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  • 151.
    Alm, A.
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Oftalmiatrik.
    Schoenfelder, J.
    McDermott, J.
    A 5-year, multicenter, open-label, safety study of adjunctive latanoprost therapy for glaucoma.2004In: Arch Ophthalmol, Vol. 122, p. 957-965Article in journal (Refereed)
  • 152.
    Alm, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Stjernschantz, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    The Scandinavian Latanoprost Study Group,
    Effects on intraovular pressure and side effects of 0.005% latanoprost once daily, evening and morning. A comparison with timolol1995In: Ophthalmology, Vol. 102, p. 1743-Article in journal (Refereed)
  • 153.
    Alm, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Widengard, D
    Kjellgren, M
    Soderstrom, B
    Fristrom, A
    Heijl, A
    Stjernschantz, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Latanoprost administered once daily causes maintained reduction of intraocular pressure in glaucoma patients treated concomitantly with timolol1995In: Brit J Ophthalmol, Vol. 79, p. 12-Article in journal (Refereed)
  • 154.
    Alm, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Widengard, I
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Latanoprost: Experience of 2-year treatment in Scandinavia.2000In: Acta Ophthalmol. Scand., Vol. 78, p. 71-Article in journal (Refereed)
  • 155.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Oftalmiatrik.
    Can NSAIDS and prostaglandins be combined?2006In: Br J Ophthalmol, Vol. 90, p. 259-260Article in journal (Refereed)
  • 156.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Comparative Phase III Clinical Trial of latanoprost and Timolol in Patients with Elevated Intraocular Pressure1995In: Advances inProstaglandin, Thromboxane and Leukotriene Research, Vol. 23, p. 527-Article in journal (Refereed)
  • 157.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Diagnosis, untreated intraocular pressure, and initial and long-term effect on intraocular pressure.1998Article in journal (Refereed)
  • 158.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Effects on intraocular pressure restoration and blood aqueous barrier after long-term treatment with latanoprost in POAG and ocular hypertension1997In: British Journal Ophthalmology, Vol. 81, p. 370-Article in journal (Refereed)
  • 159.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Etiological and Pharmacological Aspects on Blood Flow and Glaucoma1996In: Vascular Risk Factors and Neuroprotection in Glaucoma, Kugler Publications , 1996, p. 167-Chapter in book (Other scientific)
  • 160.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Glaucoma and Ocular Blood Flow. Glaucoma - changing concepts in management.1998Article in journal (Refereed)
  • 161.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Oftalmiatrik.
    How much is the brain involved in glaucoma?2006In: Br J Ophthalmol, Vol. 90, p. 663-664Article in journal (Refereed)
  • 162.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Introduction. In Uveoscleral outflow. Biology and Clinical Aspects.1998Article in journal (Refereed)
  • 163.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Optic nerve and choroidal ciruculation: Physiology.1998In: Nitric Oxide and Endothelin in the Pathogenesis of Glaucoma., I O Haeflger, J Flammer, Lippincott, Raven, Philadelphia , 1998, p. 34-Chapter in book (Other scientific)
  • 164.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Phase 3 studies with latanoprost.1998In: Prostaglandins in Ophthalmology, 1998, p. 87-Chapter in book (Other scientific)
  • 165.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Prostaglandin analogues in treatment of glaucoma. Glaucoma - changing concepts in management.1998Article in journal (Refereed)
  • 166.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Prostaglandin Derivates as Ocular Hypotensive Agents.1998In: Prog Retinal and Eye Research, Vol. 17, p. 292-Article in journal (Refereed)
  • 167.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Retinal blood flow and different diagnostic procedures1998In: Ophthalmology Clinics of North America, Vol. 11, p. 491-Article in journal (Refereed)
  • 168.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    The physiology of choroidal circulation.1997In: Indocyanine Green Angiography, L A Yanuxxi, R W Flower, J S Slakter, Mosby, St louis , 1997, p. 36-Chapter in book (Other scientific)
  • 169.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    The prostaglandin analogue latanoprost - an update.1995In: Glaucoma Update, G.K. Krieglstein, K Verlag, Heidelberg , 1995, Vol. V, p. 217-Chapter in book (Other scientific)
  • 170.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Uveoscleral outflow.2000In: Eye, Vol. 14, p. 488-Article in journal (Refereed)
  • 171.
    Alm, Albert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Uveoscleral Outflow. Biology and Clinical Aspects.1. Introduction1998Chapter in book (Other scientific)
  • 172.
    Alm, Albert
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Camras, Carl B
    Watson, Peter G
    Phase III Latanoprost Studies in Scandinavia, the United Kingdom and the United States1997In: Survey of Ophthalmology, Vol. 41 suppl 2, p. 105-Article in journal (Refereed)
  • 173.
    Alm, Albert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Grierson, Ian
    Shields, M. Bruce
    Side effects associated with prostaglandin analog therapy2008In: Survey of ophthalmology, ISSN 0039-6257, E-ISSN 1879-3304, Vol. 53, no Suppl. 1, p. S93-S105Article, review/survey (Refereed)
    Abstract [en]

    Topical prostaglandin analogs, which have become first-line therapy in the medical management of glaucoma, have an excellent safety profile with regard to systemic side effects, but are associated with several ocular side effects. Some of these are common, with no apparent serious consequences other than cosmetic, whereas others are much less common but represent potentially sight-threatening side effects. The former group includes conjunctival hyperemia, elongation and darkening of eyelashes, induced iris darkening, and periocular skin pigmentation. The latter group of side effects, which are relatively rare and lack definitive causal relationship to prostaglandin analog therapy, includes iris cysts, cystoid macular edema, anterior uveitis, and reactivation of herpes simplex keratitis. Most of the literature regarding side effects associated with prostaglandin analogs involves the use of latanoprost, probably because it was the first to be studied. There is no evidence, however, aside from less conjunctival hyperemia with latanoprost, that the commercially available prostaglandin analogs differ significantly with regard to side effects.

