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  • 101.
    Moulin, Thiago
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ferro, Federico
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Hoyer, Angela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Cheung, Pierre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    The Drosophila melanogaster Levodopa-Induced Depression Model Exhibits Negative Geotaxis Deficits and Differential Gene Expression in Males and Females2021In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 15, article id 653470Article in journal (Refereed)
    Abstract [en]

    More than 320 million people live with depression in the world, a disorder that severely limits psychosocial functioning and diminishes quality of life. The prevalence of major depression is almost two times higher in women than in men. However, the molecular mechanisms of its sex-specific pathophysiology are still poorly understood. Drosophila melanogaster is an established model for neurobiological research of depression-like states, as well as for the study of molecular and genetic sex differences in the brain. Here, we investigated sex-specific effects on forced-climbing locomotion (negative geotaxis) and gene expression of a fly model of depression-like phenotypes induced by levodopa administration, which was previously shown to impair normal food intake, mating frequency, and serotonin concentration. We observed that both males and females show deficits in the forced-climbing paradigm; however, modulated by distinct gene expression patterns after levodopa administration. Our results suggest that Drosophila models can be a valuable tool for identifying the molecular mechanisms underlying the difference of depressive disorder prevalence between men and women.

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  • 102.
    Moulin, Thiago
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo Meis, Rio De Janeiro, Brazil.
    Rayee, Danielle
    Univ Fed Rio de Janeiro, Inst Biomed Sci, Rio De Janeiro, Brazil.;Albert Einstein Coll Med, Dept Ophthalmol & Visual Sci, New York, NY USA..
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    The Synaptic Scaling Literature: A Systematic Review of Methodologies and Quality of Reporting2020In: Frontiers in Cellular Neuroscience, E-ISSN 1662-5102, Vol. 14, article id 164Article, review/survey (Refereed)
    Abstract [en]

    The maintenance of the excitability of neurons and circuits is a fundamental process for healthy brain functions. One of the main homeostatic mechanisms responsible for such regulation is synaptic scaling. While this type of plasticity is well-characterized through a robust body of literature, there are no systematic evaluations of the methodological and reporting features from these studies. Our review yielded 168 articles directly investigating synaptic scaling mechanisms, which display relatively high impact, with a median impact factor of 7.76 for the publishing journals. Our methodological analysis identified that 86% of the articles made use of inhibitory interventions to induce synaptic scaling, while only 41% of those studies contain excitatory manipulations. To verify the effects of synaptic scaling, the most assessed outcome was miniature excitatory postsynaptic current (mEPSC) recordings, performed in 71% of the articles. We could also observe that the field is mostly focused on mechanistic studies of the synaptic scaling pathways (70%), rather than the interaction with other types of plasticity, such as Hebbian processes (4%). We found that more than half of the articles failed to describe simple features, such as regulatory compliance statements, ethics committee approval, or statements of conflict of interests. In light of these results, we discuss the strengths and pitfalls existing in synaptic scaling literature.

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  • 103.
    Moulin, Thiago
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Rayêe, Danielle
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Sweden; Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Dendritic spine density changes and homeostatic synaptic scaling: a meta-analysis of animal studies2022In: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 17, no 1, p. 20-24Article in journal (Refereed)
    Abstract [en]

    Mechanisms of homeostatic plasticity promote compensatory changes of cellular excitability in response to chronic changes in the network activity. This type of plasticity is essential for the maintenance of brain circuits and is involved in the regulation of neural regeneration and the progress of neurodegenerative disorders. One of the most studied homeostatic processes is synaptic scaling, where global synaptic adjustments take place to restore the neuronal firing rate to a physiological range by the modulation of synaptic receptors, neurotransmitters, and morphology. However, despite the comprehensive literature on the electrophysiological properties of homeostatic scaling, less is known about the structural adjustments that occur in the synapses and dendritic tree. In this study, we performed a meta-analysis of articles investigating the effects of chronic network excitation (synaptic downscaling) or inhibition (synaptic upscaling) on the dendritic spine density of neurons. Our results indicate that spine density is consistently reduced after protocols that induce synaptic scaling, independent of the intervention type. Then, we discuss the implication of our findings to the current knowledge on the morphological changes induced by homeostatic plasticity.

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  • 104.
    Moulin, Thiago
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Excitability, synaptic balance, and addiction: The homeostatic dynamics of ionotropic glutamatergic receptors in VTA after cocaine exposure2020In: Behavioral and Brain Functions, E-ISSN 1744-9081, Vol. 16, no 1, article id 6Article in journal (Refereed)
    Abstract [en]

    Glutamatergic AMPA and NMDA receptors in the ventral tegmental area (VTA) are central for cocaine first exposure and posterior craving maintenance. However, the exact rules that coordinate the synaptic dynamics of these receptors in dopaminergic VTA neurons and behavioral outcomes are poorly understood. Additionally, synaptic homeostatic plasticity is present in response to chronic excitability changes in neuronal circuits, adjusting the strength of synapses to stabilize the firing rate. Despite having correspondent mechanisms, little is known about the relationship between continuous cocaine exposure and homeostatic synaptic changes in the VTA neurons. Here, we assess the role of homeostatic mechanisms in the neurobiology of cocaine addiction by providing a brief overview of the parallels between cocaine-induced synaptic potentiation and long-term synaptic adaptations, focusing on the regulation of GluA1- and GluN1- containing receptors.

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  • 105.
    Moulin, Thiago
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    van Egmond, Lieve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    A possible role for pollutants in mental disorders via gut microbiota2019In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 693, article id 133639Article in journal (Other academic)
  • 106.
    Mustafá, Emilio R.
    et al.
    Natl Univ La Plata UNLP, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Bectrophysiol, La Plata, Argentina.;Natl Univ La Plata UNLP, Prov Buenos Aires CIC PBA, Sci Res Commiss, La Plata, Argentina..
    Cordisco González, Santiago
    Natl Univ La Plata UNLP, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Bectrophysiol, La Plata, Argentina.;Natl Univ La Plata UNLP, Prov Buenos Aires CIC PBA, Sci Res Commiss, La Plata, Argentina..
    Damian, Marjorie
    Univ Montpellier, Inst Biomol Max Mousseron IBMM, CNRS, Montpellier, France..
    Cantel, Sonia
    Univ Montpellier, Inst Biomol Max Mousseron IBMM, CNRS, Montpellier, France..
    Denoyelle, Severine
    Univ Montpellier, Inst Biomol Max Mousseron IBMM, CNRS, Montpellier, France..
    Wagner, Renaud
    Ecole Super Biotechnol Strasbourg, Biotechnol & Signalisat Cellulaire, CNRS UMR7242, Plateforme IMPReSs, Strasbourg, France..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biothechnol, Moscow, Russia.
    Fehrentz, Jean-Alain
    Univ Montpellier, Inst Biomol Max Mousseron IBMM, CNRS, Montpellier, France..
    Banères, Jean-Louis
    Univ Montpellier, Inst Biomol Max Mousseron IBMM, CNRS, Montpellier, France..
    Perelló, Mario
    Natl Univ La Plata UNLP, Prov Buenos Aires CIC PBA, Sci Res Commiss, La Plata, Argentina.;Natl Univ La Plata UNLP, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Argentina..
    Raingo, Jesica
    Natl Univ La Plata UNLP, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Bectrophysiol, La Plata, Argentina.;Natl Univ La Plata UNLP, Prov Buenos Aires CIC PBA, Sci Res Commiss, La Plata, Argentina..
    LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling2021In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 12Article in journal (Refereed)
    Abstract [en]

    The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on CaV2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSR-binding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR.

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  • 107.
    Mwinyi, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Kanders, Sofia H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Strippoli, Marie-Pierre
    Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Eap, Chin B.
    Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland.
    Lasserre, Aurélie M.
    Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland.
    Vandeleur, Caroline L.
    Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland.
    Marques-Vidal, Pedro
    Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland..
    Preisig, Martin
    Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland.
    Antidepressant therapy, subtypes of major depressive disorder and the risk for weight gain: effect on body mass index, waist circumference, and fat massManuscript (preprint) (Other academic)
  • 108.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Brain Structure and Function in Adolescents with Atypical Anorexia Nervosa2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Atypical anorexia nervosa (AAN) has a high incidence in adolescents, resulting in significant morbidity and mortality. The weight loss is generally less pronounced than that experienced in full-syndrome anorexia nervosa (AN), but the medical consequences can be as severe. Neuroimaging could improve our knowledge regarding the pathogenesis of eating disorders, however research on adolescents is limited, and no neuroimaging studies have been conducted in AAN. In paper I, we investigated brain structure through a voxel-based morphometry analysis in 22 drug-naïve adolescent females newly-diagnosed with AAN, and 38 age- and sex-matched healthy controls. In Paper II, we investigated white matter microstructural integrity on 25 drug-naïve adolescent patients with AAN and 25 healthy controls, using diffusion tensor imaging with a tract-based spatial statistics approach. No differences in brain structure could be detected, indicating preserved regional grey matter volumes and white matter diffusivity in patients with AAN compared to controls. These findings suggest that previous observations of brain structure alterations in full syndrome AN may constitute state-related consequences of severe underweight. Alternatively, the preservation of brain structure might indeed differentiate AAN from AN. In paper III, we investigated resting-state functional connectivity in 22 drug-naïve adolescent patients with AAN, and 24 healthy controls. We report reduced connectivity in patients in brain areas involved in face-processing and social cognition, while an increased connectivity, correlating with depressive symptoms, was found in areas involved in the multimodal integration of sensory stimuli, aesthetic judgment, and social rejection anxiety. These findings point toward a core role for an altered development of socio-emotional skills in the pathogenesis of AAN. In Paper IV, we investigated neural connectivity underlying visual processing of foods with different caloric content in a sample of 28 adolescent females diagnosed with AAN, and 33 age- and sex-matched healthy controls. Our results showed higher connectivity in patients in pathways related to the integration of sensory input and memory retrieval, in response to food with high caloric content. This, however, was coupled to lower connectivity in salience and attentional networks, and lower connectivity between areas involved in visual food cues processing and appetite regulatory regions. Thus, despite food with high caloric content is associated to greater processing of somatosensory information in patients, it is attributed less salience and engages patients’ attention less than food with low caloric content.

