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  • 1. Andersson, Christin
    et al.
    Blennow, Kaj
    Almkvist, Ove
    Andreasen, Niels
    Engfeldt, Peter
    Örebro University, School of Health and Medical Sciences.
    Johansson, Sven-Erik
    Lindau, Maria
    Eriksdotter-Jönhagen, Maria
    Increasing CSF phospho-tau levels during cognitive decline and progression to dementia2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 10, p. 1466-1473Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Little is known about longitudinal changes of cerebrospinal fluid (CSF) biomarkers during cognitive decline in neurodegenerative disease progression.

    OBJECTIVE: To investigate longitudinal changes in CSF biomarkers--total-tau (T-tau), phospho-tau (P-tau) and beta-amyloid (Abeta42)--during cognitive decline.

    METHODS: Forty memory clinic patients (47.5% females), aged 61.3+/-7.6 (S.D.) years, non-demented at baseline, underwent lumbar puncture and neuropsychological testing at two occasions. Baseline mean MMSE-score was 28.3+/-1.8. Patients were divided into three groups based on baseline memory functioning; severely impaired (SIM), moderately impaired (MIM) and no impairment (NIM).

    RESULTS: There was a significant increase in P-tau in the SIM-group during follow-up, while P-tau in MIM and NIM did not change. Eighty-three percent of the SIM-patients converted to dementia (80% AD), while most MIM- and NIM-patients remained non-demented. T-tau- and Abeta42-levels did not change in any of the memory groups during follow-up.

    CONCLUSION: Increasing P-tau levels during cognitive decline and conversion to dementia suggest that P-tau may be useful as a longitudinal marker of the neurodegenerative process.

  • 2.
    Axelsson, Markus
    et al.
    University of Gothenburg, Gothenburg, Sweden .
    Malmeström, Clas
    University of Gothenburg, Gothenburg, Sweden .
    Gunnarsson, Martin
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    Zetterberg, Henrik
    University of Gothenburg, Mölndal, Sweden; Institute of Neurology, The University College London (UCL), London, UK.
    Sundstrom, Peter
    Umeå University, Umeå, Sweden .
    Lycke, Jan
    University of Gothenburg, Gothenburg, Sweden .
    Svenningsson, Anders
    Umeå University, Umeå, Sweden .
    Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis2014In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 20, no 1, p. 43-50Article in journal (Refereed)
    Abstract [en]

    Background: In progressive multiple sclerosis (PMS), disease-modifying therapies have not been shown to reduce disability progression.

    Objective: The impact from immunosuppressive therapy in PMS was explored by analyzing cerebrospinal fluid (CSF) biomarkers of axonal damage (neurofilament light protein, NFL), astrogliosis (glial fibrillary acidic protein, GFAP), and B-cell regulation (CXCL13).

    Methods: CSF was obtained from 35 patients with PMS before and after 12-24 months of mitoxantrone (n=30) or rituximab (n=5) treatment, and from 14 age-matched healthy control subjects. The levels of NFL, GFAP, and CXCL13 were determined by immunoassays.

    Results: The mean NFL level decreased by 51% (1781 ng/l, SD 2018 vs. 874 ng/l, SD 694, p=0.007), the mean CXCL13 reduction was 55% (9.71 pg/ml, SD 16.08, vs. 4.37 pg/ml, SD 1.94, p=0.008), while GFAP levels remained unaffected. Subgroup analysis showed that the NFL reduction was confined to previously untreated patients (n=20) and patients with Gd-enhancing lesions on magnetic resonance imaging (n=12) prior to study baseline.

    Conclusions: Our data imply that 12-24 months of immunosuppressive therapy reduces axonal damage in PMS, particularly in patients with ongoing disease activity. Determination of NFL levels in CSF is a potential surrogate marker for treatment efficacy and as endpoint in phase II trials of MS.

  • 3.
    Bergman, Olle
    et al.
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Westberg, Lars
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Elias
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, Sweden.
    Study on the possible association of brain-derived neurotrophic factor polymorphism with the developmental course of symptoms of attention deficit and hyperactivity2011In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 14, no 10, p. 1367-1376Article in journal (Refereed)
    Abstract [en]

    Several studies have, with conflicting results, investigated the relationship between the Val⁶⁶Met polymorphism in brain-derived neurotrophic factor (BDNF) and attention deficit hyperactivity disorder (ADHD). We assessed longitudinal, quantitative phenotypes of hyperactivity-impulsivity and inattention in order to determine whether the Val⁶⁶Met polymorphism is associated with age-specific and/or persistent symptoms of hyperactivity-impulsivity and/or inattention in a community-based cohort of 1236 Swedish individuals for which ADHD symptom data were collected when the participants were aged 8-9, 13-14 and 16-17 yr. The Met allele was associated with symptoms of ADHD at ages 8-9 and 13-14 yr. A multivariate regression analysis revealed that the observed effect of the Met allele on ADHD symptoms reflects an influence on persistent hyperactivity-impulsivity symptoms. The present findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The results highlight the importance of distinguishing between hyperactivity-impulsivity and inattention, respectively, and demonstrate the value of using a longitudinal approach in genetic studies of ADHD symptoms.

  • 4.
    Borg, J.
    et al.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Cervenka, S.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, R
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Matheson, G. J.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Jönsson, E. G.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, Psychiatry Section, University of Oslo, Oslo, Norway.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Henningsson, S.
    Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark.
    Ichimiya, T.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Stenkrona, P.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Halldin, C.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Farde, L.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; AstraZeneca Translational Science Center, Karolinska Institutet, Stockholm, Sweden.
    Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain2016In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 8, p. 1077-1084Article in journal (Refereed)
    Abstract [en]

    The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

  • 5.
    Brander, Gustaf
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Pérez-Vigil, Ana
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Systematic review of environmental risk factors for Obsessive-Compulsive Disorder: A proposed roadmap from association to causation2016In: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 65, p. 36-62Article, review/survey (Refereed)
    Abstract [en]

    Objective: To synthesize the current knowledge on possible environmental risk factors for Obsessive-Compulsive Disorder (OCD).

    Method: We conducted a systematic review following PRISMA guidelines. The Embase, PubMed and Scopus databases were searched up until October 6, 2015, employing relevant keywords and MeSH terms.

    Results: 128 studies met inclusion criteria. Potential environmental risk factors for OCD have been identified in the broad areas of perinatal complications, reproductive cycle, and stressful life events. There is limited evidence regarding other potential risk factors, such as parental age, season of birth, socioeconomic status, parental rearing practices, infections, traumatic brain injury, substance use or vitamin deficiency. In general, studies were of limited methodological quality.

    Conclusions: At present, no environmental risk factors have convincingly been associated with OCD. We propose a roadmap for future studies, consisting of longitudinal, population-based research, employing quasi-experimental family and twin designs to identify risk factors that are not only associated with the disorder but also contribute to its causation either directly or moderating the effect of genes.

  • 6.
    Breimer, Lars H.
    et al.
    Fac Med & Hlth, Dept Lab Med, Örebro University Hospital, Örebro, Sweden.
    Nilsson, Torbjorn K.
    Dept Med Biosci, Clin Chem, Umeå Univ, Umeå, Sweden.
    Shedded cell membrane proteins in plasma: Pure waste, or informative biomarkers of pathophysiological processes?2015In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 75, no 6, p. 441-443Article in journal (Refereed)
  • 7.
    Brenner, P.
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Burkill, S.
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Jokinen, J.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Sciences, Umeå University, Umeå, Sweden.
    Hillert, J.
    Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Bahmanyar, S.
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Multiple sclerosis and risk of attempted and completed suicide: a cohort study2016In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 23, no 8, p. 1329-1336Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Patients with multiple sclerosis (MS) are known to have an elevated suicide risk, but attempted suicide is incompletely investigated. The relation between education level and suicidality has not been investigated in MS patients. Our objective was to estimate attempted suicide and completed suicide risks amongst MS patients.