  • 174.
    Alm, Albert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Grunden, John W.
    Kwok, Kenneth K.
    Five-year, Multicenter Safety Study of Fixed-combination Latanoprost/Timolol (Xalacom) for Open-angle Glaucoma and Ocular Hypertension2011In: Journal of glaucoma, ISSN 1057-0829, E-ISSN 1536-481X, Vol. 20, no 4, p. 215-222Article in journal (Refereed)
    Abstract [en]

    Purpose: To evaluate the safety of fixed-combination latanoprost/timolol (Xalacom) in patients requiring additional intraocular pressure (IOP) reduction over 5 years. Methods: This phase 3b, open-label, multicenter study included prostaglandin-naive participants with open-angle glaucoma or ocular hypertension insufficiently responsive to beta-blockers and requiring additional IOP reduction. Participants were evaluated at eleven 6-month visits. A masked assessor evaluated iris/eyelash changes at baseline and 12, 36, and 60 months. Increased iris pigmentation incidence was compared with a historic control from a similarly designed study evaluating latanoprost. Ocular and systemic adverse events were recorded. Results: Among 828/974 treated participants with assessable iris photographs, 233 (28.1%) developed increased iris pigmentation versus 127/380 (33.4%) in the historic controls. Participants with mixed eye colors exhibited greater susceptibility to overall increased iris pigmentation (85.8% in both studies). In this study, most participants (80.3%) with increased iris pigmentation developed only a weak increase. Eyelash changes were seen in 58.1% of participants and darkening of the eyelids in 5-6%; 14.1% experienced a serious adverse event. Adverse events resulted in treatment withdrawal in 133 (13.7%) participants. Most were nonserious ocular adverse events, about half of them ocular irritation. Only 3 of 13 serious systemic adverse events were considered to be drug related by the investigator. Mean IOP reductions were stable over 5 years. Conclusions: After 5 years, more than 70% of participants treated with fixed-combination latanoprost/timolol had no increased iris pigmentation. The fixed combination is safe and well tolerated for long-term treatment in patients with open-angle glaucoma or ocular hypertension.

  • 175.
    Alm, Albert
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Lambrou, George
    Maepea, Olav
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Nilsson, Siv
    Department of Comparative Medicine.
    Percicot, Christine
    Ocular blood flow in experimental glaucoma: a study in cynomolgus monkey1997In: Ophthalmologica, Vol. 211, p. 178-Article in journal (Refereed)
  • 176.
    Alm, Albert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nilsson, Siv F. E.
    Uveoscleral outflow: A review2009In: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 88, no 4, p. 760-768Article, review/survey (Refereed)
    Abstract [en]

    The uveoscleral outflow route was described more than 40 years ago. Part of aqueous leaves the eye through the iris root. The ciliary muscle, and there are large species differences in the fraction of aqueous outflow that leaves the eye through this route. In non-human primates 40-50% of aqueous leaves the eye by the uveoscleral route. In human eyes most data has been collected by indirect calculations, with results suggesting a similar fraction, at least in eyes from younger individuals. An age-dependent reduction in uveoscleral flow in human eyes may explain the initial difference seen between non-human primate and human eyes. Unlike trabecular outflow, intraocular pressures within the normal range have little effect on uveoscleral outflow. This may be explained by the fact that changes in intraocular pressure have little effect on the pressure gradient for flow through the ciliary muscle, which is likely to be the rate-limiting step in uveoscleral outflow. The state of the ciliary muscle is important and contraction reduces while relaxation increases uveoscleral flow. Similar effects are achieved with cholinergic agonists and antagonists. Epinephrine increases uveoscleral flow, most likely through stimulating beta(2)-adrenergic receptors. Prostaglandin F-2 alpha and prostaglandin F-2 alpha-analogues effectively reduce intraocular pressure by increasing uveoscleral flow. This is mediated by structural changes in the extracellular matrix of the ciliary muscle, and is likely to contribute to a valuable excess route for aqueous and proteins during intraocular inflammation. Whether uveoscleral flow plays a significant role in any other eye disease is not clear. Thus, 40 years later we are able to successfully increase aqueous flow through the uveoscleral route, a valuable contribution to glaucoma treatment, but we still have only a limited understanding on its physiological role.