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  • 109.
    Olivo, Gaia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala Univ, Dept Neurosci Funct Pharmacol, S-75124 Uppsala, Sweden.
    Gaudio, Santino
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Campus Biomed Roma, CIR, Area Diagnost Imaging, I-00128 Rome, Italy.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow 119146, Russia.
    Brain and Cognitive Development in Adolescents with Anorexia Nervosa: A Systematic Review of fMRI Studies2019In: Nutrients, E-ISSN 2072-6643, Vol. 11, no 8, article id 1907Article, review/survey (Refereed)
    Abstract [en]

    Anorexia nervosa (AN) is an eating disorder often occurring in adolescence. AN has one of the highest mortality rates amongst psychiatric illnesses and is associated with medical complications and high risk for psychiatric comorbidities, persisting after treatment. Remission rates range from 23% to 33%. Moreover, weight recovery does not necessarily reflect cognitive recovery. This issue is of particular interest in adolescence, characterized by progressive changes in brain structure and functional circuitries, and fast cognitive development. We reviewed existing literature on fMRI studies in adolescents diagnosed with AN, following PRISMA guidelines. Eligible studies had to: (1) be written in English; (2) include only adolescent participants; and (3) use block-design fMRI. We propose a pathogenic model based on normal and AN-related neural and cognitive maturation during adolescence. We propose that underweight and delayed puberty-caused by genetic, environmental, and neurobehavioral factors-can affect brain and cognitive development and lead to impaired cognitive flexibility, which in turn sustains the perpetuation of aberrant behaviors in a vicious cycle. Moreover, greater punishment sensitivity causes a shift toward punishment-based learning, leading to greater anxiety and ultimately to excessive reappraisal over emotions. Treatments combining physiological and neurobehavioral rationales must be adopted to improve outcomes and prevent relapses.

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  • 110.
    Olivo, Gaia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Zhukovsky, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Salonen-Ros, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Department of Human Biology, University of Cape Town, Cape Town, South Africa; School of Natural Sciences and Psychology, Research Centre for Brain & Behaviour, Byrom Street, Liverpool, UK.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Functional connectivity underlying hedonic response to food in female adolescents with atypical AN: The role of somatosensory and salience networks2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, article id 276Article in journal (Refereed)
    Abstract [en]

    Atypical Anorexia Nervosa (AN) usually occurs during adolescence. Patients are often in the normal-weight range at diagnosis, however they often present with signs of medical complications and severe restraint over eating, body dissatisfaction, and low self-esteem. We investigated functional circuitry underlying the hedonic response in 28 female adolescent patients diagnosed with atypical AN and 33 healthy controls. Participants were shown images of food with high (HC) or low (LC) caloric content in alternating blocks during functional MRI. The HC > LC contrast was calculated. Based on previous literature on full-threshold AN, we hypothesized that patients would exhibit increased connectivity in areas involved in sensory processing and bottom-up responses, coupled to increased connectivity from areas related to top-down inhibitory control, compared with controls. Patients showed increased connectivity in pathways related to multimodal somatosensory processing and memory retrieval. The connectivity was on the other hand decreased in patients in salience and attentional networks, and in a wide cerebello-occipital network. Our study was the first investigation of food-related neural response in atypical AN. Our findings support higher somatosensory processing in patients in response to HC food images compared with controls, however HC food was less efficient than LC food in engaging patients’ bottom-up salient responses, and was not associated with connectivity increases in inhibitory control regions. These findings suggest that the psychopathological mechanisms underlying food restriction in atypical AN differ from full-threshold AN. Elucidating the mechanisms underlying the development and maintenance of eating behaviour in atypical AN might help designing specific treatment strategies.

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  • 111.
    Pacheco, André P
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Gut microbiome as a therapeutic target in the treatment of sleep disorders: where we are2021In: Sleep Medicine Reviews, ISSN 1087-0792, E-ISSN 1532-2955, Vol. 60, article id 101547Article in journal (Refereed)
  • 112.
    Partinen, Markku
    et al.
    Univ Helsinki, Dept Clin Neurosci, Clinicum Unit, Helsinki, Finland.;Helsinki Sleep Clin, Terveystalo Healthcare Serv, Helsinki, Finland..
    Holzinger, Brigitte
    Med Univ Vienna, Inst Dream & Consciousness Res, Vienna, Austria..
    Morin, Charles M.
    Univ Laval, Ctr Etud Troubles Sommeil, Ctr Rech CERVO, Brain Res Ctr,Ecole Psychol, Quebec City, PQ, Canada..
    Espie, Colin
    Univ Oxford, Sleep & Circadian Neurosci Inst, Nuffield Dept Clin Neurosci, Oxford, England..
    Chung, Frances
    Univ Hlth Network, Dept Anesthesiol & Pain Med, Toronto, ON, Canada..
    Penzel, Thomas
    Charite, Sleep Med Ctr, Berlin, Germany..
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Bolstad, Courtney J.
    Mississippi State Univ, Dept Psychol, Mississippi State, MS USA..
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Northwestern Univ, Dept Med, Div Endocrinol Metab & Mol Med, Feinberg Sch Med, Chicago, IL USA..
    Chan, Rachel Ngan Yin
    Chinese Univ Hong Kong, Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, Hong Kong, Peoples R China..
    Dauvilliers, Yves
    Univ Hosp Ctr Montpellier, Gui De Chauliac Hosp, Natl Reference Ctr Narcolepsy, Dept Neurol,Sleep & Wake Unit, Montpellier, France..
    De Gennaro, Luigi
    Sapienza Univ Rome, Dept Psychol, Rome, Lazio, Italy.;IRCCS Fdn Santa Lucia, Rome, Italy..
    Han, Fang
    Peking Univ, Dept Pulm Med, Peoples Hosp, Beijing, Peoples R China..
    Inoue, Yuichi
    Tokyo Med Univ, Dept Somnol, Shinjuku Ku, Tokyo, Japan.;Japan Somnol Ctr, Neuropsychiat Res Inst, Tokyo, Japan..
    Matsui, Kentaro
    Natl Inst Mental Hlth, Natl Ctr Neurol & Psychiat, Dept Clin Lab, Kodaira, Tokyo, Japan.;Natl Inst Mental Hlth, Natl Ctr Neurol & Psychiat, Dept Sleep Wake Disorders, Kodaira, Tokyo, Japan.;Tokyo Womens Med Univ, Dept Psychiat, Shinjuku Ku, Tokyo, Japan..
    Leger, Damien
    Hop Hotel Dieu Paris, Sleep & Vigilance Ctr, Paris, France.;Univ Paris, VIFASOM EA 7331 Vigilance Fatigue Sommeil & Sante, Paris, France..
    Cunha, Ana Suely
    Univ Fed Rio Grande do Norte, Prod Engn Dept, Natal, RN, Brazil..
    Merikanto, Ilona
    Univ Helsinki, Fac Med, Res Programs Unit, Helsinki, Finland..
    Mota-Rolim, Sergio
    Onofre Lopes Univ Hosp, Brain Inst, Petropolis, RJ, Brazil.;Univ Fed Rio Grande do Norte, Physiol & Behav Dept, Natal, RN, Brazil..
    Nadorff, Michael
    Mississippi State Univ, Dept Psychol, Mississippi State, MS USA..
    Plazzi, Giuseppe
    IRCCS Ist Sci Neurol Bologna, Bologna, Italy.;Univ Modena & Reggio Emilia, Dept Biomed Metab & Neural Sci, Modena, Italy..
    Schneider, Jules
    Univ Oxford, Sleep & Circadian Neurosci Inst, Nuffield Dept Clin Neurosci, Oxford, England..
    Sieminski, Mariusz
    Med Univ Gdansk, Dept Emergency Med, Gdansk, Poland..
    Wing, Yun-Kwok
    Chinese Univ Hong Kong, Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, Hong Kong, Peoples R China..
    Bjorvatn, Bjorn
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.;Haukeland Hosp, Norwegian Competence Ctr Sleep Disorders, Bergen, Norway..
    Sleep and daytime problems during the COVID-19 pandemic and effects of coronavirus infection, confinement and financial suffering: a multinational survey using a harmonised questionnaire2021In: BMJ Open, E-ISSN 2044-6055, Vol. 11, no 12, article id e050672Article in journal (Refereed)
    Abstract [en]

    Objectives Sleep is important for human health and well-being. No previous study has assessed whether the COVID-19 pandemic impacts sleep and daytime function across the globe. Methods This large-scale international survey used a harmonised questionnaire. Fourteen countries participated during the period of May-August 2020. Sleep and daytime problems (poor sleep quality, sleep onset and maintenance problems, nightmares, hypnotic use, fatigue and excessive sleepiness) occurring 'before' and 'during' the pandemic were investigated. In total, 25 484 people participated and 22 151 (86.9%) responded to the key parameters and were included. Effects of COVID-19, confinement and financial suffering were considered. In the fully adjusted logistic regression models, results (weighted and stratified by country) were adjusted for gender, age, marital status, educational level, ethnicity, presence of sleep problems before COVID-19 and severity of the COVID-19 pandemic in each country at the time of the survey. Results The responders were mostly women (64%) with a mean age 41.8 (SD 15.9) years (median 39, range 18-95). Altogether, 3.0% reported having had COVID-19; 42.2% reported having been in confinement; and 55.9% had suffered financially. All sleep and daytime problems worsened during the pandemic by about 10% or more. Also, some participants reported improvements in sleep and daytime function. For example, sleep quality worsened in about 20% of subjects and improved in about 5%. COVID-19 was particularly associated with poor sleep quality, early morning awakening and daytime sleepiness. Confinement was associated with poor sleep quality, problems falling asleep and decreased use of hypnotics. Financial suffering was associated with all sleep and daytime problems, including nightmares and fatigue, even in the fully adjusted logistic regression models. Conclusions Sleep problems, fatigue and excessive sleepiness increased significantly worldwide during the first phase of the COVID-19 pandemic. Problems were associated with confinement and especially with financial suffering.

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  • 113.
    Paula Cornejo, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Natl Univ La Plata, Lab Neurophysiol, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, La Plata, Buenos Aires, Argentina;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina.
    Castrogiovanni, Daniel
    Natl Univ La Plata, Lab Neurophysiol, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, La Plata, Buenos Aires, Argentina;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Reynaldo, Mirta
    Natl Univ La Plata, Lab Neurophysiol, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, La Plata, Buenos Aires, Argentina;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina.
    Marie, Jacky
    Univ Montpellier, Fac Pharm, Inst Biomol Max Mousseron, UMR 5247,CNRS,ENSCM, Montpellier, France.
    Fehrentz, Jean-Alain
    Univ Montpellier, Fac Pharm, Inst Biomol Max Mousseron, UMR 5247,CNRS,ENSCM, Montpellier, France.
    Perello, Mario
    Natl Univ La Plata, Lab Neurophysiol, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, La Plata, Buenos Aires, Argentina;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina.
    Growth hormone secretagogue receptor signalling affects high-fat intake independently of plasma levels of ghrelin and LEAP2, in a 4-day binge eating model2019In: Journal of neuroendocrinology, ISSN 0953-8194, E-ISSN 1365-2826, Vol. 31, no 10, article id e12785Article in journal (Refereed)
    Abstract [en]

    The growth hormone secretagogue receptor (GHSR) is a G protein-coupled receptor that is highly expressed in the central nervous system. GHSR acts as a receptor for ghrelin and for liver-expressed antimicrobial peptide 2 (LEAP2), which blocks ghrelin-evoked activity. GHSR also displays ligand-independent activity, including a high constitutive activity that signals in the absence of ghrelin and is reduced by LEAP2. GHSR activity modulates a variety of food intake-related behaviours, including binge eating. Previously, we reported that GHSR-deficient mice daily and time-limited exposed to a high-fat (HF) diet display an attenuated binge-like HF intake compared to wild-type mice. In the present study, we aimed to determine whether ligand-independent GHSR activity affects binge-like HF intake in a 4-day binge-like eating protocol. We found that plasma levels of ghrelin and LEAP2 were not modified in mice exposed to this binge-like eating protocol. Moreover, systemic administration of ghrelin or LEAP2 did not alter HF intake in our experimental conditions. Interestingly, we found that central administration of LEAP2 or K-(D-1-Nal)-FwLL-NH2, which are both blockers of constitutive GHSR activity, reduced binge-like HF intake, whereas central administration of ghrelin or the ghrelin-evoked GHSR activity blockers [D-Lys3]-GHRP-6 and JMV2959 did not modify binge-like HF intake. Taken together, current data indicate that GHSR activity in the brain affects binge-like HF intake in mice independently of plasma levels of ghrelin and LEAP2.