    Methods: A total of 29 617 Swedish MS patients were identified through the Swedish Patient Register and matched with 296 164 people without MS from the general population. Cox regression analysis estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of MS with attempted and completed suicide, with adjustment for age, sex, education and calendar period.

    Results: The adjusted HR for attempted suicide amongst MS patients is 2.18 (95% CI 1.97-2.43) compared with the general population cohort. For completed suicide the HR is 1.87 (95% CI 1.53-2.30). In both groups women are at higher risk of attempting suicide, whilst men are at higher risk of completing suicide. Education level is inversely associated with completed suicide amongst the non-MS cohort (0.68, 0.51-0.91), but not amongst MS patients (1.10, 0.60-2.04).

    Conclusion: Multiple sclerosis patients are at higher risk of both attempted and completed suicide. No evidence was found of an inverse association between educational level and risk of completed suicide amongst MS patients.

  • 8.
    Cederlöf, Martin
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bergen, Sarah E.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Swedish Prison and Probation Service R andD, Norrköping, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Boman, Marcus
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Craddock, Nick
    Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom .
    Östberg, Per
    Division of Speech and Language Pathology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Sweden; Department of Speech-Language Pathology, Karolinska University Hospital, Huddinge, Sweden .
    Lundström, Sebastian
    Centre for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Gothenburg, Sweden; Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden .
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Nordlind, Klas
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden .
    Landén, Mikael
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden .
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    The association between Darier disease, bipolar disorder, and schizophrenia revisited: a population-based family study2015In: Bipolar Disorders, ISSN 1398-5647, E-ISSN 1399-5618, Vol. 17, no 3, p. 340-344Article in journal (Refereed)
    Abstract [en]

    Objectives: Darier disease is an autosomal dominant skin disorder caused by mutations in the ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 (ATP2A2) gene and previously reported to cosegregate with bipolar disorder and schizophrenia in occasional pedigrees. It is, however, unknown whether these associations exist also in the general population, and the objective of this study was to examine this question.

    Methods: We compared a national sample of individuals with Darier disease and their first-degree relatives with matched unexposed individuals from the general population and their first-degree relatives, respectively. To examine risks for bipolar disorder and schizophrenia, risk ratios and 95% confidence intervals (CIs) were estimated using conditional logistic regressions.

    Results: Individuals with Darier disease had a 4.3 times higher risk of being diagnosed with bipolar disorder (95% CI: 2.6-7.3) and a 2.3 times higher risk of being diagnosed with schizophrenia (95% CI: 1.1-5.2) than matched individuals from the general population. Relatives of individuals with Darier disease had a 1.6 times higher risk of having bipolar disorder (95% CI: 1.1-2.5) than relatives of matched individuals from the general population, but no increased risk of schizophrenia (risk ratio = 0.8, 95% CI: 0.4-1.8).

    Conclusions: The association between Darier disease and bipolar disorder is manifest also in the population, and our data suggest that genetic variability within the ATP2A2 gene that causes Darier disease also confers susceptibility for bipolar disorder. The Darier-causing mutations merit additional attention in molecular genetic research on bipolar disorder.

  • 9.
    Cheng, Arthur
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Chaillou, Thomas
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Gineste, Charlotte
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Schlittler, Maja
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Intracellular Ca(2+) handling and myofibrillar Ca(2+) sensitivity are defective in single muscle fibres of aged humans2015In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 593, no 15, p. 3237-3238Article in journal (Refereed)
  • 10.
    Cronberg, Tobias
    et al.
    Dept Neurol & Rehabil Med, Skåne Univ Hosp, Lund, Sweden; Dept Clin Sci, Lund Univ, Lund, Sweden.
    Lilja, Gisela
    Dept Neurol & Rehabil Med, Skåne Univ Hosp, Lund, Sweden; Dept Clin Sci, Lund Univ, Lund, Sweden.
    Horn, Janneke
    Acad Med Ctr, Dept Intens Care, Univ Amsterdam, Amsterdam, Netherlands.
    Kjaergaard, Jesper
    Ctr Heart, Dept Cardiol, Copenhagen Univ Hosp (Rigshosp), Copenhagen, Denmark.
    Wise, Matt P.
    Adult Crit Care, Univ Wales Hosp, Cardiff, England.
    Pellis, Tommaso
    Intens Care Unit, Santa Maria Angeli, Pordenone, Italy.
    Hovdenes, Jan
    Dept Anesthesiol, Oslo Univ Hosp (Rikshosp), Univ Oslo, Oslo, Norway.
    Gasche, Yvan
    Dept Anesthesiol Pharmacol & Intens Care, Univ Hosp Geneva, Geneva, Switzerland.
    Aneman, Anders
    Dept Intens Care, Liverpool Hosp, Sydney NSW, Australia.
    Stammet, Pascal
    Dept Anesthesiol & Intens Care, Ctr Hosp, Luxembourg, Luxembourg.
    Erlinge, David
    Dept Clin Sci, Lund Univ, Lund, Sweden; Dept Cardiol, Lund Univ, Lund, Sweden.
    Friberg, Hans
    Dept Clin Sci, Lund, Lund Univ, Sweden; Dept Intens & Perioperat Care, Skåne Univ Hosp, Lund, Sweden.
    Hassager, Christian
    Ctr Heart, Dept Cardiol, Copenhagen Univ Hosp (Rigshosp), Copenhagen, Denmark.
    Kuiper, Michael
    Acad Med Ctr, Dept Intens Care, Univ Amsterdam, Amsterdam, Netherlands; Dept Intens Care, Med Ctr Leeuwarden, Leeuwarden, Netherlands.
    Wanscher, Michael
    Ctr Heart, Dept Cardiothorac Anesthesiol, Copenhagen Univ Hosp (Rigshosp), Copenhagen, Denmark.
    Bosch, Frank
    Dept Intens Care, Rijnstaate Hosp, Arnhem, Netherlands.
    Cranshaw, Julius
    Dept Intens Care, Royal Bournemouth Hosp, Bournemouth, England.
    Kleger, Gian-Reto
    Dept Intens Care, Kantonsspital, St Gallen, Switzerland.
    Persson, Stefan
    Dept Anesthesia & Intens Care, Örebro University Hospital, Örebro, Sweden.
    Unden, Johan
    Dept Intens & Perioperat Care, Skåne Univ Hosp, Malmö, Sweden.
    Walden, Andrew
    Dept Intens Care, Royal Berkshire Hosp, Reading, England.
    Winkel, Per
    Ctr Clin Intervent Res, Copenhagen Trial Unit, Copenhagen Univ Hosp R(igshosp), Copenhagen, Denmark.
    Wetterslev, Jorn
    Ctr Clin Intervent Res, Copenhagen Trial Unit, Copenhagen Univ Hosp (Rigshosp), Copenhagen, Denmark.
    Nielsen, Niklas
    Dept Clin Sci, Lund Univ, Lund, Sweden; Anesthesia & Intens Care, Helsingborg Hosp, Helsingborg, Sweden.
    Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33 degrees C vs 36 degrees C After Out-of-Hospital Cardiac Arrest A Randomized Clinical Trial2015In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 72, no 6, p. 634-641Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Brain injury affects neurologic function and quality of life in survivors after cardiac arrest. OBJECTIVE To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939. INTERVENTIONS Targeted temperature management at 33 degrees C vs 36 degrees C. MAIN OUTCOMES AND MEASURES Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2. RESULTS In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33 degrees C group (interquartile range [IQR], 0-28) vs 17 in the 36 degrees C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33 degrees C and 36 degrees C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33 degrees C group median, 28; IQR, 26-30; vs 36 degrees C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33 degrees C group median, 79.5; IQR, 78.0-85.9; vs 36 degrees C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33 degrees C group vs 61.8% in the 36 degrees C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm. CONCLUSIONS AND RELEVANCE Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33 degrees C or 36 degrees C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales.