  • 177.
    Alm, Albert
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Weinreb, R N
    Uveoscleral Outflow. Biology and Clinical Aspects.Edited by Alm A & Weinreb R N1998Book (Other scientific)
  • 178.
    Alm, Albert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Wikström, Carl Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ekström, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Öhman, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    The effect of metoprolol on intra-ocular pressure in glaucoma. A pilot study.1979In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 57, no 2, p. 236-242, article id j.1755-3768.1979.tb00487.xArticle in journal (Refereed)
  • 179.
    Alm, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Scholz, Birger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, MMS, Medical Mass Spectrometry.
    Andrén, Per E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, MMS, Medical Mass Spectrometry.
    Fex-Svenningsen, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex2008In: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 29, no 4, p. 628-637Article in journal (Refereed)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs) are environmental contaminants found in human and animal tissues worldwide. Neonatal exposure to the flame retardant 2,2', 4,4',5-pentabromodiphenyl ether (PBDE-99) disrupts normal brain development in mice, and results in disturbed spontaneous behavior in the adult. The mechanisms underlying the late effects of early exposure are not clear. To gain insight into the initial neurodevelopmental damage inflicted by PBDE-99, we investigated the short-term effects of PBDE-99 on protein expression in the developing cerebral cortex of neonatal mice, and the cytotoxic and apoptotic effects of PBDE-99 in primary cultures of fetal rat cortical cells. We used two-dimensional difference gel electrophoresis (2D-DIGE) to analyze protein samples isolated from the cortex of NMRI mice 24h after exposure to a single oral dose of 12 mg/kg PBDE-99 on post-natal day 10. Protein resolution was enhanced by sample pre-fractionation. In the cell model, we determined cell viability using the trypan blue exclusion assay, and apoptosis using immunocytochemical detection of cleaved caspase-3. We determined the identity of 111 differentially expressed proteins, 32 (29%) of which are known to be cytoskeleton-related. Similar to previous findings in the striatum, we found elevated levels of the neuron growth-associated protein Gap43 in the cortex. In cultured cortical cells, a high concentration of PBDE-99 (30 microM) induced cell death without any apparent increase in caspase-3 activity. These results indicate that the permanent neurological damage induced by PBDE-99 during the brain growth spurt involve detrimental effects on cytoskeletal regulation and neuronal maturation in the developing cerebral cortex.

  • 180.
    Alm, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    A new framework for understanding stuttering: The dual premotor model2007In: Research, Treatment, and Self-Help in Fluency Disorders: New Horizons : Proceedings of the Fifth World Congress on Fluency Disorders, Dublin, 25-28th July 2006 / [ed] James Au-Yeung and Margaret M. Leahy, Dublin: The International Fluency Association , 2007, p. 77-83Conference paper (Other academic)
  • 181.
    Alm, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Cluttering: a neurological perspective2011In: Cluttering: a handbook of research, intervention, and education / [ed] D. Ward & K. Scaler Scott, London: Psychology Press , 2011Chapter in book (Other academic)
  • 182.
    Alm, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    The Dual Premotor Model of Stuttering and Cluttering2010In: Theoretical Issues of Fluency Disorders / [ed] L. Beliakova, 2010Chapter in book (Other academic)
  • 183.
    Alm, Per A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Is it Thinking and not Feeling that influence variability of stuttering in social situations?: About stuttering and social cognition2015In: 10Th Oxford Dysfluency Conference, ODC 2014, 2015, p. 289-290Conference paper (Refereed)
  • 184.
    Alm, Per A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Stamning och skenande tal (løbsk tale): Om orsaker, mekanismer och behandling, med utgångspunkt från hjärnan2008In: Proceedings fra 1ste nordiske konference om stammen løbsk tale, Nyborg, Danmark, 2008Conference paper (Other academic)
  • 185.
    Alm, Per A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Stuttering in relation to anxiety, temperament, and personality: Review and analysis with focus on causality2014In: Journal of fluency disorders, ISSN 0094-730X, E-ISSN 1873-801X, Vol. 40, p. 5-21Article, review/survey (Refereed)
    Abstract [en]

    Anxiety and emotional reactions have a central role in many theories of stuttering, for example that persons who stutter would tend to have an emotionally sensitive temperament. The possible relation between stuttering and certain traits of temperament or personality were reviewed and analyzed, with focus on temporal relations (i.e., what comes first). It was consistently found that preschool children who stutter (as a group) do not show any tendencies toward elevated temperamental traits of shyness or social anxiety compared with children who do not stutter. Significant group differences were, however, repeatedly reported for traits associated with inattention and hyperactivity/impulsivity, which is likely to reflect a subgroup of children who stutter. Available data is not consistent with the proposal that the risk for persistent stuttering is increased by an emotionally reactive temperament in children who stutter. Speech-related social anxiety develops in many cases of stuttering, before adulthood. Reduction of social anxiety in adults who stutter does not in itself appear to result in significant improvement of speech fluency. Studies have not revealed any relation between the severity of the motor symptoms of stuttering and temperamental traits. It is proposed that situational variability of stuttering, related to social complexity, is an effect of interference from social cognition and not directly from the emotions of social anxiety. In summary, the studies in this review provide strong evidence that persons who stutter are not characterized by constitutional traits of anxiety or similar constructs. Educational Objectives: This paper provides a review and analysis of studies of anxiety, temperament, and personality, organized with the objective to clarify cause and effect relations. Readers will be able to (a) understand the importance of effect size and distribution of data for interpretation of group differences; (b) understand the role of temporal relations for interpretation of cause and effect; (c) discuss the results of studies of anxiety, temperament and personality in relation to stuttering; and (d) discuss situational variations of stuttering and the possible role of social cognition. (C) 2014 Elsevier Inc. All rights reserved.

  • 186.
    Alm, Per A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Dreimanis, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Neuropathic pain: transcranial electric motor cortex stimulation using high frequency random noise: Case report of a novel treatment2013In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 6, p. 479-486Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 187.
    Alm, Per A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Karlsson, Ragnhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sundberg, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Axelson, Hans W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hemispheric Lateralization of Motor Thresholds in Relation to Stuttering2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, p. e76824-Article in journal (Refereed)
    Abstract [en]

    Stuttering is a complex speech disorder. Previous studies indicate a tendency towards elevated motor threshold for the left hemisphere, as measured using transcranial magnetic stimulation (TMS). This may reflect a monohemispheric motor system impairment. The purpose of the study was to investigate the relative side-to-side difference (asymmetry) and the absolute levels of motor threshold for the hand area, using TMS in adults who stutter (n = 15) and in controls (n = 15). In accordance with the hypothesis, the groups differed significantly regarding the relative side-to-side difference of finger motor threshold (p = 0.0026), with the stuttering group showing higher motor threshold of the left hemisphere in relation to the right. Also the absolute level of the finger motor threshold for the left hemisphere differed between the groups (p = 0.049). The obtained results, together with previous investigations, provide support for the hypothesis that stuttering tends to be related to left hemisphere motor impairment, and possibly to a dysfunctional state of bilateral speech motor control.