  • 114.
    Pauls, Dennis
    et al.
    Univ Wurzburg, Bioctr, Theodor Boveri Inst, Neurobiol & Genet, D-97074 Wurzburg, Germany.;Univ Leipzig, Inst Biol, Dept Anim Physiol, Talstr 33, D-04103 Leipzig, Germany..
    Selcho, Mareike
    Univ Wurzburg, Bioctr, Theodor Boveri Inst, Neurobiol & Genet, D-97074 Wurzburg, Germany.;Univ Leipzig, Inst Biol, Dept Anim Physiol, Talstr 33, D-04103 Leipzig, Germany..
    Raederscheidt, Johanna
    Univ Wurzburg, Bioctr, Theodor Boveri Inst, Neurobiol & Genet, D-97074 Wurzburg, Germany..
    Amatobi, Kelechi M.
    Univ Wurzburg, Bioctr, Julius von Sachs Inst, Pharmaceut Biol, Julius von Sachs Pl 2, D-97082 Wurzburg, Germany..
    Fekete, Agnes
    Univ Wurzburg, Bioctr, Julius von Sachs Inst, Pharmaceut Biol, Julius von Sachs Pl 2, D-97082 Wurzburg, Germany..
    Krischke, Markus
    Univ Wurzburg, Bioctr, Julius von Sachs Inst, Pharmaceut Biol, Julius von Sachs Pl 2, D-97082 Wurzburg, Germany..
    Hermann-Luibl, Christiane
    Univ Wurzburg, Bioctr, Theodor Boveri Inst, Neurobiol & Genet, D-97074 Wurzburg, Germany..
    Ozbek-Unal, Ayten Gizem
    Univ Wurzburg, Bioctr, Theodor Boveri Inst, Neurobiol & Genet, D-97074 Wurzburg, Germany..
    Ehmann, Nadine
    Univ Leipzig, Inst Biol, Dept Anim Physiol, Talstr 33, D-04103 Leipzig, Germany..
    Itskov, Pavel M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Easy Behav, Rua Sao Tome & Principe 23, P-2765282 Estoril, Portuga.
    Kittel, Robert J.
    Univ Leipzig, Inst Biol, Dept Anim Physiol, Talstr 33, D-04103 Leipzig, Germany..
    Helfrich-Foerster, Charlotte
    Univ Wurzburg, Bioctr, Theodor Boveri Inst, Neurobiol & Genet, D-97074 Wurzburg, Germany..
    Kuehnlein, Ronald P.
    Karl Franzens Univ Graz, Inst Mol Biosci, Humboldtstr 50, A-8010 Graz, Austria.;BioTechMed Graz, A-8010 Graz, Austria.;Karl Franzens Univ Graz, Field Excellence BioHlth, Humboldtstr 50, A-8010 Graz, Austria..
    Mueller, Martin J.
    Univ Wurzburg, Bioctr, Julius von Sachs Inst, Pharmaceut Biol, Julius von Sachs Pl 2, D-97082 Wurzburg, Germany..
    Wegener, Christian
    Univ Wurzburg, Bioctr, Theodor Boveri Inst, Neurobiol & Genet, D-97074 Wurzburg, Germany..
    Endocrine signals fine-tune daily activity patterns in Drosophila2021In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 31, no 18, p. 4076-+Article in journal (Refereed)
    Abstract [en]

    Animals need to balance competitive behaviors to maintain internal homeostasis. The underlying mechanisms are complex but typically involve neuroendocrine signaling. Using Drosophila, we systematically manipulated signaling between energy-mobilizing endocrine cells producing adipokinetic hormone (AKH), octopaminergic neurons, and the energy-storing fat body to assess whether this neuroendocrine axis involved in starvation-induced hyperactivity also balances activity levels under ad libitum access to food. Our results suggest that AKH signals via two divergent pathways that are mutually competitive in terms of activity and rest. AKH increases activity via the octopaminergic system during the day, while it prevents high activity levels during the night by signaling to the fat body. This regulation involves feedback signaling from octopaminergic neurons to AKH-producing cells (APCs). APCs are known to integrate a multitude of metabolic and endocrine signals. Our results add a new facet to the versatile regulatory functions of APCs by showing that their output contributes to shape the daily activity pattern under ad libitum access to food.

  • 115.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
    Lundin, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Preisig, Martin
    Gholam-Rezaee, Mehdi
    Castelao, Enrique
    Pistis, Giorgio
    Merikangas, Kathleen R.
    Glaus, Jennifer
    Squassina, Alessio
    Del Zompo, Maria
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Major depression subtypes are differentially associated with migraine subtype, prevalence and severity2020In: Cephalalgia, ISSN 0333-1024, E-ISSN 1468-2982, Vol. 40, no 4, p. 347-356Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Migraine and major depressive disorder show a high rate of comorbidity, but little is known about the associations between the subtypes of major depressive disorder and migraine. In this cross-sectional study we aimed at investigating a) the lifetime associations between the atypical, melancholic, combined and unspecified subtype of major depressive disorder and migraine with and without aura and b) the associations between major depressive disorder and its subtypes and the severity of migraine.

    METHODS: A total of 446 subjects with migraine (migraine without aura: n = 294; migraine with aura: n = 152) and 2511 controls from the population-based CoLaus/PsyCoLaus study, Switzerland, were included. Associations between major depressive disorder subtypes and migraine characteristics were tested using binary logistic or linear regression.

    RESULTS: Melancholic, combined and unspecified major depressive disorder were associated with increased frequency of migraine with aura, whereas only melancholic major depressive disorder was associated with increased frequency of migraine without aura. Lifetime and unspecified major depressive disorder were associated with severe migraine intensity among subjects with migraine with aura but not migraine without aura, while combined major depressive disorder was associated with higher migraine frequency independently from migraine subtype.

    CONCLUSION: This study suggests that melancholic but not atypical major depressive disorder is associated with migraine and migraine subtypes. Future studies exploring pathophysiological mechanisms shared between melancholic depression and migraine are warranted.

  • 116.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, I-09042 Cagliari, Italy.;Uppsala Univ, Sect Funct Pharmacol & Neurosci, Dept Surg Sci, S-75124 Uppsala, Sweden..
    Meloni, Anna
    Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, I-09042 Cagliari, Italy..
    Severino, Giovanni
    Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, I-09042 Cagliari, Italy..
    Squassina, Alessio
    Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, I-09042 Cagliari, Italy.;Dalhousie Univ, Dept Psychiat, Fac Med, Halifax, NS B3H 2E2, Canada..
    Genetic and Epigenetic Markers of Lithium Response2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 3, p. 1555-, article id 1555Article in journal (Refereed)
    Abstract [en]

    The mood stabilizer lithium represents a cornerstone in the long term treatment of bipolar disorder (BD), although with substantial interindividual variability in clinical response. This variability appears to be modulated by genetics, which has been significantly investigated in the last two decades with some promising findings. In addition, recently, the interest in the role of epigenetics has grown significantly, since the exploration of these mechanisms might allow the elucidation of the gene-environment interactions and explanation of missing heritability. In this article, we provide an overview of the most relevant findings regarding the pharmacogenomics and pharmacoepigenomics of lithium response in BD. We describe the most replicated findings among candidate gene studies, results from genome-wide association studies (GWAS) as well as post-GWAS approaches supporting an association between high genetic load for schizophrenia, major depressive disorder or attention deficit/hyperactivity disorder and poor lithium response. Next, we describe results from studies investigating epigenetic mechanisms, such as changes in methylation or noncoding RNA levels, which play a relevant role as regulators of gene expression. Finally, we discuss challenges related to the search for the molecular determinants of lithium response and potential future research directions to pave the path towards a biomarker guided approach in lithium treatment.

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  • 117.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Sp 8 Sestu Monserrato, I-09042 Cagliari, Italy.
    Squassina, A.
    Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Sp 8 Sestu Monserrato, I-09042 Cagliari, Italy.;Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada..
    Rationale of the potential role of lithium in the antiaging arena2020In: Drugs of the future, ISSN 0377-8282, E-ISSN 2013-0368, Vol. 45, no 6, p. 397-407Article, review/survey (Refereed)
    Abstract [en]

    Lithium is the mainstay treatment in the management of bipolar disorder. A growing body of findings suggests that lithium could be considered a neuroprotective agent that might slow the progression of neurobiological abnormalities in Alzheimer's disease and possibly in other neurodegenerative disorders. Additionally, the effect of lithium on telomere length, as well as the increased overall survival associated with microdoses of lithium in drinking water, led to hypothesize that lithium might have "antiaging" properties. In this review, we summarize available evidence from preclinical and clinical studies investigating the potential beneficial effects of lithium in the antiaging arena and in neurodegenerative disorders, as well as the putative underlying molecular mechanisms, including inhibition of the glycogen synthase kinase-3 (GSK-3) enzyme, reduction of oxidative stress and counteraction of telomere shortening. Additionally, we present a timely overview of currently active clinical trials that might enhance our understanding of the beneficial properties of lithium and highlight the potential for drug repurposing.

  • 118.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy.
    Squassina, Alessio
    Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy;Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada.
    Treatment-Resistant Schizophrenia: Insights From Genetic Studies and Machine Learning Approaches2019In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 10, article id 617Article, review/survey (Refereed)
    Abstract [en]

    Schizophrenia (SCZ) is a severe psychiatric disorder affecting approximately 23 million people worldwide. It is considered the eighth leading cause of disability according to the Wood Health Organization and is associated with a significant reduction in life expectancy. Antipsychotics represent the first-choice treatment in SCZ, but approximately 30% of patients fail to respond to acute treatment. These patients are generally defined as treatment-resistant and are eligible for clozapine treatment. Treatment-resistant patients show a more severe course of the disease, but it has been suggested that treatment-resistant schizophrenia (TRS) may constitute a distinct phenotype that is more than just a more severe form of SCZ. TRS is heritable, and genetics has been shown to play an important role in modulating response to antipsychotics. Important efforts have been put into place in order to better understand the genetic architecture of TRS, with the main goal of identifying reliable predictive markers that might improve the management and quality of life of TRS patients. However, the number of candidate gene and genome-wide association studies specifically focused on TRS is limited, and to date, findings do not allow the disentanglement of its polygenic nature. More recent studies implemented polygenic risk score, gene-based and machine learning methods to explore the genetics of TRS, reporting promising findings. In this review, we present an overview on the genetics of TRS, particularly focusing our discussion on studies implementing polygenic approaches.