  • 11.
    Eriksson, Eva Wiman
    et al.
    Dept Dent Sleep Med, Postgrad Dent Educ Ctr, Region Örebro County, Örebro, Sweden.
    Leissner, Lena
    Sleep Unit, Dept Neurol, Örebro University Hospital, Örebro, Sweden.
    Isacsson, Göran
    Dept Orofacial Pain, Västmanland Cty Hosp, Västerås, Sweden.
    Fransson, Anette
    Örebro University Hospital. Dept Orthodont, Postgrad Dent Educ Ctr, , Region Örebro County, Örebro, Sweden; Dent Sleep Med Clin, Postgrad Dent Educ Ctr, Region Örebro County, Örebro, Sweden.
    A prospective 10-year follow-up polygraphic study of patients treated with a mandibular protruding device2015In: Sleep and Breathing, ISSN 1520-9512, E-ISSN 1522-1709, Vol. 19, no 1, p. 393-401Article in journal (Refereed)
    Abstract [en]

    This 10-year follow-up prospective study aimed to evaluate the effects of treatment with a mandibular protruding device (MPD) on respiratory parameters and subjective symptoms in patients with obstructive sleep apnea (OSA) or snoring. Seventy-seven consecutive patients diagnosed with OSA or snoring were treated with an MPD. At baseline and the 10-year follow-up, a polygraphic examination and questionnaires on sleep quality were administrated and weight, and neck size was measured. At the 10-year follow-up, we examined 64 of the 77 patients and recorded their current treatment (45 MPD, 9 continuous positive airway pressure (CPAP), and 10 no treatment). For MPD patients, 89 % reported MPD use every night and 9 % several nights a week. Compared to baseline, MPD users with OSA had a significantly decreased oxygen desaturation index (ODI) (p = 0.006) and increased lowest arterial oxygen saturation, SaO(2) nadir (p = 0.007) after 10 years. MPD treatment was successful for 70 % of OSA patients, yet 89 % subjectively considered themselves cured, indicating overestimation of the treatment effect. OSA patients who responded to treatment maintained baseline weight and neck size, while these increased for non-responders. Of the baseline snorers still using an MPD, 93 % maintained an ODI value of < 5. All CPAP users had an ODI value of < 5. Both OSA and snorers using an MPD had significantly fewer self- and relative reports of snoring, apnea, daytime tiredness, and poor night sleep quality (p < 0.001). MPD treatment is well tolerated and effective in a long-term, 10-year perspective. Weight gain may jeopardize MPD effects. Both patients and relatives reported significantly less snoring and fewer periods of apnea.

  • 12.
    Fang, Fang
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
    Valdimarsdóttir, Unnur
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; Centre of Public Health Sciences,University of Iceland, Reykjavik, Iceland.
    Fürst, Carl Johan
    Stockholms Sjukhem, Palliative Care Unit, Stockholm.
    Hultman, Christina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; Department of Neuroscience, Psychiatry, Ulleråker,Uppsala University,Uppsala.
    Fall, Katja
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
    Sparén, Pär
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
    Ye, Weimin
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
    Suicide among patients with amyotrophic lateral sclerosis2008In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 131, no 10, p. 2729-33Article in journal (Refereed)
    Abstract [en]

    Studies on the suicide risk among patients with amyotrophic lateral sclerosis (ALS) in countries without legalized euthanasia or assisted suicide are important additions to data on the wish to die of these patients. We conducted a population-based cohort study in Sweden between 1965 and 2004, which comprised of 6,642 patients with incident ALS identified from the Swedish Inpatient Register. We calculated the standardized mortality ratios (SMRs) of suicide among the patients using the suicide rates of the general Swedish population as a reference. In total, 21 patients committed suicide during follow-up, compared to the predicted 3.6 suicides. Thus, we noted an almost 6-fold increased risk for suicide among ALS patients [SMR 5.8, 95% confidence interval (CI) 3.6-8.8]. Patients who committed suicide were, on average, around 7 years younger at the time of their first period of hospitalization than patients who did not commit suicide. The highest relative risk for suicide was observed within the first year after the patient's first period of hospitalization (SMR 11.2, 95% CI 5.8-19.6). After that, the relative risks decreased with time after hospitalization (P-value for trend = 0.006), but remained elevated 3 years later. The relative risks of suicide among ALS patients did not show a clear trend over time in contrast to the decreasing trend of relative risks for suicide among patients with cancer during the same period. Patients with ALS are at excess risk of suicide in Sweden and the relative risk is higher during the earlier stage of the disease.

  • 13. Fernell, Elisabeth
    et al.
    Karagiannakis, Aristea
    Örebro University, Department of Clinical Medicine.
    Edman, Gunnar
    Bjerkenstedt, Lars
    Wiesel, Frits-Axel
    Venizelos, Nikolaos
    Örebro University, Department of Clinical Medicine.
    Aberrant amino acid transport in fibroblasts from children with autism2007In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 418, no 1, p. 82-86Article in journal (Refereed)
    Abstract [en]

    Autism is a developmental, cognitive disorder clinically characterized by impaired social interaction, communication and restricted behaviours. The present study was designed to explore whether an abnormality in transport of tyrosine and/or alanine is present in children with autism. Skin biopsies were obtained from 11 children with autism (9 boys and 2 girls) fulfilling the DSM-IV diagnostic criteria for autistic disorder and 11 healthy male control children. Transport of amino acids tyrosine and alanine across the cell membrane of cultured fibroblasts was studied by the cluster tray method. The maximal transport capacity, Vmax and the affinity constant of the amino acid binding sites, Km, were determined. Significantly increased Vmax for alanine (p = 0.014) and increased Km for tyrosine (p = 0.007) were found in children with autism. The increased transport capacity of alanine across the cell membrane and decreased affinity for transport sites of tyrosine indicates the involvement of two major amino acid transport systems (L- and A-system) in children with autism. This may influence the transport of several other amino acids across the blood–brain-barrier. The significance of the findings has to be further explored. © 2007 Elsevier Ireland Ltd. All rights reserved

  • 14.
    Forsberg, Anette
    et al.
    Division of neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Family Medicine Research Centre, Örebro county council, Örebro, Sweden.
    Press, Rayomand
    Division of neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Widén Holmqvist, Lotta
    Division of neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Division of physiotherapy, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Residual disability 10 years after falling ill in Guillain-Barré syndrome: a prospective follow-up study2012In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 317, no 1-2, p. 74-79Article in journal (Refereed)
    Abstract [en]

    Objective: To describe residual disability 10years after onset of Guillain-Barré syndrome (GBS) and longitudinal changes from 2weeks after onset until 10years afterwards. The Erasmus GBS Outcome score (EGOS) was applied for predicting prognosis at 2 and 10years.

    Methods: Twenty-nine patients, mean age at onset 49years, were followed prospectively from 2weeks to 10years after GBS onset. Measures included; GBS disability score, EGOS, Barthel Index, Frenchay Activity Index, Sickness Impact Profile (SIP), Overall Neuropathy Limitations Scale (ONLS), Walk-12, and Fatigue Severity Scale.