  • 188.
    Alm, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Risberg, Jarl
    Stuttering in adults: the acoustic startle response, temperamental traits, and biological factors2007In: Journal of Communication Disorders, ISSN 0021-9924, E-ISSN 1873-7994, Vol. 40, no 1, p. 1-41Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the relation between stuttering and a range of variables of possible relevance, with the main focus on neuromuscular reactivity, and anxiety. The explorative analysis also included temperament, biochemical variables, heredity, preonset lesions, and altered auditory feedback (AAF). An increased level of neuromuscular reactivity in stuttering adults has previously been reported by [Guitar, B. (2003). Acoustic startle responses and temperament in individuals who stutter. Journal of Speech Language and Hearing Research, 46, 233-240], also indicating a link to anxiety and temperament. The present study included a large number of variables in order to enable analysis of subgroups and relations between variables. Totally 32 stuttering adults were compared with nonstuttering controls. The acoustic startle eyeblink response was used as a measure of neuromuscular reactivity. No significant group difference was found regarding startle, and startle was not significantly correlated with trait anxiety, stuttering severity, or AAF. Startle was mainly related to calcium and prolactin. The stuttering group had significantly higher scores for anxiety and childhood ADHD. Two subgroups of stuttering were found, with high versus low traits of childhood ADHD, characterized by indications of preonset lesions versus heredity for stuttering. The study does not support the view that excessive reactivity is a typical characteristic of stuttering. The increased anxiety is suggested to mainly be an effect of experiences of stuttering. Learning outcomes: As a result of reading this article, the reader will be able to: (a) critically discuss the literature regarding stuttering in relation to acoustic startle, anxiety, and temperament; (b) describe the effect of calcium on neuromuscular reactivity; (c) discuss findings supporting the importance of early neurological incidents in some cases of stuttering, and the relation between such incidents and traits of ADHD or ADD; and (d) discuss the role of genetics in stuttering.

  • 189. Alm, P.O.
    et al.
    af Klinteberg, B.
    Humble, K.
    Leppert, J.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Sorensen, S.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Thorell, L.-H.
    Lidberg, L.
    Oreland, L.
    Department of Neuroscience.
    Psychopathy, platelet MAO activety and criminality among former juvenile delinquents1996In: Acta Psychiat Scand, Vol. 94, p. 105-Article in journal (Refereed)
  • 190.
    Alm, Susanne
    et al.
    Stockholm Univ, Swedish Inst Social Res, SE-10691 Stockholm, Sweden.
    Laftman, Sara Brolin
    Stockholm Univ, Dept Publ Hlth Sci, Ctr Hlth Equity Studies CHESS, SE-10691 Stockholm, Sweden.
    Bohman, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Stockholm Cty Council, Stockholm Hlth Care Serv, S-10422 Stockholm, Sweden.
    Poor Family Relationships in Adolescence and the Risk of Premature Death: Findings from the Stockholm Birth Cohort Study2019In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 16, no 10, article id 1690Article in journal (Refereed)
    Abstract [en]

    Poor family relationships during childhood have been shown to have long-term negative effects on an offspring's health. However, few studies have followed the offspring to retirement age, and relatedly, knowledge about the link between poor family relationships and premature death is scarce. The aim of this study was to examine the association between poor family relationships in adolescence and the risk of premature death, even when considering other adverse childhood conditions. Prospective data from the Stockholm Birth Cohort study were used, with 2636 individuals born in 1953 who were followed up until age 65. Information on family relations was based on interviews with the participants' mothers in 1968. Information on mortality was retrieved from administrative register data from 1969-2018. Cox proportional hazards regressions showed that poor family relationships in adolescence were associated with an increased risk of premature death, even when adjusting for childhood conditions in terms of household social class, household economic poverty, contact with the child services, parental alcohol abuse, and parental mental illness (Hazard Ratio (HR), 2.08, 95% Confidence Interval (CI), 1.40-3.09). The findings show that poor family relationships in adolescence can have severe and long-lasting health consequences, highlighting the importance of early interventions.

  • 191.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, George
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chrousos, George P.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Genome wide analysis reveals association of a FTO gene variant with epigenetic changes2012In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 99, no 3, p. 132-137Article in journal (Refereed)
    Abstract [en]

    Variants of the FTO gene show strong association with obesity, but the mechanisms behind this association remain unclear. We determined the genome wide DNA methylation profile in blood from 47 female preadolescents. We identified sites associated with the genes KARS, TERF2IP, DEXI, MSI1,STON1 and BCAS3 that had a significant differential methylation level in the carriers of the FTO risk allele (rs9939609). In addition, we identified 20 differentially methylated sites associated with obesity. Our findings suggest that the effect of the FTO obesity risk allele may be mediated through epigenetic changes. Further, these sites might prove to be valuable biomarkers for the understanding of obesity and its comorbidites.

  • 192.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Shaik, Jafar H. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sreedharan, Smitha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Marcus, Claude
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The obesity gene, TMEM18, is of ancient origin, found in majority of neuronal cells in all major brain regions and associated with obesity in severely obese children2010In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 11, p. 58-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    TMEM18 is a hypothalamic gene that has recently been linked to obesity and BMI in genome wide association studies. However, the functional properties of TMEM18 are obscure.