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  • 119.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Dept Biomed Sci, Cagliari, Italy..
    Welander, Nike Zoe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Association between migraine prevalence, treatment with proton-pump inhibitors and CYP2C19 phenotypes in UK Biobank2021In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 143, article id 112234Article in journal (Refereed)
    Abstract [en]

    Proton-pump inhibitors (PPIs) are used to suppress gastric acid secretion in several gastrointestinal conditions. While these drugs are generally well tolerated, their long-term use may be associated with different adverse effects, including migraine. We analyzed the association between treatment with PPIs (omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole) and migraine prevalence in the UK Biobank cohort through a cross-sectional analysis (using baseline data for 468,280 participants, 16,390 of whom had migraine) and a longitudinal analysis (including 145,007 participants with no migraine at baseline, of whom 3786 had probable migraine without aura [MWOA] and 9981 probable migraine with aura [MWA] or both MWOA and MWA at an average follow-up time of 10.06 years). We also evaluated the modulating role of the metabolizer phenotype of CYP2C19, the major enzyme involved in PPI clearance. Treatment with PPIs was associated with higher migraine prevalence at baseline (odds ratio [OR] = 1.25, p < 0.0001). CYP2C19 rapid metabolizer phenotype was associated with lower prevalence of migraine exclusively in participants treated with PPIs (OR = 0.89, p = 0.029). In addition, treatment with PPIs was associated with higher incidence of both probable MWOA (OR = 1.24, p = 0.002) and MWA (OR = 1.43, p < 0.0001) at follow-up. Treatment with PPIs and CYP2C19 poor metabolizer status were associated with higher incidence of probable chronic migraine exclusively in men. Our results suggest a significant association between treatment with PPIs and migraine in this large population-based cohort and support a potential relevant role of gender and CYP2C19 phenotype.

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  • 120.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Del Zompo, Maria
    Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy.
    Squassina, Alessio
    Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, article id 315Article in journal (Refereed)
    Abstract [en]

    Patients with bipolar disorder (BD) show higher frequency of obesity and type 2 diabetes (T2D), but the underlying genetic determinants and molecular pathways are not well studied. Using large publicly available datasets, we (1) conducted a gene-based analysis using MAGMA to identify genes associated with BD and body mass index (BMI) or T2D and investigated their functional enrichment; and (2) performed two meta-analyses between BD and BMI, as well as BD and T2D using Metasoft. Target druggability was assessed using the Drug Gene Interaction Database (DGIdb). We identified 518 and 390 genes significantly associated with BD and BMI or BD and T2D, respectively. A total of 52 and 12 genes, respectively, were significant after multiple testing correction. Pathway analyses conducted on nominally significant targets showed that genes associated with BD and BMI were enriched for the Neuronal cell body Gene Ontology (GO) term (p = 1.0E-04; false discovery rate (FDR) = 0.025) and different pathways, including the Signaling by Hedgehog pathway (p = 4.8E -05, FDR = 0.02), while genes associated with BD and T2D showed no specific enrichment. The meta-analysis between BD and BMI identified 64 relevant single nucleotide polymorphisms (SNPs). While the majority of these were located in intergenic regions or in a locus on chromosome 16 near and in the NPIPL1 and SH2B1 genes (best SNP: rs4788101, p = 2.1E-24), five were located in the ETV5 gene (best SNP: rs1516725, p= 1E-24), which was previously associated with both BD and obesity, and one in the RPGRIP1L gene (rs1477199, p = 5.7E-09), which was also included in the Signaling by Hedgehog pathway. The meta-analysis between BD and T2D identified six significant SNPs, three of which were located in ALAS1 (best SNP: rs352165, p = 3.4E-08). Thirteen SNPs associated with BD and BMI, and one with BD and T2D, were located in genes which are part of the druggable genome. Our results support the hypothesis of shared genetic determinants between BD and BMI and point to genes involved in Hedgehog signaling as promising targets.

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  • 121.
    Rasmusson, Annica J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Cervenka: Psychiatry.
    Gallwitz, Maike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Cervenka: Psychiatry.
    Soltanabadi, Bardia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Cervenka: Psychiatry.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Mengel-From, Jonas
    Univ Southern Denmark, Danish Twin Registry, Epidemiol Biostat & Biodemog, Dept Publ Hlth, Odense, Denmark.;Odense Univ Hosp, Dept Clin Genet, Odense, Denmark..
    Christensen, Kaare
    Univ Southern Denmark, Danish Twin Registry, Epidemiol Biostat & Biodemog, Dept Publ Hlth, Odense, Denmark.;Odense Univ Hosp, Dept Clin Genet, Odense, Denmark.;Odense Univ Hosp, Dept Clin Biochem & Pharmacol, Odense, Denmark..
    Nygaard, Marianne
    Univ Southern Denmark, Danish Twin Registry, Epidemiol Biostat & Biodemog, Dept Publ Hlth, Odense, Denmark.;Odense Univ Hosp, Dept Clin Genet, Odense, Denmark..
    Soerensen, Mette
    Univ Southern Denmark, Danish Twin Registry, Epidemiol Biostat & Biodemog, Dept Publ Hlth, Odense, Denmark.;Odense Univ Hosp, Dept Clin Genet, Odense, Denmark.;Odense Univ Hosp, Dept Clin Biochem & Pharmacol, Odense, Denmark..
    Boström, Adrian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Czamara, Darina
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Binder, Elisabeth B.
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Cervenka: Psychiatry.
    Toll-like receptor 4 methylation grade is linked to depressive symptom severity2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, article id 371Article in journal (Refereed)
    Abstract [en]

    This study explores potential associations between the methylation of promoter-associated CpG sites of the toll-like receptor (TLR)-family, plasma levels of pro-inflammatory proteins and depressive symptoms in young female psychiatric patients. Ratings of depressive symptoms and blood samples were obtained from 92 young women seeking psychiatric care. Methylation of 32 promoter-associated CpG sites in TLR1 to TLR10 was analysed using the Illumina Infinium Methylation EPIC BeadChip. Expression levels of 91 inflammatory proteins were determined by proximity extension assay. Statistical correlations between depressive state, TLR1-10 methylation and inflammatory proteins were investigated. Four additional cohorts were studied to evaluate the generalizability of the findings. In the discovery cohort, methylation grade of cg05429895 (TLR4) in blood was inversely correlated with depressive symptoms score in young adults. After correction for multiple testing, plasma levels of macrophage inflammatory protein 1 beta (MIP-1 beta/CCL4) were associated with both TLR4 methylation and depressive symptom severity. A similar inverse association between TLR4 methylation in blood and affective symptoms score was also found in a cohort of 148 both males and females (<40 years of age) from the Danish Twin Registry. These findings were not, however, replicated in three other external cohorts; which differed from the first two cohorts by a higher age and mixed ethnicities, thus limiting the generalizability of our findings. However, TLR4 methylation inversely correlated with TLR4 mRNA expression in the Danish Twin Study indicating a functional significance of methylation at this particular CpG. Higher depression scores in young Scandinavian adults was associated with decreased methylation of TLR4 in blood.

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  • 122.
    Rukh, Gull
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Dang, Junhua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Personality, lifestyle and job satisfaction: causal association between neuroticism and job satisfaction using Mendelian randomisation in the UK biobank cohort2020In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 10, no 1, article id 11Article in journal (Refereed)
    Abstract [en]

    Job-related stress has been associated with poor health outcomes but little is known about the causal nature of these findings. We employed Mendelian randomisation (MR) approach to investigate the causal effect of neuroticism, education, and physical activity on job satisfaction. Trait-specific genetic risk score (GRS) based on recent genome wide association studies were used as instrumental variables (IV) using the UK Biobank cohort (N = 315,536). Both single variable and multivariable MR analyses were used to determine the effect of each trait on job satisfaction. We observed a clear evidence of a causal association between neuroticism and job satisfaction. In single variable MR, one standard deviation (1 SD) higher genetically determined neuroticism score (4.07 units) was associated with -0.31 units lower job satisfaction (95% confidence interval (CI): -0.38 to -0.24; P = 9.5 x 10(-20)). The causal associations remained significant after performing sensitivity analyses by excluding invalid genetic variants from GRS(Neuroticism) (beta(95%CI): -0.28(-0.35 to -0.21); P = 3.4 x 10(-15)). Education (0.02; -0.08 to 0.12; 0.67) and physical activity (0.08; -0.34 to 0.50; 0.70) did not show any evidence for causal association with job satisfaction. When genetic instruments for neuroticism, education and physical activity were included together, the association of neuroticism score with job satisfaction was reduced by only -0.01 units, suggesting an independent inverse causal association between neuroticism score (P = 2.7 x 10(-17)) and job satisfaction. Our findings show an independent causal association between neuroticism score and job satisfaction. Physically active lifestyle may help to increase job satisfaction despite presence of high neuroticism scores. Our study highlights the importance of considering the confounding effect of negative personality traits for studies on job satisfaction.

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  • 123.
    Shalimova, Alena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow 119991, Russia..
    Babasieva, Viktoria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow 119991, Russia..
    Chubarev, Vladimir N.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow 119991, Russia..
    Tarasov, Vadim V.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow 119991, Russia.;IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow 119991, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow 119991, Russia..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Therapy response prediction in major depressive disorder: current and novel genomic markers influencing pharmacokinetics and pharmacodynamics2021In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 22, no 8, p. 485-503Article, review/survey (Refereed)
    Abstract [en]

    Major depressive disorder is connected with high rates of functional disability and mortality. About a third of the patients are at risk of therapy failure. Several pharmacogenetic markers especially located in CYP450 genes such as CYP2D6 or CYP2C19 are of relevance for therapy outcome prediction in major depressive disorder but a further optimization of predictive tools is warranted. The article summarizes the current knowledge on pharmacogenetic variants, therapy effects and side effects of important antidepressive therapeutics, and sheds light on new methodological approaches for therapy response estimation based on genetic markers with relevance for pharmacokinetics, pharmacodynamics and disease pathology identified in genome-wide association study analyses, highlighting polygenic risk score analysis as a tool for further optimization of individualized therapy outcome prediction.