    Results: At 10years, the facial paralysis found in 5 participants at 2years was still present, 11 participants (38%) experienced paresthesia, 6 (21%) had limitations in their arms, and 15 (52%) had limitations in walking. Decreased health-related quality of life on comparison to the general population was seen in the physical dimension of SIP at 10years. The median EGOS at 2weeks was 4.5, which correlated highly only with the Barthel Index at 2years and the ONLS arm scale at 10years.

    Conclusion: The residual disabilities at 1-2years comprised mainly of reduced walking ability, and are still persistent 10years after GBS onset. For some individuals, facial paralysis caused major disability. The EGOS only partly predicted residual disability at 2 and 10years after onset.

  • 15.
    Genove, G.
    et al.
    Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Mollick, Tanzina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Johansson, Kjell
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Photoreceptor degeneration, structural remodeling and glial activation: a morphological study on a genetic mouse model for pericyte deficiency2014In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 279, p. 269-284Article in journal (Refereed)
    Abstract [en]

    Interaction between pericytes and endothelial cells via platelet-derived growth factor B (PDGF-B) signaling is critical for the development of the retinal microvasculature. The PDGF-B retention motif controls the spatial distribution range of the growth factor in the vicinity of its producing endothelial cells allowing its recognition by PDGF receptor beta-(PDGFR-beta)-carrying pericytes; this promotes recruitment of pericytes to the vascular basement membrane. Impairment of the PDGF-B signaling mechanism causes development of vascular abnormalities, and in the retina this consequently leads to defects in the neurological circuitry. The vascular pathology in the pdgf-b(ret/ret) (PDGF-B retention motif knockout) mouse retina has been previously reported; our study investigates the progressive neuronal defects and changes in the retinal morphology of this pericyte-deficient mouse model. Immunohistochemical analysis revealed retinal injuries to occur as early as postnatal day (P) 10 with substantial damage progressing from P15 and onward. Vascular abnormalities were apparent from P10, however, prominent neuronal defects were mostly observed from P15, beginning with the compromised integrity of the laminated retinal structure characterized by the presence of rosettes and focally distorted regions. Photoreceptor degeneration was observed by loss of both rod and cone cells, including the disassembly and altered structure of their synaptic terminals. Significant shortening of cone outer segments was observed from P10 and later stages; however, decrease in cone density was only observed at P28. Disorganization and dendrite remodeling of rod bipolar cells also added to the diminished neural and synaptic integrity. Moreover, in response to retinal injuries, Muller and microglial cells were observed to be in the reactive phenotype from P15 and onward. Such a sequence of events indicates that the pdgf-b(ret/ret) mouse model displays a short time frame between P10 and P15, during which the retina shifts to a retinopathic phase by the development of prominently altered morphological features.

  • 16. Gustavsson, Anders
    et al.
    Svensson, Mikael
    Örebro University, Swedish Business School at Örebro University.
    Jacobi, Frank
    Allgulander, Christer
    Alonso, Jordi
    Beghi, Ettore
    Dodel, Richard
    Ekman, Mattias
    Faravelli, Carlo
    Fratiglioni, Laura
    Gannon, Brenda
    Jones, David Hilton
    Jennum, Poul
    Jordanova, Albena
    Jonsson, Linus
    Karampampa, Korinna
    Knapp, Martin
    Kobelt, Gisela
    Kurth, Tobias
    Lieb, Roselind
    Linde, Mattias
    Ljungcrantz, Christina
    Maercker, Andreas
    Melin, Beatrice
    Moscarelli, Massimo
    Musayev, Amir
    Norwood, Fiona
    Preisig, Martin
    Pugliatti, Maura
    Rehm, Juergen
    Salvador-Carulla, Luis
    Schlehofer, Brigitte
    Simon, Roland
    Steinhausen, Hans-Christoph
    Stovner, Lars Jacob
    Vallat, Jean-Michel
    Van den Bergh, Peter
    van Os, Jim
    Vos, Pieter
    Xu, Weili
    Wittchen, Hans-Ulrich
    Jonsson, Bengt
    Olesen, Jes
    Cost of disorders of the brain in Europe 20102011In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 21, no 10, p. 718-779Article in journal (Refereed)
    Abstract [en]

    Background: The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of 386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people. Aims: To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country. Methods: The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27 + Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010. Results: The total cost of disorders of the brain was estimated at (sic)798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between (sic)285 for headache and (sic)30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was (sic)1550 on average but varied by country. The cost (in billion (sic)PPP 2010) of the disorders of the brain included in this study was as folows: addiction: (sic)65.7; anxiety disorders: (sic)74.4; brain tumor: (sic)5.2; child/adolescent disorders: (sic)21.3; dementia: (sic)105.2; eating disorders: (sic)0.8; epilepsy: (sic)13.8; headache: (sic)43.5; mental retardation: (sic)43.3; mood disorders: (sic)113.4; multiple sclerosis: (sic)14.6; neuromuscular disorders: (sic)7.7; Parkinson's disease: (sic)13.9; personality disorders: (sic)27.3; psychotic disorders: (sic)93.9; sleep disorders: (sic)35.4; somatoform disorder: (sic)21.2; stroke: (sic)64.1; traumatic brain injury: (sic)33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted (sic)477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US. Discussion: This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges. Recommendations: Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives. (C) 2011 Published by Elsevier B.V.

  • 17.
    Humble, Mats B.
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Uppsala university.
    Bejerot, Susanne
    Uppsala university.
    Bergqvist, Peter B. F.
    AstraZeneca, Lund, Sweden.
    Reactivity of serotonin in whole blood: response to Mulder et al.2002In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 51, no 3, p. 267-268Article in journal (Other academic)
  • 18.
    Ingberg, Edvin
    Örebro University, School of Medical Sciences. Avdelningen för neuro- och inflammationsvetenskap, Linköpings universitet, Linköping, Sweden.
    Challenges in experimental stroke research: The 17β-estradiol example2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ischemic stroke causes millions of deaths around the world each year, and surviving patients often suffer from long-term disability. Hundreds of promising drug candidates have been identified in animal models, but the clinical trials have repeatedly failed. Lack of methodological quality in the animal studies, e.g. low statistical power as a result of small group sizes in combination with high outcome variability and high mortality, has been suggested to in part explain the lack of translational success. In the meta-analytical Papers II and Paper V, we therefore investigated how method parameters impact infarct size variation and mortality in rodent stroke studies. These findings can help researchers to optimize their animal models or to more exactly predict variability and mortality given a certain experimental setup.

    The relation between ischemic stroke and estrogens is complex. Premenopausal women have a lower risk of stroke than men of the same age, suggesting that female sex hormones provide protection against cerebrovascular events. The idea of a beneficial effect on the brain of estrogens was also supported by epidemiological studies showing that estrogens given as postmenopausal hormone replacement therapy decreased the risk of stroke. However, subsequent clinical trials reported the opposite, an increased risk. Interestingly, discrepancies exist also in the animal stroke literature. The majority of the rodent studies on the effects of estrogens have shown protection, but there are also several examples of increased damage. Based on experimental results and a meta-analysis, it was hypothesized that differences in hormone administration methods and their resulting plasma concentrations of estrogens might explain the previous discordant animal findings. Paper I investigated the commonly used methods for 17β-estradiol administration and found that the popular slow-release pellets produced high and unpredictable serum concentrations. A novel method with 17β-estradiol administered orally in Nutella® was also evaluated with promising results. Paper III extracted data regarding methodological choices from all previously published estrogen-stroke studies, and showed through metaanalysis that slow-release pellets are more prone to render estrogens damaging. Finally, Paper IV tested whether estrogens could both exert neuroprotection and promote detrimental effects merely depending on dose and irrespective of the administration route. Surprisingly, and in contrast to the hypothesis, a significant negative correlation was found between 17β-estradiol dose group and infarct size meaning that the higher the dose, the smaller the infarcts.