    METHODS:

    The evolutionary history of TMEM18 was inferred using phylogenetic and bioinformatic methods. The gene's expression profile was investigated with real-time PCR in a panel of rat and mouse tissues and with immunohistochemistry in the mouse brain. Also, gene expression changes were analyzed in three feeding-related mouse models: food deprivation, reward and diet-induced increase in body weight. Finally, we genotyped 502 severely obese and 527 healthy Swedish children for two SNPs near TMEM18 (rs6548238 and rs756131).

    RESULTS:

    TMEM18 was found to be remarkably conserved and present in species that diverged from the human lineage over 1500 million years ago. The TMEM18 gene was widely expressed and detected in the majority of cells in all major brain regions, but was more abundant in neurons than other cell types. We found no significant changes in the hypothalamic and brainstem expression in the feeding-related mouse models. There was a strong association for two SNPs (rs6548238 and rs756131) of the TMEM18 locus with an increased risk for obesity (p = 0.001 and p = 0.002).

    CONCLUSION:

    We conclude that TMEM18 is involved in both adult and childhood obesity. It is one of the most conserved human obesity genes and it is found in the majority of all brain sites, including the hypothalamus and the brain stem, but it is not regulated in these regions in classical energy homeostatic models.

  • 193.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kalnina, Ineta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Genome-wide analysis reveals DNA methylation markers that vary with both age and obesity2014In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 548, no 1, p. 61-67Article in journal (Refereed)
    Abstract [en]

    The combination of the obesity epidemic and an aging population presents growing challenges for the healthcare system. Obesity and aging are major risk factors for a diverse number of diseases and it is of importance to understand their interaction and the underlying molecular mechanisms. Herein the authors examined the methylation levels of 27578 CpG sites in 46 samples from adult peripheral blood. The effect of obesity and aging was ascertained with general linear models. More than one hundred probes were correlated to aging, nine of which belonged to the KEGG group map04080. Additionally, 10 CpG sites had diverse methylation profiles in obese and lean individuals, one of which was the telomerase catalytic subunit (TERT). In eight of ten cases the methylation change was reverted between obese and lean individuals. One region proved to be differentially methylated with obesity (LINC00304) independent of age. This study provides evidence that obesity influences age driven epigenetic changes, which provides a molecular link between aging and obesity. This link and the identified markers may prove to be valuable biomarkers for the understanding of the molecular basis of aging, obesity and associated diseases.

  • 194.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nordström, Karl J V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mapping the human membrane proteome: a majority of the human membrane proteins can be classified according to function and evolutionary origin2009In: BMC Biology, ISSN 1741-7007, E-ISSN 1741-7007, Vol. 7, p. 50-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Membrane proteins form key nodes in mediating the cell's interaction with the surroundings, which is one of the main reasons why the majority of drug targets are membrane proteins. RESULTS: Here we mined the human proteome and identified the membrane proteome subset using three prediction tools for alpha-helices: Phobius, TMHMM, and SOSUI. This dataset was reduced to a non-redundant set by aligning it to the human genome and then clustered with our own interactive implementation of the ISODATA algorithm. The genes were classified and each protein group was manually curated, virtually evaluating each sequence of the clusters, applying systematic comparisons with a range of databases and other resources. We identified 6,718 human membrane proteins and classified the majority of them into 234 families of which 151 belong to the three major functional groups: receptors (63 groups, 1,352 members), transporters (89 groups, 817 members) or enzymes (7 groups, 533 members). Also, 74 miscellaneous groups with 697 members were determined. Interestingly, we find that 41% of the membrane proteins are singlets with no apparent affiliation or identity to any human protein family. Our results identify major differences between the human membrane proteome and the ones in unicellular organisms and we also show a strong bias towards certain membrane topologies for different functional classes: 77% of all transporters have more than six helices while 60% of proteins with an enzymatic function and 88% receptors, that are not GPCRs, have only one single membrane spanning alpha-helix. Further, we have identified and characterized new gene families and novel members of existing families. CONCLUSION: Here we present the most detailed roadmap of gene numbers and families to our knowledge, which is an important step towards an overall classification of the entire human proteome. We estimate that 27% of the total human proteome are alpha-helical transmembrane proteins and provide an extended classification together with in-depth investigations of the membrane proteome's functional, structural, and evolutionary features.