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  • 124.
    Sokolov, Aleksandr V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Dostdar, Samira A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Krasilnikova, Aleksandra A.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Ilina, Anastasia A.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Nabieva, Amina Sh
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Lisitsyna, Anna A.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Chubarev, Vladimir N.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Tarasov, Vadim V.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia.;IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Brain Cancer Drug Discovery: Clinical Trials, Drug Classes, Targets, and Combinatorial Therapies2021In: Pharmacological Reviews, ISSN 0031-6997, E-ISSN 1521-0081, Vol. 73, no 4, p. 1-32Article, review/survey (Refereed)
    Abstract [en]

    Brain cancer is a formidable challenge for drug development, and drugs derived from many cutting-edge technologies are being tested in clinical trials. We manually characterized 981 clinical trials on brain tumors that were registered in ClinicalTrials. gov from 2010 to 2020. We identified 582 unique therapeutic entities targeting 581 unique drug targets and 557 unique treatment combinations involving drugs. We performed the classification of both the drugs and drug targets based on pharmacological and structural classifications. Our analysis demonstrates a large diversity of agents and targets. Currently, we identified 32 different pharmacological directions for therapies that are based on 42 structural classes of agents. Our analysis shows that kinase inhibitors, chemotherapeutic agents, and cancer vaccines are the three most common classes of agents identified in trials. Agents in clinical trials demonstrated uneven distribution in combination approaches; chemotherapy agents, proteasome inhibitors, and immune modulators frequently appeared in combinations, whereas kinase inhibitors, modified immune effector cells did not as was shown by combination networks and descriptive statistics. This analysis provides an extensive overview of the drug discovery field in brain cancer, shifts that have been happening in recent years, and challenges that are likely to come. Significance Statement-This review provides comprehensive quantitative analysis and discussion of the brain cancer drug discovery field, including classification of drug, targets, and therapies.

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  • 125.
    Squassina, Alessio
    et al.
    Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy;Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada.
    Meloni, Anna
    Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy.
    Chillotti, Caterina
    Univ Hosp Cagliari, Unit Clin Pharmacol, Cagliari, Italy.
    Pisanu, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy.
    Zinc finger proteins in psychiatric disorders and response to psychotropic medications2019In: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 29, no 5, p. 132-141Article, review/survey (Refereed)
    Abstract [en]

    Zinc finger proteins are a large family of abundantly expressed small motifs that play a crucial role in a wide range of physiological and pathophysiological mechanisms. Findings published so far support an involvement of zinc fingers in psychiatric disorders. Most of the evidence has been provided for the zinc finger protein 804A (ZNF804A) gene, which has been suggested to be implicated in schizophrenia and bipolar disorder. This evidence has been corroborated by a wide range of functional studies showing that ZNF804A regulates the expression of genes involved in cell adhesion and plays a crucial role in neurite formation and maintenance of dendritic spines. On the other hand, far less is known on other zinc finger proteins and their involvement in psychiatric disorders. In this review, we discussed studies exploring the role of zinc finger proteins in schizophrenia, bipolar disorder, and major depressive disorder as well as in pharmacogenetics of psychotropic drugs.

  • 126.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Does the Common Type 2 Diabetes-Susceptibility Variant in the MTNR1B Gene Matter for Glycemic Control Among Patients on Antidiabetic Pharmacotherapy?2021In: Mayo Clinic proceedings, ISSN 0025-6196, E-ISSN 1942-5546, Vol. 96, no 5, p. 1372-1374Article in journal (Refereed)
  • 127.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Increased Risk of Myocardial Infarction Among Patients With Type 2 Diabetes Who Carry the Common rs10830963 Variant in the MTNR1B Gene2020In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 43, no 9, p. 2289-2292Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE The common MTNR1B single nucleotide polymorphism rs10830963 associates with risk of type 2 diabetes (T2D). Here, we examine the association between this gene variant and the risk of myocardial infarction (MCI) among patients with T2D. MCI is a main cause of death and disability among such individuals.

    RESEARCH DESIGN AND METHODS Data from the UK Biobank cohort were used in order to examine the association between rs10830963 and incidence of MCI (fatal and nonfatal) among 13,655 participants with probable T2D during a follow-up period of 6.8 years.

    RESULTS Assuming an additive genetic model, a positive association was found between the rs10830963 variant in the MTNR1B gene and the risk for incident MCI during the 6.8-year follow-up (adjusted hazard ratio per G allele 1.19 [95% CI 1.02, 1.40],P= 0.03).

    CONCLUSIONS The rs10830963 polymorphism may be a useful genetic marker for MCI in patients with T2D.

  • 128.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Sleep characteristics and HbA1c in patients with type 2 diabetes on glucose-lowering medication2020In: BMJ Open Diabetes Research & Care, ISSN 2052-4897, Vol. 8, no 1, article id e001702Article in journal (Refereed)
    Abstract [en]

    Introduction To examine the association of sleep duration, insomnia, and obstructive sleep apnea (OSA) with hemoglobin A1c (HbA1c) in a cohort of patients with type 2 diabetes (T2D) on glucose-lowering medications.

    Research design and methods 13 346 patients with T2D were included in the present analysis (mean age: 60.2 years; 56.6% were on antidiabetic drug monotherapy; 43.4% received at least two glucose-lowering medications). Sleep duration (short: ≤6 hours/day; normal: 7–8 hours/day; long: ≥9 hours/day) and frequency of insomnia symptoms were self-reported. The risk of OSA was considered high if at least two of the following conditions were fulfilled: regular snoring, frequent daytime sleepiness, and either obesity (≥30 kg/m2) or hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg). Associations between sleep variables and HbA1c were investigated by analysis of covariance or linear regression (adjusted for, eg, participants’ age, sex, ethnic background, and systolic blood pressure).

    Results Long sleep duration and a high risk for OSA were independently associated with higher HbA1c values (long vs normal sleep duration: +0.10% (95% CI 0.03 to 0.18); high vs low risk for OSA: +0.07% (95% CI 0.02 to 0.11), both p=0.004). No robust association was found of short sleep duration and frequent insomnia symptoms with HbA1c. Finally, a positive dose–response association between the number of sleep problems per subject (range: 0–3) and HbA1c was observed (β=0.04% (0.02 to 0.06), p=0.002). However, all significant associations were small.

    Conclusion Screening for and treatment of sleep problems may help lower HbA1c levels in patients with T2D on glucose-lowering medications.

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  • 129.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Associations between chronotype, MTNR1B genotype and risk of type 2 diabetes in UK Biobank2020In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 287, no 2, p. 189-196Article in journal (Refereed)
    Abstract [en]

    Objective

    To examine the association between the MTNR1B G risk allele, type 2 diabetes (T2D) and chronotype in the UK Biobank.

    Methods

    Data from the baseline investigation of the UK Biobank were utilized (n = 337 083 White British; mean age: 56.9 years; 54% women). MTNR1B rs10830963 was directly genotyped [CC (reference group), CG and GG]. Chronotype was divided into four categories: definitely morning (reference group); more morning than evening; more evening than morning; and definitely evening. Logistic regression analyses were performed to estimate odds ratios and 95% confidence intervals (CIs) for T2D, controlling for age, sex and other confounders.

    Results

    Carriers of the rs10830963 risk allele had a higher risk of T2D [CG vs. CC: OR (95% CI) 1.10 (1.07, 1.15); GG vs. CC: 1.21 (1.14, 1.29)]. Compared with definitely morning chronotype, participants with definitely evening chronotype exhibited the highest risk of T2D [1.25 (1.17, 1.33)]. Despite a nonsignificant interaction between chronotype and the risk allele [0.98 (0.94, 1.01), P = 0.176 for interaction term], we found that definitely evening chronotype (vs. definitely morning) was linked with a higher risk of T2D amongst CC and CG but not GG carriers. Additionally, we saw that the GG genotype (vs. CC) was associated with a higher risk of T2D across all chronotype categories, except for definitely evening.

    Conclusion

    Our findings suggest that the MTNR1B G risk allele and late chronotype increase the risk of T2D. The association between late chronotype and higher risk of T2D appears to vary across MTNR1B rs10830963 genotypes.

  • 130.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Cook, Jesse D.
    Univ Wisconsin, Dept Psychiat, Sch Med & Publ Hlth, Madison, WI 53706 USA.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Consumer sleep trackers: a new tool to fight the hidden epidemic of obstructive sleep apnoea?2019In: The Lancet Respiratory Medicine, ISSN 2213-2600, E-ISSN 2213-2619, Vol. 7, no 12, p. 1012-1012Article in journal (Other academic)
  • 131.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Self-reported difficulty initiating sleep and early morning awakenings are associated with nocturnal diastolic non-dipping in older white Swedish men2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 13355Article in journal (Refereed)
    Abstract [en]

    Chronically blunted nocturnal blood pressure (BP) dipping has been shown to increase the future risk of cardiovascular diseases. In the present cross-sectional study, we investigated whether self-reported insomnia symptoms were associated with an altered 24-h BP profile and blunted nocturnal BP dipping (night-to-day BP ratio >0.90) in older men. For the analysis, we used 24-h ambulatory blood pressure data and reports of insomnia symptoms (difficulty initiating sleep, DIS; and early morning awakenings, EMA) from 995 Swedish men (mean age: 71 years). Compared to men without DIS, those reporting DIS (10% of the cohort) had a higher odds ratio of diastolic non-dipping (1.85 [1.15, 2.98], P=0.011). Similarly, men who reported EMA (19% of the cohort) had a higher odds ratio of diastolic non-dipping than those without EMA (1.57 [1.09, 2.26], P=0.015). Despite a slightly higher nocturnal diastolic BP among men with EMA vs. those without EMA (+1.4 mmHg, P=0.042), no other statistically significant differences in BP and heart rate were found between men with and those without insomnia symptoms. Our findings suggest that older men reporting difficulty initiating sleep or early morning awakenings may have a higher risk of nocturnal diastolic non-dipping. Our findings must be replicated in larger cohorts that also include women.

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  • 132.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Department of Clinical Neuroscience, Karolinska Institutet.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Franzon, Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Reverse Dipping of Systolic Blood Pressure Is Associated With Increased Dementia Risk in Older Men: A Longitudinal Study Over 24 Years2021In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 77, no 4, p. 1383-1390Article in journal (Refereed)
    Abstract [en]

    A lower day-to-night systolic blood pressure (BP) dip has previously been associated with poor brain health and cognitive functions. Here, we sought to examine whether reduced (nighttime/daytime ratio of systolic BP >0.9 and ≤1) and reverse (nighttime/daytime ratio of systolic BP >1) dipping of systolic BP is associated with the prospective risk of being diagnosed with any dementia in Swedish older men. Twenty-four-hour ambulatory BP monitoring was used to estimate the nocturnal systolic BP dipping status of men at mean age 71 (n=997; 35% on antihypertensive medication) and 77.6 (n=611; 41% on antihypertensive medication). Dementia incidence during the observational period up to 24 years (n=286 cases) was determined by reviewing participants' medical history and independently confirmed by at least 2 experienced geriatricians. Using time-updated Cox regression (ie, time-updated information on covariates and exposure), we found that reverse systolic BP dipping was associated with a higher risk of being diagnosed with any dementia (adjusted HR, 1.64 [95% CI, 1.14-2.34], P=0.007) and Alzheimer's disease (1.67 [1.01-2.76], P=0.047) but not vascular dementia (1.29 [0.55-3.06], P=0.559). In contrast, reduced dipping of nocturnal systolic BP was not associated with a higher risk of being diagnosed with dementia. Our findings suggest that reverse systolic BP dipping may represent an independent risk factor for dementia and Alzheimer's disease in older men. Future studies should decipher whether therapies lowering nocturnal systolic BP below daytime levels, such as bedtime dosing of antihypertensive medication, can meaningfully curb the development of dementia.