    In summary, this thesis does not confirm the hypothesis of dose-related neuroprotective vs neurodamaging effects of estrogens on ischemic stroke. If high estrogen doses/plasma concentrations per se can cause increased stroke damage, such a phenomenon is not very robust, and seems to depend on tight dose ranges and/or other experimental circumstances. Although not directly applicable to the clinical situation, hopefully in a long-term perspective these findings may contribute in elucidating when estrogens are beneficial and when they are harmful. Further, it adds to the growing literature on how the quality of experimental stroke research can be increased to try to overcome translational difficulties.

    List of papers
    1. Methods for long-term 17β-estradiol administration to mice
    Open this publication in new window or tab >>Methods for long-term 17β-estradiol administration to mice
    2012 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, no 1, p. 188-193Article in journal (Refereed) Published
    Abstract [en]

    Rodent models constitute a cornerstone in the elucidation of the effects and biological mechanisms of 17β-estradiol. However, a thorough assessment of the methods for long-term administration of 17β-estradiol to mice is lacking. The fact that 17β-estradiol has been demonstrated to exert different effects depending on dose emphasizes the need for validated administration regimens. Therefore, 169 female C57BL/6 mice were ovariectomized and administered 17β-estradiol using one of the two commonly used subcutaneous methods; slow-release pellets (0.18 mg, 60-day release pellets; 0.72 mg, 90-day release pellets) and silastic capsules (with/without convalescence period, silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with a 14 mm column of 36 μg 17β-estradiol/mL sesame oil), or a novel peroral method (56 μg 17β-estradiol/day/kg body weight in the hazelnut cream Nutella). Forty animals were used as ovariectomized and intact controls. Serum samples were obtained weekly for five weeks and 17β-estradiol concentrations were measured using radioimmunoassay. The peroral method resulted in steady concentrations within--except on one occasion--the physiological range and the silastic capsules produced predominantly physiological concentrations, although exceeding the range by maximum a factor three during the first three weeks. The 0.18 mg pellet yielded initial concentrations an order of magnitude higher than the physiological range, which then decreased drastically, and the 0.72 mg pellet produced between 18 and 40 times higher concentrations than the physiological range during the entire experiment. The peroral method and silastic capsules described in this article constitute reliable modes of administration of 17β-estradiol, superior to the widely used commercial pellets.

    Place, publisher, year, edition, pages
    Maryland Heigths, USA: Elsevier, 2012
    Keywords
    Estradiol, mice, slow-release pellets, silastic capsule, Per os, uterine weight
    National Category
    Medical and Health Sciences Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:oru:diva-48106 (URN)10.1016/j.ygcen.2011.11.014 (DOI)000299065800022 ()22137913 (PubMedID)2-s2.0-84855192470 (Scopus ID)
    Available from: 2016-02-08 Created: 2016-02-08 Last updated: 2019-04-05Bibliographically approved
    2. Method parameters' impact on mortality and variability in rat stroke experiments: a meta-analysis
    Open this publication in new window or tab >>Method parameters' impact on mortality and variability in rat stroke experiments: a meta-analysis
    2013 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 14, article id 41Article in journal (Refereed) Published
    Abstract [en]

    Background: Even though more than 600 stroke treatments have been shown effective in preclinical studies, clinically proven treatment alternatives for cerebral infarction remain scarce. Amongst the reasons for the discrepancy may be methodological shortcomings, such as high mortality and outcome variability, in the preclinical studies. A common approach in animal stroke experiments is that A) focal cerebral ischemia is inflicted, B) some type of treatment is administered and C) the infarct sizes are assessed. However, within this paradigm, the researcher has to make numerous methodological decisions, including choosing rat strain and type of surgical procedure. Even though a few studies have attempted to address the questions experimentally, a lack of consensus regarding the optimal methodology remains.

    Methods: We therefore meta-analyzed data from 502 control groups described in 346 articles to find out how rat strain, procedure for causing focal cerebral ischemia and the type of filament coating affected mortality and infarct size variability.

    Results: The Wistar strain and intraluminal filament procedure using a silicone coated filament was found optimal in lowering infarct size variability. The direct and endothelin methods rendered lower mortality rate, whereas the embolus method increased it compared to the filament method.

    CONCLUSIONS: The current article provides means for researchers to adjust their middle cerebral artery occlusion (MCAo) protocols to minimize infarct size variability and mortality.

    Place, publisher, year, edition, pages
    London, United Kingdom: BioMed Central, 2013
    Keywords
    Brain infarction, middle cerebral artery occlusion, rats, methods, mortality, variability
    National Category
    Medical and Health Sciences Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:oru:diva-48100 (URN)10.1186/1471-2202-14-41 (DOI)000318616000001 ()23548160 (PubMedID)2-s2.0-84875538383 (Scopus ID)
    Available from: 2016-02-08 Created: 2016-02-08 Last updated: 2019-04-05Bibliographically approved
    3. Impact of methodology on estrogens' effects on cerebral ischemia in rats: an updated meta-analysis
    Open this publication in new window or tab >>Impact of methodology on estrogens' effects on cerebral ischemia in rats: an updated meta-analysis
    2014 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 15, article id 22Article in journal (Refereed) Published
    Abstract [en]

    Background: Although most animal stroke studies have demonstrated potent neuroprotective effects of estrogens, there are a number of articles reporting the opposite. In 2009, we made the case that this dichotomy was related to administered estrogen dose. Several other suggestions for the discordant results have also been propagated, including the age of the experimental animals and the length of hypoestrogenicity prior to estrogen administration. These two suggestions have gained much popularity, probably because of their kinship with the window of opportunity hypothesis, which is commonly used to explain the analogous dichotomy among human studies. We were therefore encouraged to perform an updated meta-analysis, and to improve it by including all relevant variables in a large multiple regression model, where the impact of confounders could be controlled for.

    Results: The multiple regression model revealed an indisputable impact of estrogen administration mode on the effects of estrogens in ischemic stroke. Subcutaneous slow-release pellets differed from the injection and silastic capsule treatments in terms of impact of estrogens on ischemic stroke, showing that the first mentioned were more prone to render estrogens damaging. Neither the use of elderly animals nor the adoption of longer wash-out periods influenced estrogens' effects on experimental ischemic stroke in rats.

    Conclusions: We conclude that the discordant results regarding estrogens' effects in rat models of ischemic stroke are a consequence of differences in estrogen administration modes. These results are not only of importance for the ongoing debate regarding menopausal hormone therapy, but also have an important bearing on experimental stroke methodology and the apparent translational roadblock for suggested stroke interventions.

    Place, publisher, year, edition, pages
    London: BioMed Central, 2014
    Keywords
    Cerebral ischemia, Estradiol, Estrogens, Meta-analysis, Rats, Stroke
    National Category
    Neurology
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:oru:diva-35219 (URN)10.1186/1471-2202-15-22 (DOI)000334885400001 ()24495535 (PubMedID)2-s2.0-84893182322 (Scopus ID)
    Note

    Funding Agencies:

    County Council of Örebro

    Linköping University, Sweden

    Available from: 2014-06-02 Created: 2014-06-02 Last updated: 2018-06-07Bibliographically approved
    4. Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats
    Open this publication in new window or tab >>Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats
    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 20228Article in journal (Refereed) Published
    Abstract [en]

    The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17β-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n = 40 per group) were randomized into three groups, subcutaneously administered different doses of 17β-estradiol and subjected to transient middle cerebral artery occlusion. The modified sticky tape test was performed after 24 h and the rats were subsequently sacrificed for infarct size measurements. In contrast to our hypothesis, a significant negative correlation between 17β-estradiol dose and infarct size was found (p = 0.018). Thus, no support was found for the hypothesis that 17β-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the findings indicate that the higher the dose of 17β-estradiol, the smaller the infarct.