  • 195.
    Alping, P.
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Fink, K.
    Karolinska Inst, Stockholm, Sweden..
    Gunnarsson, M.
    Orebro Univ Hosp, Orebro, Sweden..
    Lycke, J.
    Univ Gothenburg, Gothenburg, Sweden..
    Nilsson, P.
    Lund Univ, Lund, Sweden..
    Salzer, J.
    Umea Univ, Umea, Sweden..
    Vrethem, M.
    Linkoping Univ, Linkoping, Sweden..
    Langer-Gould, A.
    Kaiser Permanente Southern Calif, Pasadena, CA USA..
    Svenningsson, A.
    Karolinska Inst, Stockholm, Sweden..
    Frisell, T.
    Karolinska Inst, Stockholm, Sweden..
    Piehl, F.
    Karolinska Inst, Stockholm, Sweden..
    Baseline characteristics from the COMBAT-MS study: Initial analyses suggest main driver for therapy choice is geographic location2017In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 23, p. 714-714Article in journal (Other academic)
  • 196.
    Alping, P.
    et al.
    Danderyd Hosp, Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Svenningsson, A.
    Danderyd Hosp, Karolinska Inst, Clin Sci, Stockholm, Sweden..
    Salzer, J.
    Umea Univ, Pharmacol & Clin Neurosci, Umea, Sweden..
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala Univ, Neurosci, Uppsala, Sweden..
    Dahle, C.
    Linkoping Univ, Clin & Expt Med, Linkopin, Sweden..
    Fink, K.
    Danderyd Hosp, Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Hillert, J.
    Danderyd Hosp, Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Lycke, J.
    Univ Gothenburg, Clin Neurosci & Rehabil, Gothenburg, Sweden..
    Landtblom, A-M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Martin, C.
    Danderyd Hosp, Karolinska Inst, Clin Sci, Stockholm, Sweden..
    Nilsson, P.
    Lund Univ, Neurol, Lund, Sweden..
    Walentin, F.
    Orebro Univ Hosp, Neurol, Orebro, Sweden..
    Olsson, T.
    Danderyd Hosp, Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Frisell, T.
    Karolinska Inst, Med Solna, Stockholm, Sweden..
    Piehl, F.
    Danderyd Hosp, Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Rituximab in multiple sclerosis; data from the swedish MS registry.2016In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, no suppl. 3, p. 49-49Article in journal (Refereed)
  • 197.
    Alping, Peter
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Piehl, Fredrik
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden;Stockholm Hlth Serv, Acad Specialist Ctr, Stockholm, Sweden;Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden.
    Langer-Gould, Annette
    Kaiser Permanente, Southern Calif Permanente Med Grp, Southern Clin & Translat Neurosci, Clin & Translat Neurosci, Pasadena, CA USA;Kaiser Permanente, Southern Calif Permanente Med Grp, Clin & Translat Neurosci, Pasadena, CA USA.
    Frisell, Thomas
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Div, Stockholm, Sweden.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Fink, Katharina
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Fogdell-Hahn, Anna
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Gunnarsson, Martin
    Orebro Univ, Ctr Hlth & Med Psychol, Orebro, Sweden.
    Hillert, Jan
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Kockum, Ingrid
    Stockholm Hlth Serv, Acad Specialist Ctr, Stockholm, Sweden.
    Lycke, Jan
    Univ Gothenburg, Dept Clin Neurosci & Rehabil, Gothenburg, Sweden.
    Nilsson, Petra
    Lund Univ, Dept Clin Sci Neurol, Lund, Sweden.
    Olsson, Tomas
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Salzer, Jonatan
    Umea Univ, Dept Pharmacol & Clin Neurosci, Umea, Sweden.
    Svenningsson, Anders
    Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Stockholm, Sweden.
    Virtanen, Suvi
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Vrethem, Magnus
    Validation of the Swedish Multiple Sclerosis Register: Further Improving a Resource for Pharmacoepidemiologic Evaluations2019In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 30, no 2, p. 230-233Article in journal (Refereed)
    Abstract [en]

    The Swedish Multiple Sclerosis Register is a national register monitoring treatment and clinical course for all Swedish multiple sclerosis (MS) patients, with high coverage and close integration with the clinic. Despite its great value for epidemiologic research, it has not previously been validated. In this brief report, we summarize a large validation of >3,000 patients in the register using clinical chart review in the context of the COMBAT-MS study. While further improving the data quality for a central cohort of patients available for future epidemiologic research, this study also allowed us to estimate the accuracy and completeness of the register data.

  • 198.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    From Food Preference to Craving: Behavioural Traits and Molecular Mechanisms2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Preference for palatable and energy-dense foods may be a risk factor for body weight gain and has both genetic and environmental components. Once obesity develops in an individual, weight loss is difficult to achieve. Indeed, obesity is often characterized by repeated attempts to reduce the overconsumption of energy-dense foods, followed by food craving and relapse to overconsumption. Relapse and loss of control over intake are observed also in drug addicts, and it has been shown that obesity and drug addiction not only share behavioural features but also neural circuitry, e.g. the mesolimbic dopamine pathway. In this thesis, we sought to investigate the mechanisms related to food preferences and craving using animal models previously used in addiction research.

    The risk of gaining weight may implicate behavioural traits and emotional states. We showed in rats that a risk-taking behavioural profile was associated both with increased preference for a high-fat (HF) diet and with increased motivational response to a palatable high-sucrose (HS) diet. Hypothalamic urocortin 2 expression was associated with the preference for the HF diet. We also tested the hypothesis that consumption of HS and HF diets separately or provided simultaneously (HFHS) affect anxiety-like behaviour and locomotion.

    Furthermore, we showed that withdrawal from HFHS food affects diet-induced obesity-prone (OP) and obesity-resistant (OR) animals differently. OP animals had increased motivation (craving) for HS food pellets as measured by the operant self-administration technique during withdrawal. Dopamine receptor expression in the striatum differed between OP and OR animals both at access to HFHS and during withdrawal. This strongly implicates dopaminergic signaling in the OP phenotype.

    In humans, food preferences may be monitored using questionnaires. We analyzed food preference data from parents of preschool children, and identified an inverse association of parental preference for high-fat high-protein food and overweight in children.

    In conclusion, we have employed animal models previously used in the addiction field to identify molecular mechanisms related both to food preference and vulnerability to obesity, and to food craving associated with withdrawal from palatable food. These findings add to our current understanding of obesity.