  • 133.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    van Egmond, Lieve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    The role of exercise-induced peripheral factors in sleep regulation2020In: Molecular Metabolism, ISSN 2212-8778, Vol. 42, article id 101096Article, review/survey (Refereed)
    Abstract [en]

    Background: Recurrently disrupted sleep is a widespread phenomenon in our society. This is worrisome as chronically impaired sleep increases the risk of numerous diseases that place a heavy burden on health services worldwide, including type 2 diabetes, obesity, depression, cardiovascular disease, and dementia. Therefore, strategies mitigating the current societal sleep crisis are needed. Scope of review: Observational and interventional studies have found that regular moderate to intensive exercise is associated with better subjective and objective sleep in humans, with and without pre-existing sleep disturbances. Here, we summarize recent findings from clinical studies in humans and animal experiments suggesting that molecules that are expressed, produced, and released by the skeletal muscle in response to exercise may contribute to the sleep-improving effects of exercise. Major conclusions: Exercise-induced skeletal muscle recruitment increases blood concentrations of signaling molecules, such as the myokine brain-derived neurotrophic factor (BDNF), which has been shown to increase the depth of sleep in animals. As reviewed herein, BDNF and other muscle-induced factors are likely to contribute to the sleep-promoting effects of exercise. Despite progress in the field, however, several fundamental questions remain. For example, one central question concerns the optimal time window for exercise to promote sleep. It is also unknown whether the production of muscle-induced peripheral factors promoting sleep is altered by acute and chronic sleep disturbances, which has become increasingly common in the modern 24/7 lifestyle.

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  • 134.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    van Egmond, Lieve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Partinen, Markku
    Univ Helsinki, Dept Neurol Sci, Helsinki, Finland;Helsinki Sleep Clin, VitalMed Res Ctr, Helsinki, Finland.
    Lange, Tanja
    Univ Lubeck, Dept Rheumatol & Clin Immunol, Lubeck, Germany.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    A narrative review of interventions for improving sleep and reducing circadian disruption in medical inpatients2019In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 59, p. 42-50Article, review/survey (Refereed)
    Abstract [en]

    Sleep and circadian disruptions are frequently observed in patients across hospital wards. This is alarming, since impaired nocturnal sleep and disruption of a normal circadian rhythm can compromise health and disturb processes involved in recovery from illness (eg, immune functions). With this in mind, the present narrative review discusses how patient characteristics (sleep disorders, anxiety, stress, chronotype, and disease), hospital routines (pain management, timing of medication, nocturnal vital sign monitoring, and physical inactivity), and hospital environment (light and noise) may all contribute to sleep disturbances and circadian misalignment in patients. We also propose hospital-based strategies that may help reduce sleep and circadian disruptions in patients admitted to the hospital. (C) 2018 The Authors. Published by Elsevier B.V.

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  • 135.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    van Egmond, Lieve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Partinen, Markku
    Univ Helsinki, Dept Neurol Sci, Helsinki, Finland.
    Lange, Tanja
    Helsinki Sleep Clin, VitalMed Res Ctr, Helsinki, Finland.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Response to comment on "A narrative review of interventions for improving sleep and reducing circadian disruption in medical inpatients"2019In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 59, p. 53-53Article in journal (Other academic)
  • 136.
    Titova, Olga E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Elmståhl, Sölve
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Seasonal variations in sleep duration and sleep complaints: A Swedish cohort study in middle-aged and older individuals2022In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 31, no 1, article id e13453Article in journal (Refereed)
    Abstract [en]

    Subjective sleep reports are widely used research tools in epidemiology. Whether sleep reports can differ between seasons is less clear. Using multivariable binary or multinomial logistic regression analyses, in the present Swedish cross-sectional two-centre cohort study (N = 19,254; mean age 61 years), we found that participants surveyed during the summer (June-August) were more likely to report short sleep duration (defined as ≤ 6 hr) compared with those interviewed during the autumn (odds ratio [95% confidence interval] = 1.14 [1.04-1.25]). Individuals interviewed in the winter (December-February) were less likely to report early awakenings compared with participants surveyed in the autumn (September-November; odds ratio [95% confidence interval] = 0.85 [0.75-0.96]). Complaints of difficulties in falling asleep and disturbed sleep were less common among participants interviewed during spring (March-May) compared with those interviewed during the autumn (odds ratio [95% confidence interval] = 0.86 [0.74-0.99] and 0.88 [0.79-0.98], respectively). No seasonal variations in reports of long sleep, difficulty maintaining sleep, or feeling not rested after sleep were observed. Additional subgroup analysis revealed that summer participants were more likely to report short sleep duration and early morning awakenings than individuals surveyed in winter. In conclusion, this Swedish study indicates that self-reported sleep characteristics may vary across seasons. Further studies are needed to confirm our findings.

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  • 137.
    Titova, Olga E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Elmståhl, Sölve
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Association between sleep duration and executive function differs between diabetic and non-diabetic middle-aged and older adults.2020In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 111, article id 104472Article in journal (Refereed)
    Abstract [en]

    Executive function is defined as a set of cognitive skills that are necessary to plan, monitor, and execute a sequence of goal-directed complex actions. Executive function is influenced by a variety of factors, including habitual sleep duration and diabetes. In the present study, we investigated in 18,769 Swedish adults (mean age: 61 y) the association between executive function, diabetes, and self-reported sleep duration. We observed a significant interaction between diabetes and sleep duration for the Trail Making Test (TMT) ratio (P < 0.01). This ratio is a measure of executive function where higher values indicate worse performance. Among diabetic participants (n = 1,523), long (defined as ≥9 h per day) vs. normal sleep duration (defined as 7-8 hours per day) was associated with a higher TMT ratio (P < 0.05). Similar significant results were observed in diabetic individuals without pharmacological treatment for diabetes (n = 1,062). Among non-diabetic participants (n = 17,246), no association between long sleep duration and the TMT ratio was observed (P > 0.05). Instead, short (defined as <7 h per day) vs. normal sleep duration was linked to a higher TMT ratio (P < 0.05). These findings suggest that the association between sleep duration and executive function differs between diabetic and non-diabetic middle-aged and older adults. Based on the cross-sectional design of the study, no firm conclusions can be drawn on the causality of the relations.

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  • 138.
    Tortoriello, Giuseppe
    et al.
    Karolinska Inst, Dept Neurosci, Biomed, Stockholm, Sweden..
    Beiersdorf, Johannes
    Med Univ Vienna, Ctr Brain Res, Dept Mol Neurosci, Spitalgasse 4, A-1090 Vienna, Austria..
    Romani, Susana
    Kings Coll London, Wolfson Ctr Age Related Dis, London, England..
    Williams, Gareth
    Kings Coll London, Wolfson Ctr Age Related Dis, London, England..
    Cameron, Gary A.
    Univ Aberdeen, Sch Appl Med & Dent, Aberdeen, Scotland..
    Mackie, Ken
    Indiana Univ, Dept Psychol & Brain Sci, Gill Ctr Biomol Sci, Bloomington, IN USA..
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Di Marzo, Vincenzo
    CNR, Endocannabinoid Res Grp, Ist Chim Biomol, Pozzuoli, Italy.;Univ Laval, Canada Excellence Res Chair, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada.;Univ Laval, Inst Nutr & Aliments Fonct, Quebec City, PQ, Canada..
    Keimpema, Erik
    Med Univ Vienna, Ctr Brain Res, Dept Mol Neurosci, Spitalgasse 4, A-1090 Vienna, Austria..
    Doherty, Patrick
    Kings Coll London, Wolfson Ctr Age Related Dis, London, England..
    Harkany, Tibor
    Karolinska Inst, Dept Neurosci, Biomed, Stockholm, Sweden.;Med Univ Vienna, Ctr Brain Res, Dept Mol Neurosci, Spitalgasse 4, A-1090 Vienna, Austria..
    Genetic Manipulation of sn-1-Diacylglycerol Lipase and CB1 Cannabinoid Receptor Gain-of-Function Uncover Neuronal 2-Linoleoyl Glycerol Signaling in Drosophila melanogaster2021In: Cannabis and cannabinoid research, ISSN 2578-5125, Vol. 6, no 2, p. 119-136Article in journal (Refereed)
    Abstract [en]

    Introduction: In mammals, sn-1-diacylglycerol lipases (DAGL) generate 2-arachidonoylglycerol (2-AG) that, as the major endocannabinoid, modulates synaptic neurotransmission by acting on CB1 cannabinoid receptors (CB1R). Even though the insect genome codes for inaE, which is a DAGL ortholog (dDAGL), its products and their functions remain unknown particularly because insects lack chordate-type cannabinoid receptors. Materials and Methods: Gain-of-function and loss-of-function genetic manipulations were carried out in Drosophila melanogaster, including the generation of both dDAGL-deficient and mammalian CB1R-overexpressing flies. Neuroanatomy, dietary manipulations coupled with targeted mass spectrometry determination of arachidonic acid and 2-linoleoyl glycerol (2-LG) production, behavioral assays, and signal transduction profiling for Akt and Erk kinases were employed. Findings from Drosophilae were validated by a CB1R-binding assay for 2-LG in mammalian cortical homogenates with functionality confirmed in neurons using high-throughput real-time imaging in vitro. Results: In this study, we show that dDAGL is primarily expressed in the brain and nerve cord of Drosophila during larval development and in adult with 2-LG being its chief product as defined by dietary precursor availability. Overexpression of the human CB1R in the ventral nerve cord compromised the mobility of adult Drosophilae. The causality of 2-LG signaling to CB1R-induced behavioral impairments was shown by inaE inactivation normalizing defunct motor coordination. The 2-LG-induced activation of transgenic CB(1)Rs affected both Akt and Erk kinase cascades by paradoxical signaling. Data from Drosophila models were substantiated by showing 2-LG-mediated displacement of [H-3]CP 55,940 in mouse cortical homogenates and reduced neurite extension and growth cone collapsing responses in cultured mouse neurons. Conclusions: Overall, these results suggest that 2-LG is an endocannabinoid-like signal lipid produced by dDAGL in Drosophila.