    Place, publisher, year, edition, pages
    London, United Kingdom: Nature Publishing Group, 2016
    National Category
    Medical and Health Sciences Neurology
    Identifiers
    urn:nbn:se:oru:diva-48094 (URN)10.1038/srep20228 (DOI)000369323500001 ()26839007 (PubMedID)2-s2.0-84957824658 (Scopus ID)
    Note

    Funding Agency:

    County Council of Östergötland, Sweden

    Available from: 2016-02-08 Created: 2016-02-08 Last updated: 2019-03-01Bibliographically approved
    5. Method parameters' impact on mortality and variability in mouse stroke experiments: a meta-analysis
    Open this publication in new window or tab >>Method parameters' impact on mortality and variability in mouse stroke experiments: a meta-analysis
    Show others...
    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 21086Article in journal (Refereed) Published
    Abstract [en]

    Although hundreds of promising substances have been tested in clinical trials, thrombolysis currently remains the only specific pharmacological treatment for ischemic stroke. Poor quality, e.g. low statistical power, in the preclinical studies has been suggested to play an important role in these failures. Therefore, it would be attractive to use animal models optimized to minimize unnecessary mortality and outcome variability, or at least to be able to power studies more exactly by predicting variability and mortality given a certain experimental setup. The possible combinations of methodological parameters are innumerous, and an experimental comparison of them all is therefore not feasible. As an alternative approach, we extracted data from 334 experimental mouse stroke articles and, using a hypothesis-driven meta-analysis, investigated the method parameters' impact on infarct size variability and mortality. The use of Swiss and C57BL6 mice as well as permanent occlusion of the middle cerebral artery rendered the lowest variability of the infarct size while the emboli methods increased variability. The use of Swiss mice increased mortality. Our study offers guidance for researchers striving to optimize mouse stroke models.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2016
    National Category
    Neurology
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:oru:diva-48937 (URN)10.1038/srep21086 (DOI)000370034300001 ()26876353 (PubMedID)2-s2.0-84958259183 (Scopus ID)
    Note

    Funding Agency:

    County Council of Östergötland, Sweden

    Available from: 2016-03-07 Created: 2016-03-04 Last updated: 2019-03-01Bibliographically approved
  • 19.
    Lebwohl, Benjamin
    et al.
    Dept Med, Celiac Dis Ctr, Columbia Univ Coll Phys & Surg, New York NY, USA; Dept Med Epidemiol & Biostat, Karolinska Univ Hosp, Stockholm, Sweden; Karolinska Institute, Stockholm, Sweden; Dept Med, Columbia Univ Coll Phys & Surg, New York, NY, USA; Med Ctr, Mailman Sch Publ Hlth, Dept Epidemiol, Columbia Univ, New York NY, USA.
    Luchsinger, Jose A.
    Dept Med, Columbia Univ Coll Phys & Surg, New York NY, USA; Med Ctr, Mailman Sch Publ Hlth, Dept Epidemiol, Columbia Univ, New York NY, USA.
    Freedberg, Daniel E.
    Dept Med, Columbia Univ Coll Phys & Surg, New York NY, USA.
    Green, Peter H. R.
    Dept Med, Celiac Dis Ctr, Columbia Univ Coll Phys & Surg, New York NY, USA.
    Ludvigsson, Jonas F.
    Örebro University Hospital. Dept Med Epidemiol & Biostat, Karolinska Univ Hosp, Stockholm, Sweden; Karolinska Inst, Stockholm, Sweden; Dept Pediat, Örebro University Hospital, Örebro, Sweden.
    Risk of Dementia in Patients with Celiac Disease: A Population-Based Cohort Study2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 49, no 1, p. 179-185Article in journal (Refereed)
    Abstract [en]

    Background: Patients with celiac disease (CD) frequently report cognitive symptoms when they are exposed to gluten, and cognitive deficits have been quantified in patients with newly diagnosed CD. Objective: To determine whether patients with CD have an increased risk of dementia. Methods: Using a population-based database of older adults (age >= 50 years) with histologically proven CD (duodenal/jejunal villous atrophy) from all 28 pathology departments in Sweden, we compared the incidence of a subsequent dementia diagnosis to those of age-and gender-matched controls. Results: Among patients with CD (n = 8,846) and controls (n = 43,474), the median age was 63 years and 56% were female. During a median follow-up time of 8.4 years, dementia was diagnosed in 4.3% of CD patients and 4.4% of controls (HR 1.07; 95% CI 0.95-1.20). Although there was an increased risk of dementia in the first year following a diagnosis of CD (HR 1.73; 95% CI 1.15-2.61), this risk was not present in the whole observation period. Among those subjects with a dementia subtype specified, the increased risk was restricted to vascular dementia (HR 1.28; 95% CI 1.00-1.64) and was not present for Alzheimer's dementia (HR 1.12; 95% CI 0.91-1.37). Conclusions: Patients with CD are not at increased risk for dementia overall, though subgroup analysis suggests that they may be at increased risk for vascular dementia.

  • 20.
    Lidström Holmqvist, Kajsa
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ivarsson, Ann-Britt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Holmefur, Marie
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Occupational therapist practice patterns in relation to clients with cognitive impairment following acquired brain injury2014In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 28, no 11, p. 1365-1373Article in journal (Refereed)
    Abstract [en]

    Primary objective: To describe Swedish occupational therapist practice patterns for clients with cognitive impairment following acquired brain injury.

    Research design: A cross-sectional stratified random sample of 462 occupational therapists.

    Methods: An online questionnaire was used to collect data.

    Main results: The predominant practice pattern was the use of ADL-activities for assessment and therapy regardless of whether limitations in occupational performance or cognitive function were assessed or whether the approach was remedial or compensatory. For assessment, general ADL-instruments were used more often than instruments that assessed cognitive function. Instruments were used less often within municipal rehabilitation facilities compared to regional, county and primary care facilities. The most common focus of the therapies was in regard to abilities related to executive functioning. Another prominent practice pattern was a collaborative approach involving clients, relatives and other staff. The theories used in practice were, to a large extent, general in nature and did not focus specifically on cognitive functioning.

    Conclusions: Swedish occupational therapy practice for clients with cognitive impairments following acquired brain injury focuses highly on occupational performance. Therapies targeting executive functioning seem particularly important in practice and a collaborative approach involving clients, relatives and other staff is a prominent feature in practice.

  • 21.
    Merwood, Andrew
    et al.
    MRC Social Genetic and Developmental Psychiatry Centre, PO80, Institute of Psychiatry, King's College London, London, UK.
    Asherson, Philip
    MRC Social Genetic and Developmental Psychiatry Centre, PO80, Institute of Psychiatry, King's College London, London, UK.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, Sweden.
    Genetic associations between the ADHD symptom dimensions and Cloninger's temperament dimensions in adult twins2013In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, no 6, p. 416-425Article in journal (Refereed)
    Abstract [en]

    Previous studies have identified phenotypic associations between Cloninger's temperament dimensions and the symptoms of attention deficit hyperactivity disorder (ADHD) in adults. However the underlying aetiology of these associations remains unclear. We investigate the extent to which genetic and environmental influences contribute to the relationship between temperament and ADHD, examining the ADHD symptoms of inattention (IA) and hyperactivity/impulsivity (HI) separately. Participants were 886 adult twin pairs aged 19-20 years. ADHD symptoms of IA and HI were measured using a DSM-IV based rating scale. Temperament was measured using Cloninger's Temperament and Character Inventory (TCI), across four dimensions: novelty seeking (NS), harm avoidance (HA), reward dependence (RD) and persistence (PS). The twin method was used to decompose phenotypic variance/covariance among these variables into genetic and environmental components. We found that NS was genetically associated with both ADHD symptom dimensions (IA and HI), but that HA was genetically associated with IA only. There was also some evidence of genetic association between PS, IA and HI. These findings suggest that unique profiles of temperament are genetically related to the two ADHD symptom dimensions in adults. Further work is now needed to elucidate the mechanisms that underlie both the combined and separate symptom factor domains of ADHD.