     

    List of papers
    1. Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 2
    Open this publication in new window or tab >>Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 2
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    2009 (English)In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 8, no 2, p. 193-202Article in journal (Refereed) Published
    Abstract [en]

    The aim of this study was to investigate whether the preference for a palatable high-fat diet (HFD) is associated with response to novelty and with anxiety-like behavior in rats and whether such fat preference correlates with gene expression of hypothalamic neuropeptides related to feeding. We subjected male rats to two tests of exploration of novel environments: the multivariate concentric square field (MCSF) and the elevated plus maze (EPM). The rats were then exposed to a 5-day test of preference for a palatable HFD versus reference diets. Messenger RNA (mRNA) levels of 21 neuropeptides were investigated by quantitative polymerase chain reaction. We found a strong positive correlation of HFD preference and open-arm activity in the EPM (% open-arm time, r(s) = 0.629, df = 26, P < 0.001). Thus, HFD preference was inversely associated with anxiety-like behavior. The same association was found for HFD preference and behavior in the MCSF (bridge entries, r(s) = 0.399, df = 23, P = 0.048). In addition, the HFD preference was positively correlated (r(s) = 0.433, df = 25, P = 0.021) with hypothalamic mRNA levels of urocortin 2 (Ucn 2). Moreover, behavior in the EPM was significantly correlated with expression levels of the receptor for Ucn 2, the corticotropin-releasing factor receptor 2, in the hypothalamus (r(s) = 0.382, df = 33, P = 0.022, pituitary (r(s) = 0.494, df = 31, P = 0.004) and amygdala (r(s) = 0.381, df = 30, P = 0.032). We conclude that preference for palatable HFD is inversely associated with anxiety and propose that Ucn 2 signaling may play a role in this association.

    Keywords
    Anxiety, corticotropin-releasing factor receptor, dietary fat, elevated plus maze, exploratory behavior, food preferences, multivariate concentric square field, novelty seeking, palatable, urocortin 2, Wistar
    National Category
    Pharmacology and Toxicology Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-117598 (URN)10.1111/j.1601-183X.2008.00464.x (DOI)000263756100007 ()19077174 (PubMedID)
    Available from: 2010-03-01 Created: 2010-02-21 Last updated: 2018-01-12Bibliographically approved
    2. Locomotor adaptation and elevated expression of reward-relevant genes following free-choice high-fat diet exposure
    Open this publication in new window or tab >>Locomotor adaptation and elevated expression of reward-relevant genes following free-choice high-fat diet exposure
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Obesity may be induced in rodents by long-term access to dietary fat. Such treatment has been reported to have behavioural effects including reduced anxiety-like behaviour and diminished operant responding for psychostimulants. It is unclear whether such effects are secondary to metabolic changes due to excess body weight, or to the extended access to palatable food reward. The aim of this study was to investigate the effects of a short palatable diet exposure (10 days) on performance in the open field test of novelty-induced locomotion and anxiety-like behaviour in rats. We subjected rats to a free-choice high-fat or high-sugar diet, or both, for a period of 10 days. Increased caloric intake was observed in all groups but body weight at Day 10 did not differ from chow-fed controls. We report that consumption of the free-choice high-fat diets was associated with higher novelty-induced activity and reduced anxiety-like behaviour in the open field test. In addition, we used RT-PCR to show that the high-fat group had 39% higher expression of mu opioid receptor in the lateral hypothalamus, and that tyrosine hydroxylase expression was elevated more than two-fold in the ventral tegmental area of rats with access to both high-fat and high-sugar. In conclusion, these results show that subchronic exposure to a free-choice high-fat diet induces behavioural adaptations such as elevated locomotor activity and attenuated experimental anxiety. The changes observed in gene expression related to reward after high-fat diet exposure indicate that these behavioural adaptations are related to reward function.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-119489 (URN)
    Available from: 2010-03-01 Created: 2010-02-25 Last updated: 2013-01-08
    3. Motivation for sucrose in sated rats is predicted by low anxiety-like behavior
    Open this publication in new window or tab >>Motivation for sucrose in sated rats is predicted by low anxiety-like behavior
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    2009 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 454, no 3, p. 193-197Article in journal (Refereed) Published
    Abstract [en]

    Anxiety has been implicated in obesity and in the overconsumption of highly palatable foods such as those high in fat, sugar, or both. Also, the novelty-seeking trait has been associated with failure in weight-loss programs. The aim of this study was to investigate the associations of experimental anxiety and the self-administration of sucrose and high fat pellets in non-food deprived rats across different operant schedules. Male Wistar rats were subjected to the elevated plus-maze test (EPM) of anxiety-like behavior. The rats were tested for fixed ratio 5 (FR5) and progressive ratio (PR) operant responding for 50% sucrose, 95% sucrose, and high-fat pellets. PR active lever press response for 95% sucrose, but not the other pellet types, was correlated to % time spent on open arms (P=0.019) in the EPM. On the FR5 schedule, activity (closed arm entries) was correlated to the self-administration of 50% sucrose (P=0.027) and high-fat (P=0.002). This indicates an association of novelty-induced activity and self-administration of palatable food in sated rats, as well as a specific association of PR lever press response for 95% sucrose and low anxiety-like behavior. It has been argued that such active lever press response on PR may be interpreted as craving for the reinforcer; thus, our findings indicate an inverse relationship of experimental anxiety and craving for sucrose. This connection may have implications for human situations, since anxiety and novelty-seeking have been associated with obesity and failure in weight-loss programs.

    Place, publisher, year, edition, pages
    Elsevier, 2009
    Keywords
    Craving; Sucrose, Dietary fat, Progressive ratio, Anxiety, Novelty-seeking
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-117599 (URN)10.1016/j.neulet.2009.03.045 (DOI)000265275500005 ()19429082 (PubMedID)
    Available from: 2010-03-01 Created: 2010-02-21 Last updated: 2017-12-12Bibliographically approved
    4. Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals
    Open this publication in new window or tab >>Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals
    2009 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 204, no 3, p. 431-443Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION:

    Vulnerability for weight gain is an individual trait. Obese people undertake dieting, but permanent weight loss is difficult to attain due to repeated phases of relapse to excess consumption.

