sectra AB, Linkoping, Sweden.
    Garvin, Stina
    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.
    West, Rebecca A.
    Leeds Teaching Hosp NHS Trust, England; Dewsbury & Dist Hosp, England.
    Lundström, Claes
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV). Sectra AB, Linkoping, Sweden.
    Treanor, Darren
    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, Clinical pathology. Leeds Teaching Hosp NHS Trust, England; Univ Leeds, England.
    The human-in-the-loop: an evaluation of pathologists interaction with artificial intelligence in clinical practice2021In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 79, no 2, p. 210-218Article in journal (Refereed)
    Abstract [en]

    Aims: One of the major drivers of the adoption of digital pathology in clinical practice is the possibility of introducing digital image analysis (DIA) to assist with diagnostic tasks. This offers potential increases in accuracy, reproducibility, and efficiency. Whereas stand-alone DIA has great potential benefit for research, little is known about the effect of DIA assistance in clinical use. The aim of this study was to investigate the clinical use characteristics of a DIA application for Ki67 proliferation assessment. Specifically, the human-in-the-loop interplay between DIA and pathologists was studied. Methods and results: We retrospectively investigated breast cancer Ki67 areas assessed with human-in-the-loop DIA and compared them with visual and automatic approaches. The results, expressed as standard deviation of the error in the Ki67 index, showed that visual estimation (eyeballing) (14.9 percentage points) performed significantly worse (P < 0.05) than DIA alone (7.2 percentage points) and DIA with human-in-the-loop corrections (6.9 percentage points). At the overall level, no improvement resulting from the addition of human-in-the-loop corrections to the automatic DIA results could be seen. For individual cases, however, human-in-the-loop corrections could address major DIA errors in terms of poor thresholding of faint staining and incorrect tumour-stroma separation. Conclusion: The findings indicate that the primary value of human-in-the-loop corrections is to address major weaknesses of a DIA application, rather than fine-tuning the DIA quantifications.

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  • 47.
    Boettcher, Mareike
    et al.
    Univ Lubeck, Germany.
    Mueller-Fielitz, Helge
    Univ Lubeck, Germany; DZHK German Ctr Cardiovasc Res, Germany.
    Sundaram, Sivaraj M.
    Univ Lubeck, Germany.
    Gallet, Sarah
    Jean Pierre Aubert Res Ctr, France; Univ Lille, France.
    Neve, Vanessa
    Univ Lubeck, Germany.
    Shionoya, Kiseko
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Zager, Adriano
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Quan, Ning
    Florida Atlantic Univ, FL 33458 USA.
    Liu, Xiaoyu
    Florida Atlantic Univ, FL 33458 USA.
    Schmidt-Ullrich, Ruth
    Max Delbruck Ctr MDC Mol Med, Germany.
    Haenold, Ronny
    FLI, Germany; Friedrich Schiller Univ Jena, Germany.
    Wenzel, Jan
    Univ Lubeck, Germany; DZHK German Ctr Cardiovasc Res, Germany.
    Blomqvist, Anders
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. 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.
    Prevot, Vincent
    Jean Pierre Aubert Res Ctr, France; Univ Lille, France.
    Schwaninger, Markus
    Univ Lubeck, Germany; DZHK German Ctr Cardiovasc Res, Germany.
    NF-kappa B signaling in tanycytes mediates inflammation-induced anorexia2020In: Molecular Metabolism, ISSN 2212-8778, Vol. 39, article id 101022Article in journal (Refereed)
    Abstract [en]

    Objectives: Infections, cancer, and systemic inflammation elicit anorexia. Despite the medical significance of this phenomenon, the question of how peripheral inflammatory mediators affect the central regulation of food intake is incompletely understood. Therefore, we have investigated the sickness behavior induced by the prototypical inflammatory mediator IL-1 beta. Methods: IL-1 beta was injected intravenously. To interfere with IL-1 beta signaling, we deleted the essential modulator of NF-kappa B signaling (Nemo) in astrocytes and tanycytes. Results: Systemic IL-1 beta increased the activity of the transcription factor NF-kB in tanycytes of the mediobasal hypothalamus (MBH). By activating NF-kappa B signaling, IL-1 beta induced the expression of cyclooxygenase-2 (Cox-2) and stimulated the release of the anorexigenic prostaglandin E-2 (PGE(2)) from tanycytes. When we deleted Nemo in astrocytes and tanycytes, the IL-1 beta-induced anorexia was alleviated whereas the fever response and lethargy response were unchanged. Similar results were obtained after the selective deletion of Nemo exclusively in tanycytes. Conclusions: Tanycytes form the brain barrier that mediates the anorexic effect of systemic inflammation in the hypothalamus. (C) 2020 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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  • 48.
    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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  • 49.
    Bohannon, Briana M
    et al.
    Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
    Jowais, Jessica J
    Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
    Nyberg, Leif
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
    Liin, Sara I.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology.
    Larsson, Peter
    Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
    Mechanistic insights into robust cardiac I Ks potassium channel activation by aromatic polyunsaturated fatty acid analogues2023Manuscript (preprint) (Other academic)
    Abstract [en]

    Voltage-gated potassium (K V ) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K V channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore K V channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K V channel activators with potential applications in the treatment of arrhythmogenic disorders such as Long QT Syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac I Ks channel - a tetrameric potassium channel complex formed by K V 7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I Ks channel and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the I Ks channel by generating modified aromatic head groups designed to probe cation-pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the I Ks channel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.

  • 50.
    Bohannon, Briana M.
    et al.
    Univ Miami, FL 33136 USA.
    Jowais, Jessica J.
    Univ Miami, FL 33136 USA.
    Nyberg, Leif
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Univ Miami, FL 33136 USA.
    Olivier-Meo, Vanessa
    Univ Miami, FL 33136 USA.
    Corradi, Valentina
    Univ Calgary, Canada.
    Tieleman, D. Peter
    Univ Calgary, Canada.
    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.
    Mechanistic insights into robust cardiac I-Ks potassium channel activation by aromatic polyunsaturated fatty acid analogues2023In: eLIFE, E-ISSN 2050-084X, Vol. 12, article id e85773Article in journal (Refereed)
    Abstract [en]

    Voltage-gated potassium (K-V) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K-V channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore K-V channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K-V channel activators with potential applications in the treatment of arrhythmogenic disorders such as long QT syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac I-Ks channel - a tetrameric potassium channel complex formed by K(V)7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I-Ks channel, and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the I-Ks channel by generating modified aromatic head groups designed to probe cation-pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the I-Ks channel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.

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