  • 22.
    Mohlin, Camilla
    et al.
    Department of Chemistry and Biomedicine, Linnaeus University, Kalmar, Sweden.
    Delbro, Dick
    Örebro University, School of Medical Sciences.
    Kvanta, Anders
    Department of Clinical Neuroscience, Section for Ophthalmology and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Kjell
    Department of Science, Kristianstad University, Kristianstad, Sweden.
    Evaluation of Congo Red Staining in Degenerating Porcine Photoreceptors In Vitro: Protective Effects by Structural and Trophic Support2018In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 66, no 9, p. 631-641Article in journal (Refereed)
    Abstract [en]

    Congo red (CR) is a histological stain used for the detection of extracellular amyloids mediating various neurodegenerative diseases. Given that damaged photoreceptors appear to degenerate similarly to other nerve cells, CR staining was evaluated in experimentally injured porcine retina. CR staining appeared mostly as discrete cytosolic deposits with no obvious plaque formation during the investigated time period. Increases of CR labeling coincided temporally with the known accumulation of mislocalized opsins and increases of cell death. Coculture, either with human retinal pigment epithelium (ARPE) or human neural progenitor (ReN) cells, was accompanied by a significant reduction of CR labeling. Of particular interest was the reduction of CR labeling in cone photoreceptors, which are important for the perception of color and fine details and afflicted in age-related macular degeneration (AMD). Electron microscopy revealed inclusions in the inner segment, cell body, and occasionally synaptic terminals of photoreceptor cells in cultured specimens. Closer examinations indicated the presence of different types of inclusions resembling protein aggregates as well as inclusion bodies. The current results indicate that injury-related response resulted in accumulation of CR deposits in photoreceptor cells, and that trophic and/or structural support attenuated this response.

  • 23.
    Mollick, Tanzina
    et al.
    Örebro University, School of Medical Sciences.
    Mohlin, Camilla
    Department of Chemistry and Biomedicine, Linnaeus University, Kalmar, Sweden.
    Johansson, Kjell
    Örebro University, School of Medical Sciences.
    Human neural progenitor cells decrease photoreceptor degeneration, normalize opsin distribution and support synapse structure in cultured porcine retina2016In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1646, p. 522-534Article in journal (Refereed)
    Abstract [en]

    Retinal neurodegenerative disorders like retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy and retinal detachment decrease retinal functionality leading to visual impairment. The pathological events are characterized by photoreceptor degeneration, synaptic disassembly, remodeling of postsynaptic neurons and activation of glial cells. Despite intense research, no effective treatment has been found for these disorders. The current study explores the potential of human neural progenitor cell (hNPC) derived factors to slow the degenerative processes in adult porcine retinal explants. Retinas were cultured for 3 days with or without hNPCs as a feeder layer and investigated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunohistochemical, western blot and quantitative real time-polymerase chain reaction (qRT-PCR) techniques. TUNEL showed that hNPCs had the capacity to limit photoreceptor cell death. Among cone photoreceptors, hNPC coculture resulted in better maintenance of cone outer segments and reduced opsin mislocalization. Additionally, maintained synaptic structural integrity and preservation of second order calbindin positive horizontal cells was also observed. However, Müller cell gliosis only seemed to be alleviated in terms of reduced Müller cell density. Our observations indicate that at 3 days of coculture, hNPC derived factors had the capacity to protect photoreceptors, maintain synaptic integrity and support horizontal cell survival. Human neural progenitor cell applied treatment modalities may be an effective strategy to help maintain retinal functionality in neurodegenerative pathologies. Whether hNPCs can independently hinder Müller cell gliosis by utilizing higher concentrations or by combination with other pharmacological agents still needs to be determined.

  • 24.
    Montgomery, Scott
    et al.
    Örebro University, School of Medical Sciences.
    Bergh, Cecilia
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Udumyan, Ruzan
    Örebro University, School of Medical Sciences.
    Eriksson, Mats
    Örebro University, School of Health Sciences.
    Fall, Katja
    Örebro University, School of Medical Sciences.
    Hiyoshi, Ayako
    Örebro University, School of Medical Sciences.
    Sex of older siblings and cognitive function2017Conference paper (Refereed)
  • 25.
    Oresic, Matej
    et al.
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Anderson, Gabriella
    Florida Hospital Orlando, Neuroscience Research Institute, Orlando FL, United States.
    Mattila, Ismo
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Manoucheri, Manoucher
    Florida Hospital Orlando, Neuroscience Research Institute, Orlando FL, United States.
    Soininen, Hilkka
    Department of Neurology, Neuro Center, Kuopio University Hospital, Kuopio, Finland; Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Basignani, Cherlynn
    Florida Hospital Orlando, Neuroscience Research Institute, Orlando FL, United States.
    Targeted Serum Metabolite Profiling Identifies Metabolic Signatures in Patients with Alzheimer's Disease, Normal Pressure Hydrocephalus and Brain Tumor2018In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 11, article id 747Article in journal (Refereed)
    Abstract [en]

    Progression to AD is preceded by elevated levels of 2,4-dihydroxybutanoic acid (2,4-DHB), implicating hypoxia in early pathogenesis. Since hypoxia may play a role in multiple CNS disorders, we investigated serummetabolite profiles across three disorders, AD, Normal Pressure Hydrocephalus (NPH) and brain tumors (BT). Blood samples were collected from27 NPH and 20 BT patients. The profiles of 21metabolites were examined. Additionally, data from 37 AD patients and 46 controls from a previous study were analyzed together with the newly acquired data. No differences in 2,4-DHB were found across AD, NPH and BT samples. In the BT group, the fatty acids were increased as compared to HC and NPH groups, while the ketone body 3-hydroxybutyrate was increased as compared to AD. Glutamic acid was increased in AD as compared to the HC group. In the AD group, 3-hydroxybutyrate tended to be decreased with respect to all other groups (mean values −30% or more), but the differences were not statistically significant. Serine was increased in NPH as compared to BT. In conclusion, AD, NPH and BT have different metabolic profiles. This preliminary study may help in identifying the blood based markers that are specific to these three CNS diseases.

  • 26.
    Pettersson, E.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Common psychiatric disorders share the same genetic origin: a multivariate sibling study of the Swedish population2016In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 5, p. 717-721Article in journal (Refereed)
    Abstract [en]

    Recent studies have shown that different mental-health problems appear to be partly influenced by the same set of genes, which can be summarized by a general genetic factor. To date, such studies have relied on surveys of community-based samples, which could introduce potential biases. The goal of this study was to examine whether a general genetic factor would still emerge when based on a different ascertainment method with different biases from previous studies. We targeted all adults in Sweden (n=3 475 112) using national registers and identified those who had received one or more psychiatric diagnoses after seeking or being forced into mental health care. In order to examine the genetic versus environmental etiology of the general factor, we examined whether participants' full- or half-siblings had also received diagnoses. We focused on eight major psychiatric disorders based on the International Classification of Diseases, including schizophrenia, schizoaffective disorder, bipolar disorder, depression, anxiety, attention-deficit/hyperactivity disorder, alcohol use disorder and drug abuse. In addition, we included convictions of violent crimes. Multivariate analyses demonstrated that a general genetic factor influenced all disorders and convictions of violent crimes, accounting for between 10% (attention-deficit/hyperactivity disorder) and 36% (drug abuse) of the variance of the conditions. Thus, a general genetic factor of psychopathology emerges when based on both surveys as well as national registers, indicating that a set of pleiotropic genes influence a variety of psychiatric disorders.