    MATERIALS AND METHODS:

    In this study, male Wistar rats were trained to operantly self-administer pellets followed by free-choice access in the homecage to high-fat high-sugar (HFHS) diet consisting of 30% sucrose, lard, standard rodent chow and water. Animals were divided into obesity-prone (OP) and obesity-resistant (OR) groups based on relative weight gain compared to normally fed controls despite equal consumption of HFHS.

    RESULTS AND DISCUSSION:

    After 4 weeks of HFHS access, OP and OR animals did not differ in motivation for food pellets in terms of progressive ratio break point, lever pressing or response rate. However, upon discontinuation of the HFHS diet, differences between the OP and OR groups were noted. OP animals increased their motivation (i.e. craving) during the second withdrawal week and reduced time spent in the centre of an open field (increased anxiety) compared to the OR animals. Both OP and OR animals consumed less of the standard rodent chow during the first week of withdrawal when compared to normally fed controls. But, while the OR animals quickly returned to control levels of food consumption, OP animals continued to consume less standard rodent chow.

    CONCLUSION:

    The results show for the first time that withdrawal from free-choice HFHS induces craving that is specific to the OP animals and suggests that OP individuals may have withdrawal symptoms that are similar to those induced by addictive drugs.

    Keywords
    Diet-induced obesity, Operant self-administration, Progressive ratio, Fixed ratio, Whole-animal physiology
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-117600 (URN)10.1007/s00213-009-1474-y (DOI)000266085700006 ()19205668 (PubMedID)
    Available from: 2010-03-01 Created: 2010-02-21 Last updated: 2017-12-12Bibliographically approved
    5. Downregulation of nucleus accumbens D1 and D2 receptor expression occurs upon exposure to and persists long-term after withdrawal from palatable food: conclusions from diet-induced obesity models
    Open this publication in new window or tab >>Downregulation of nucleus accumbens D1 and D2 receptor expression occurs upon exposure to and persists long-term after withdrawal from palatable food: conclusions from diet-induced obesity models
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-119449 (URN)
    Note
    The nucleus accumbens (NAcc) mediates feeding reward; its activity reflects tastants’ hedonic value. The NAcc dopamine guides immediate responses to reward, however, its involvement in establishing long-term responses after a period of exposure to palatable foods has not been defined. Furthermore, reward-driven overeating propels weight increase, but the scale of weight gain depends on animals’ obesity-prone (OP) or -resistant (OR) phenotype. It is unclear whether responses of NAcc dopamine to palatable foods depend on susceptibility to obesity. We investigated the effect of restricted and unrestricted extended access to high-fat high-sugar (HFHS) diet on expression of genes encoding dopamine receptors in the NAcc of OP and OR rats. We examined persistence of HFHS diet-induced changes in D1 and D2 gene expression in OP and OR rats subjected to HFHS withdrawal by receiving bland chow for 18 days after HFHS. Effects of restricted access to HFHS by pair-feeding to bland chow-fed controls were also studied. Using RT-PCR, we found that NAcc D1 mRNA was downregulated after long-term HFHS access in OP vs. OR animals. The effect persisted after 18 days of HFHS withdrawal. Noteworthy, even restricted HFHS led to downregulation of D1 as well as of D2 mRNA levels compared to chow-fed controls. Detection of concurrent expression changes of mu and kappa opioid receptors in the NAcc and caudate putamen confirmed their link to the effects of feeding reward withdrawal. We conclude that exposure to palatability has lasting consequences for the NAcc dopamine system, perhaps underlying the persistent search for feeding reward. The fact that the NAcc D1 expression changes long-term in OP animals after both un- and restricted exposure to palatability and extends well into the reward discontinuation phase, implicates the D1 receptor with the propensity to overeat and, in effect, gain weight in obesity prone individuals.Available from: 2010-03-01 Created: 2010-02-25 Last updated: 2010-03-01
    6. Parental food preferences are associated with body weight disturbance in preschool children
    Open this publication in new window or tab >>Parental food preferences are associated with body weight disturbance in preschool children
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Parental factors such as stress induced by parenting and certain food preferences are suspected to promote obesity in preschool children. In this context, especially the intake of dietary fat is assumed to play a key role for the children’s risk to become obese. Here we analyzed eating behaviors in parents of 3-year-olds in order to identify parental traits that are associated with body weight in these children. We also tested for possible interactions between psychosocial factors such as stress induced by parenting and parental food cravings. Questionnaires were sent out to 1300 parents whose children’s body weight was measured during ambulatory medical care visits (parental response rate 70.4%). Using the Food Craving Inventory scale allowed examining parental preferences for the following food categories:  high-fat/high-protein, sweets, carbohydrates, and fast food. Psychosocial stress caused by parenting was assessed with the Swedish Parenthood Stress Questionnaire (SPSQ). Our main finding was that the parental preference for foods rich in high-fat/high-protein nutrients displayed an inverse U-shaped function to the children’s body weight such that low preference for this category was associated with both overweight and underweight in offspring. Parental preference for sweet-foods were associated with higher odds for developing overweight in early childhood. The level of parental food preferences was significantly modulated by stress induced by parenting. In conclusion, we show that parental food preference is affected by stress and is associated with the body weight status of their children. The results suggest that parental intake of high-fat/high-protein foods protects against weight disturbances in preschool children.

    Identifiers
    urn:nbn:se:uu:diva-119472 (URN)
    Available from: 2010-03-01 Created: 2010-02-25 Last updated: 2010-03-01
  • 199.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.