  • 139.
    Trifonova, Olga
    et al.
    Sechenov First Moscow State Med Univ, Dept Pharm, Moscow, Russia.;JSC Krasnogorsklersredstva, Krasnogorsk, Russia..
    Evdokimova, Olga
    Minist Hlth Russian Federat, Fed State Budgetary Inst Sci Ctr Expert Evaluat O, Moscow, Russia..
    Prokofieva, Vera
    Sechenov First Moscow State Med Univ, AP Arzamastsev Dept Pharmaceut & Toxicol Chem, Moscow, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Matyushin, Alexey
    Sechenov First Moscow State Med Univ, Dept Analyt & Forens Toxicol, Moscow, Russia.;Sechenov First Moscow State Med Univ, Inst Linguist & Intercultural Commun, Moscow, Russia..
    Assessment of the granulation process effect on morpho-anatomical features and biologically active substances composition of senna leaves2021In: Farmacia, ISSN 0014-8237, E-ISSN 2065-0019, Vol. 69, no 1, p. 44-50Article in journal (Refereed)
    Abstract [en]

    Cassia senna L. and Cassia angustifolia Vahl. leaves and their preparations are widely acknowledged herbal drugs. Recent development of a novel dosage form - cut-pressed granules - enhances convenience of use in a home setting. However, manufacturing of cut-pressed granules is feasible only if the quality of the material doesn't decrease during granulation. The aim of the study was to assess possible changes in identification parameters and in composition of biologically active substances in Senna leaves after processing. It was shown that TLC chromatographic profiles of herbal drug remain unchanged. Spectrophotometric assessment confirmed that the anthracene aglycones content of the herbal material was also not affected by granulation. It can be concluded that the quality of cut-pressed granules obtained from Senna leaves is not inferior compared to the raw material.

  • 140.
    Uhlmann, Anne
    et al.
    Stellenbosch Univ, Dept Psychiat, MRC Unit Risk & Resilience Mental Disorders, POB 241, ZA-8000 Cape Town, South Africa; Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa.
    Dias, Angelo
    Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa.
    Taljaard, Lian
    Stellenbosch Univ, Dept Psychiat, MRC Unit Risk & Resilience Mental Disorders, POB 241, ZA-8000 Cape Town, South Africa.
    Stein, Dan J.
    Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa.
    Brooks, Samantha J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa.
    Lochner, Christine
    Stellenbosch Univ, Dept Psychiat, MRC Unit Risk & Resilience Mental Disorders, POB 241, ZA-8000 Cape Town, South Africa.
    White matter volume alterations in hair-pulling disorder (trichotillomania)2020In: Brain Imaging and Behavior, ISSN 1931-7557, E-ISSN 1931-7565, Vol. 14, no 6, p. 2202-2209Article in journal (Refereed)
    Abstract [en]

    Trichotillomania (TTM) is a disorder characterized by repetitive hair-pulling resulting in hair loss. Key processes affected in TTM comprise affective, cognitive, and motor functions. Emerging evidence suggests that brain matter aberrations in fronto-striatal and fronto-limbic brain networks and the cerebellum may characterize the pathophysiology of TTM. The aim of the present voxel-based morphometry (VBM) study was to evaluate whole brain grey and white matter volume alteration in TTM and its correlation with hair-pulling severity. High-resolution magnetic resonance imaging (3 T) data were acquired from 29 TTM patients and 28 age-matched healthy controls (CTRLs). All TTM participants completed the Massachusetts General Hospital Hair-Pulling Scale (MGH-HPS) to assess illness/pulling severity. Using whole-brain VBM, between-group differences in regional brain volumes were measured. Additionally, within the TTM group, the relationship between MGH-HPS scores, illness duration and brain volumes were examined. All data were corrected for multiple comparisons using family-wise error (FWE) correction at p < 0.05. Patients with TTM showed larger white matter volumes in the parahippocampal gyrus and cerebellum compared to CTRLs. Estimated white matter volumes showed no significant association with illness duration or MGH-HPS total scores. No significant between-group differences were found for grey matter volumes. Our observations suggest regional alterations in cortico-limbic and cerebellar white matter in patients with TTM, which may underlie deficits in cognitive and affective processing. Such volumetric white matter changes may precipitate impaired cortico-cerebellar communication leading to a reduced ability to control hair pulling behavior.

  • 141.
    van Egmond, Lieve
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ekman, Martin
    Summer Inst Hist Geophys, Haraldsby, Aland Islands, Sweden.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Bed and rise times during the Age of Enlightenment: A case report2019In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 28, no 6, article id e12862Article in journal (Refereed)
    Abstract [en]

    Studies have shown that our modern electrical lighting environment reduces naturally occurring seasonal variations in sleep-wake rhythms, such as longer sleep during the winter versus summer. However, less is known about how timing and duration of sleep were affected by the seasons in the premodern era, before the invention of electrical lighting. The Swedish researcher Olof Hiorter collected and documented geophysical data every hour during wakefulness in Uppsala, Sweden, between December 1746 and November 1747. In this way, his bed and rise times could be approximated. The data revealed that Hiorter's rise times occurred around 1 hr before sunrise in winter versus 1 hr after sunrise in summer. No such association was observed between the time of sunset and Hiorter's bedtimes. Finally, the time in bed was about 3.5-4 hr shorter in summer compared to winter. This 273-year-old case report suggests that time in bed and rise times of people from the premodern era exhibited seasonal variations.

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  • 142.
    van Egmond, Lieve T.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Moulin, Thiago C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Meal timing and subjective sleep disturbances in older men2020In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 141, article id 111089Article in journal (Refereed)
    Abstract [en]

    Older adults often complain about sleep disturbances, such as difficulty falling asleep and difficulty maintaining sleep in the early morning hours. Here, we investigated whether meal timing is associated with sleep problems in a cohort of older Swedish men (n = 998, mean age 71). Each participant filled out a seven-day food diary used to determine the daily eating time window, daily eating midpoint, and meal timing variability (i.e., the variance in daily eating midpoints over seven days). Questionnaires were used to assess difficulty initiating sleep and difficulty maintaining sleep. As indicated by logistic regression adjusted for potential confounders (e.g., BMI, diabetes status), no significant associations were found between the meal timing parameters and subjective sleep problems (P ≥ 0.37). Similar results were obtained when restricting the analysis to adequate reporters of daily energy intake. Therefore, our findings suggest that meal timing variations do not contribute to subjective sleep problems in older men. Our results must be replicated in cohorts that also include women and other measures of sleep.

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  • 143.
    van Egmond, Lieve
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Association between Healthy Dietary Patterns and Self-Reported Sleep Disturbances in Older Men: The ULSAM Study2019In: Nutrients, E-ISSN 2072-6643, Vol. 11, no 5, article id 1029Article in journal (Refereed)
    Abstract [en]

    To date, little is known about how dietary patterns may link to measures of sleep quality in older subjects, who often suffer from sleep problems. Here, we investigated, in an older male population from Sweden (n = 970; aged 71 +/- 1 year), whether adherence to the Healthy Diet Indicator (HDI; based on recommendations from the World Health Organization) or the Mediterranean Diet (MD) is linked to sleep disturbances. The diet scores were calculated using a seven-day food diary, and self-reported sleep initiation or maintenance problems were assessed by questionnaires. When adjusted for potential confounders, no associations between dietary scores and sleep parameters were found. In contrast, low consumption of milk and dairy products one of the dietary features of the MD was associated with better subjective sleep initiation. This association was, however, not found in men with adequate reports of daily energy intake (similar to 54% of the cohort). To summarize, our findings do not suggest that older men can mitigate perceived difficulties to fall and stay asleep by adhering to either the HDI or MD. Whether low consumption of milk and dairy products can facilitate sleep initiation must be confirmed in future studies by utilizing objective measures of sleep such as polysomnography. Finally, when investigating associations between dietary patterns and sleep, particular attention should be paid to the potential confounder of inadequate reporting of energy intake.

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  • 144.
    van Egmond, Lieve
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Titova, Olga E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Association between pet ownership and sleep in the Swedish CArdioPulmonary bioImage Study (SCAPIS)2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 7468Article in journal (Refereed)
    Abstract [en]

    Preliminary findings suggest that pets may impact the owner's sleep. By using data from the Swedish CArdioPulmonary bIoimage Study (SCAPIS) cohort, we aimed to investigate the association of pet ownership with the following self-reported sleep outcomes in 3788 to 4574 participants: (i) achieving the recommended daily sleep duration for adults (i.e., at least 7 h per day); (ii) sleep quality as measured by the Pittsburgh Sleep Quality Index (a score of > 5 indicating poor sleep quality); and (iii) difficulty falling or staying asleep. Sleep metrics were not associated with pet ownership, dog ownership, and dog walking when controlling the logistic regression for possible confounders (e.g., shift work, lack of social interaction, and chronic stress). In contrast, cat ownership was associated with a higher odds ratio of failing to achieve the recommended duration of 7 h of sleep per day (adjusted odds ratio [95% CI]:1.18 [1.02, 1.37] versus non-cat owners). Our findings suggest that certain pet groups might have a more significant impact on the owner's sleep than others. As the observed association between cat ownership and short sleep duration might be a chance finding, this observation should be seen as hypothesis-generating only.

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  • 145.
    Wang, Ludi
    et al.
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China.
    Zhou, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Chang, Qing
    Shanghai Univ Med & Hlth Sci, Jiading Dist Cent Hosp, Shanghai Gen Practice Med Educ & Res Ctr, Shanghai 201800, Peoples R China.
    Chen, Jiangen
    Jiading Ind Dist Community Hlth Serv Ctr, Dept Gen Med, Shanghai 201800, Peoples R China.
    Zhou, Xiaoguang
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China;Minjiang Univ, Sch Econ & Management, Fuzhou 350108, Fujian, Peoples R China.
    Deep Ensemble Detection of Congestive Heart Failure Using Short-Term RR Intervals2019In: IEEE Access, E-ISSN 2169-3536, Vol. 7, p. 69559-69574Article in journal (Refereed)
    Abstract [en]

    Heart rate variability (HRV) is an effective predictor of congestive heart failure (CHF). However, important challenges exist regarding the effective temporal feature extraction and efficient classification using high-dimensional HRV representations. To solve these challenges, an ensemble method for CHF detection using short-term HRV data and deep neural networks was proposed. In this paper, five opensource databases, the BIDMC CHF database (BIDMC-CHF), CHF RR interval database (CHF-RR), MITBIH normal sinus rhythm (NSR) database, fantasia database (ED), and NSR RR interval database (NSR-RR), were used. Additionally, three RR segment length types (N = 500, 1000, and 2000) were used to evaluate the proposed method. First, we extracted the expert features of RR intervals (RRIs) and then built a long short-term memory-convolutional neural network-based network to extract deep-learning (DL) features automatically. Finally, an ensemble classifier was used for CHF detection using the above features. With blindfold validation (three CHF subjects and three normal subjects), the proposed method achieved 99.85%, 99.41%, and 99.17% accuracy on N = 500, 1000, and 2000 length RRIs, respectively, using the BIDMC-CHF, NSR, and FD databases. With blindfold validation (six CHF subjects and six normal subjects), the proposed method achieved 83.84%, 87.54%, and 85.71% accuracy on N = 500, 1000, and 2000 length RRIs, respectively, using the NSR-RR and CHF-RR ndatabases. Based on feature ranking, the significant effectiveness provided by the DL features has been proven. The results have shown that the deep ensemble method can achieve reliable CHF detection using short-term heart rate signals and enable CHF detection through intelligent hardware.

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  • 146.
    Wang, Lu-di
    et al.
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China.
    Zhou, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Xing, Ying
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China.
    Liu, Na
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Movahedipour, Mahmood
    Beijing Univ Posts & Telecommun, Sch Econ & Management, Beijing 100876, Peoples R China;ACECR, Tehran 141554364, Iran.
    Zhou, Xiao-guang
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China.
    A novel method based on convolutional neural networks for deriving standard 12-lead ECG from serial 3-lead ECG2019In: FRONTIERS OF INFORMATION TECHNOLOGY & ELECTRONIC ENGINEERING, ISSN 2095-9184, Vol. 20, no 3, p. 405-413Article in journal (Refereed)
    Abstract [en]

    Reconstruction of a 12-lead electrocardiogram (ECG) from a serial 3-lead ECG has been researched in the past to satisfy the need for more wearing comfort and ambulatory situations. The accuracy and real-time performance of traditional methods need to be improved. In this study, we present a novel method based on convolutional neural networks (CNNs) for the synthesis of missing precordial leads. The results show that the proposed method receives better similarity and consumes less time using the PTB database. Particularly, the presented method shows outstanding performance in reconstructing the pathological ECG signal, which is crucial for cardiac diagnosis. Our CNN-based method is shown to be more accurate and time-saving for deployment in non-hospital situations to synthesize a standard 12-lead ECG from a reduced lead-set ECG recording. This is promising for real cardiac care.

  • 147. Wang, Ningjian
    et al.
    Sun, Ying
    Zhang, Haojie
    Chen, Chi
    Wang, Yuying
    Zhang, Jihui
    Xia, Fangzhen
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Department of Clinical Neuroscience, Karolinska Institute, Solna, Sweden.
    Lu, Yingli
    Total and regional fat-to-muscle mass ratio measured by bioelectrical impedance and risk of incident type 2 diabetes2021In: Journal of Cachexia, Sarcopenia and Muscle, ISSN 2190-5991, E-ISSN 2190-6009, Vol. 12, no 6, p. 2154-2162Article in journal (Refereed)
    Abstract [en]

    Background The fat-to-muscle mass ratio (FMR) might be an indicator to assess type 2 diabetes risk independent of general obesity. However, no longitudinal studies have explored the extent to which total and regional FMRs may confer risks. We aimed to measure the sex-specific associations between FMRs of the arm, leg, trunk and whole body and incident type 2 diabetes.

    Methods A total of 464 817 participants (207 286 men and 257 531 women, mean age 56.5 ± 8.2 and 56.2 ± 8.0 years old, respectively) free of diabetes at baseline were included in this prospective cohort study with UK Biobank data. Fat mass and muscle mass were estimated using a bioelectrical impedance assessment device (Tanita BC 418MA). FMR was calculated as fat mass divided by muscle mass in corresponding body parts (total body, arm, leg and trunk). Cox proportional hazard models were used to estimate the aforementioned associations among men and women. Interaction analyses were performed between FMRs and body mass index (BMI) categories (BMI < 25 kg/m2 and BMI ≥ 25 kg/m2).

    Results Over the median 11.0 years (5 057 534 person-years) of follow-up, we documented 11 618 cases of type 2 diabetes. There was a significantly positive association between total and regional FMR and incident type 2 diabetes, even after adjusting for BMI and other covariates. Compared with other body parts, FMRs of the whole body and leg showed the strongest relationship among men and women, respectively (hazard ratio per 1 SD, 95% confidence interval: 1.67, 1.55–1.80; 1.45, 1.39–1.53). A significant interaction (P for interaction < 0.001) between BMI category and FMRs of different body parts was observed. In the stratified analysis by BMI category and tertiles of FMRs, overweight/obese individuals with a high FMR tertile tended to have the highest hazard ratio, ranging from 5.91 to 7.94 in whole body and regional areas.

    Conclusions In this large prospective study, higher total and regional FMRs were associated with a higher risk of developing type 2 diabetes, independent of BMI. This association was markedly strengthened in participants with BMI ≥ 25 kg/m2.

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  • 148.
    Wang, Ningjian
    et al.
    Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Inst & Dept Endocrinol & Metab, Sch Med, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China..
    Sun, Ying
    Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Inst & Dept Endocrinol & Metab, Sch Med, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China..
    Zhang, Haojie
    Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Inst & Dept Endocrinol & Metab, Sch Med, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China..
    Wang, Bin
    Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Inst & Dept Endocrinol & Metab, Sch Med, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China..
    Chen, Chi
    Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Inst & Dept Endocrinol & Metab, Sch Med, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China..
    Wang, Yuying
    Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Inst & Dept Endocrinol & Metab, Sch Med, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China..
    Chen, Jie
    Chinese Univ Hong Kong, Fac Med, Dept Psychiat, Sha Tin Dist,Li Chiu Kong Family Sleep Assessment, 33 A Kung Kok St, Hong Kong 000000, Peoples R China..
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Karolinska Inst, Dept Clin Neurosci, Nobels Vag 9, S-17165 Stockholm, Sweden..
    Zhang, Jihui
    Guangdong Acad Med Sci, Guangdong Prov Peoples Hosp, Guangdong Mental Hlth Ctr, 123 Huifu West Rd, Guangzhou 510000, Peoples R China..
    Xia, Fangzhen
    Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Inst & Dept Endocrinol & Metab, Sch Med, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China..
    Qi, Lu
    Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, 1440 Canal St,Suite 1724, New Orleans, LA 70112 USA.;Harvard TH Chan Sch Publ Hlth, Dept Nutr, 677 Huntington Ave, Boston, MA 02115 USA.;Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA..
    Lu, Yingli
    Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Inst & Dept Endocrinol & Metab, Sch Med, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China..
    Long-term night shift work is associated with the risk of atrial fibrillation and coronary heart disease2021In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 42, no 40, p. 4180-+Article in journal (Refereed)
    Abstract [en]

    Aims

    The aim of this study was to test whether current and past night shift work was associated with incident atrial fibrillation (AF) and whether this association was modified by genetic vulnerability. Its associations with coronary heart disease (CHD), stroke, and heart failure (HF) were measured as a secondary aim.

    Methods and results

    This cohort study included 283657 participants in paid employment or self-employed without AF and 276009 participants free of CHD, stroke, and HF at baseline in the UK Biobank. Current and lifetime night shift work information was obtained. Cox proportional hazard models were used. Weighted genetic risk score for AF was calculated. During a median follow-up of 10.4years, 5777 incident AF cases were documented. From 'day workers', 'shift but never/rarely night shifts', and 'some night shifts' to 'usual/permanent night shifts', there was a significant increasing trend in the risk of incident AF (P for trend 0.013). Usual or permanent night shifts were associated with the highest risk [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.02-1.32]. Considering a person's lifetime work schedule and compared with shift workers never working nights, participants with a duration over 10years and an average 3-8 nights/month frequency of night shift work exposure possessed higher AF risk (HR 1.18, 95% CI 0.99-1.40 and HR 1.22, 95% CI 1.02-1.45, respectively). These associations between current and lifetime night shifts and AF were not modified by genetic predisposition to AF. Usual/permanent current night shifts, >= 10years and 3-8 nights/month of lifetime night shifts were significantly associated with a higher risk of incident CHD (HR 1.22, 95% CI 1.11-1.35, HR 1.37, 95% CI 1.20-1.58 and HR 1.35, 95% CI 1.18-1.55, respectively). These associations in stroke and HF were not significant.

    Conclusion

    Both current and lifetime night shift exposures were associated with increased AF risk, regardless of genetic AF risk. Night shift exposure also increased the risk of CHD but not stroke or HF. Whether decreasing night shift work frequency and duration might represent another avenue to improve heart health during working life and beyond warrants further study.

  • 149. Weber, Jonasz Jeremiasz
    et al.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Nguyen, Huu Phuc
    Olesoxime in neurodegenerative diseases: Scrutinising a promising drug candidate2019In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 168, p. 305-318Article, review/survey (Refereed)
    Abstract [en]

    Over the last years, the experimental compound olesoxime, a mitochondria-targeting cholesterol derivative, has emerged as a promising drug candidate for neurodegenerative diseases. Numerous preclinical studies have successfully proved olesoxime's neuroprotective properties in cell and animal models of clinical conditions such as amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, peripheral neuropathy and spinal muscular atrophy. The beneficial effects were attributed to olesoxime's potential impact on oxidative stress, mitochondrial permeability transition or cholesterol homoeostasis. Although no significant benefits have been demonstrated in patients of amyotrophic lateral sclerosis, and only the first 12 months of a phase II/III clinical trial showed an improvement in motor symptoms of spinal muscular atrophy, this orphan drug may still offer undiscovered potential in the treatment of neurological diseases. In our earlier preclinical studies, we demonstrated that administration of olesoxime in mouse and rat models of Huntington disease improved psychiatric and molecular phenotypes. Aside from stabilising mitochondrial function, the drug reduced the overactivation of calpains, a class of calcium-dependent proteases entangled in neurodegenerative conditions. This observation may be credited to olesoxime's action on calcium dyshomeostasis, a further hallmark in neurodegeneration, and linked to its targets TSPO and VDAC, two proteins of the outer mitochondrial membrane associated with mitochondrial calcium handling. Further research into the mode of action of olesoxime under pathological conditions, including its effect on neuronal calcium homeostasis, may strengthen the untapped potential of olesoxime or other similar compounds as a therapeutic for neurodegenerative diseases.

  • 150.
    Welander, Nike Zoe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan).
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
    Schiöth, Helgi Birgir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia.
    Skalkidou, Alkistis
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
    Fransson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Centre for Translational Microbiome Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Migraine as a risk factor for mixed symptoms of peripartum depression and anxiety in late pregnancy: A prospective cohort study.2021In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 295, p. 733-739Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Migraine has been identified as a risk factor for peripartum depression. However, little is known about the contribution of anxiety to this association or potential changes throughout the peripartum period.

    METHODS: In a sample of 4,831 women from the Biology, Affect, Stress, Imaging and Cognition cohort in Sweden, participants were asked about history of migraine prior to pregnancy. The participants completed the Edinburgh Postnatal Depression Scale (EPDS) at gestational weeks 17 and 32 and postpartum week 6. Multinomial logistic regression analyses were used to assess associations between migraine and symptoms of depression, anxiety or mixed depression and anxiety, while adjusting for potential confounders.

    RESULTS: In crude estimates, migraine was associated with separate and mixed symptoms of depression and anxiety at most time points. After adjustments, migraine was associated with anxiety at week 17 (adjusted odds ratio: 1.69; 95% confidence interval: 1.11-2.54) and with mixed depression and anxiety at week 32 (adjusted odds ratio: 1.45; 95% confidence interval: 1.06-1.99). None of the other associations remained statistically significant after adjustments.

    LIMITATIONS: Migraine history was self-reported. Symptoms of depression and anxiety were based on the screening tool EPDS and not on clinical diagnoses.

    CONCLUSIONS: The results demonstrate that migraine may be a risk factor for anxiety in mid- pregnancy and mixed symptoms of peripartum depression and anxiety in late pregnancy. Inflammatory and hormonal factors may underlie the association between migraine, depression and anxiety across the peripartum period.

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