  • 27.
    Ronald, A.
    et al.
    Centre for Brain and Cognitive Development, Department of Psychological Sciences, Birkbeck, University of London, London, UK.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, and Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, Sweden.
    Anckarsäter, H.
    Forensic Psychiatry, Institute of Neuroscience and Physiology, Sahlgren’s Academy, University of Gothenburg, Gothenburg, Sweden.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    A twin study of autism symptoms in Sweden2011In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 16, no 10, p. 1039-1047Article in journal (Refereed)
    Abstract [en]

    This study aimed to identify empirically the number of factors underlying autism symptoms-social impairments, communication impairments, and restricted repetitive behaviors and interests-when assessed in a general population sample. It also investigated to what extent these autism symptoms are caused by the same or different genetic and environmental influences. Autistic symptoms were assessed in a population-based twin cohort of >12,000 (9- and 12-year-old) children by parental interviews. Confirmatory factor analyses, principal component analyses and multivariate structural equation model fitting were carried out. A multiple factor solution was suggested, with nearly all analyses pointing to a three-factor model for both boys and girls and at both ages. A common pathway twin model fit the data best, which showed that there were some underlying common genetic and environmental influences across the different autism dimensions, but also significant specific genetic effects on each symptom type. These results suggest that the autism triad consists of three partly independent dimensions when assessed in the general population, and that these different autism symptoms, to a considerable extent, have partly separate genetic influences. These findings may explain the large number of children who do not meet current criteria for autism but who show some autism symptoms. Molecular genetic research may benefit from taking a symptom-specific approach to finding genes associated with autism.

  • 28.
    Roshanisefat, H.
    et al.
    Department of Neurology, Karolinska University Hospital Huddinge, Stockholm, Sweden; Neuroimmunology Unit, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Bahmanyar, S.
    Clinical Epidemiology Unit and Center for Pharmacoepidemiology, Karolinska University Hospital, Stockholm, Sweden; Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
    Hillert, J.
    Neuroimmunology Unit, Karolinska Institute, Stockholm, Sweden.
    Olsson, T.
    Neuroimmunology Unit, Karolinska Institute, Stockholm, Sweden.
    Montgomery, Scott M.
    Clinical Epidemiology Unit and Center for Pharmacoepidemiology, Karolinska University Hospital, Stockholm, Sweden; Department of Primary Care and Public Health, Charing Cross Hospital, London, UK.
    Shared genetic factors may not explain the raised risk of comorbid inflammatory diseases in multiple sclerosis2012In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 18, no 10, p. 1430-1436Article in journal (Refereed)
    Abstract [en]

    Background: Comorbid inflammatory conditions in multiple sclerosis (MS) patients suggest shared risks with MS.

    Objective: To estimate if the risk of immune-mediated disease in MS patients and their parents is increased.

    Methods: Swedish register data were analysed using Cox regression to estimate immune-mediated disease risk among 11284 fathers and 12006 mothers of MS patients, compared with 123158 fathers and 129409 mothers of index subjects without MS. Similar analyses were conducted among 20276 index subjects with MS and 203951 without.

    Results: Parents of patients with MS did not have a significantly altered immune-mediated disease risk. Patients with MS had a consistently raised risk for several immune-mediated diseases: ulcerative colitis, Crohn's disease, type 1 diabetes, psoriasis, polyarthritis nodosa and pemphigoid. The risk was more pronounced for diseases diagnosed subsequent to MS onset.

    Conclusion: The increased occurrence of other immune-mediated diseases in MS patients may not be due to shared genetic factors and surveillance bias is likely to be the main or possibly the entire explanation. If not entirely explained by surveillance bias, a modestly raised occurrence of comorbid diseases may be due to shared environmental risks or factors related to MS disease characteristics.

  • 29.
    Sariaslan, A.
    et al.
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fazel, S.
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
    Genetic and environmental determinants of violence risk in psychotic disorders: a multivariate quantitative genetic study of 1.8 million Swedish twins and siblings2016In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 9, p. 1251-1256Article in journal (Refereed)
    Abstract [en]

    Patients diagnosed with psychotic disorders (for example, schizophrenia and bipolar disorder) have elevated risks of committing violent acts, particularly if they are comorbid with substance misuse. Despite recent insights from quantitative and molecular genetic studies demonstrating considerable pleiotropy in the genetic architecture of these phenotypes, there is currently a lack of large-scale studies that have specifically examined the aetiological links between psychotic disorders and violence. Using a sample of all Swedish individuals born between 1958 and 1989 (n=3 332 101), we identified a total of 923 259 twin-sibling pairs. Patients were identified using the National Patient Register using validated algorithms based on International Classification of Diseases (ICD) 8-10. Univariate quantitative genetic models revealed that all phenotypes (schizophrenia, bipolar disorder, substance misuse, and violent crime) were highly heritable (h(2)=53-71%). Multivariate models further revealed that schizophrenia was a stronger predictor of violence (r=0.32; 95% confidence interval: 0.30-0.33) than bipolar disorder (r=0.23; 0.21-0.25), and large proportions (51-67%) of these phenotypic correlations were explained by genetic factors shared between each disorder, substance misuse, and violence. Importantly, we found that genetic influences that were unrelated to substance misuse explained approximately a fifth (21%; 20-22%) of the correlation with violent criminality in bipolar disorder but none of the same correlation in schizophrenia (Pbipolar disorder<0.001; Pschizophrenia=0.55). These findings highlight the problems of not disentangling common and unique sources of covariance across genetically similar phenotypes as the latter sources may include aetiologically important clues. Clinically, these findings underline the importance of assessing risk of different phenotypes together and integrating interventions for psychiatric disorders, substance misuse, and violence.

  • 30.
    Sayed-Noor, Arkan S.
    et al.
    Department of Orthopaedic Surgery, Sundsvall Hospital, Sundsvall, Sweden.
    Englund, Erling
    Department of Research and Development, Sundsvall Hospital, Sundsvall, Sweden .
    Wretenberg, Per
    Department of Orthopaedic Surgery, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institute, Solna, Stockholm, Sweden.
    Sjödén, Göran O.
    Department of Orthopaedic Surgery, Sundsvall Hospital, Sundsvall, Sweden; Department of Surgical and Perioperative Sciences, Norrland University Hospital, Umeå, Sweden .
    Pressure-pain threshold algometric measurement in patients with greater trochanteric pain after total hip arthroplasty2008In: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 24, no 3, p. 232-236Article in journal (Refereed)
    Abstract [en]

    Background: The evaluation of tenderness associated with greater trochanteric pain (GTP) syndrome is amenable to bias and depends on the examiner's experience. In this study, we tested whether the use of an electronic pressure algometer enhanced the reliability of this evaluation.

    Patients and methods: Pressure-pain threshold (PPT) was measured with an electronic algometer in 18 patients who developed GTP after total hip arthroplasty and in matched controls. Both groups were evaluated with visual analog scale.

    Results: The PPT measurements showed large interindividual variability across patients. The correspondence of the PPT measurements in asymptomatic patients was good. We found good validity for the algometer used. The PPT ratio of 0.8 (affected vs. unaffected side) can be used as a cut-off ratio. The PPT measurements at the greater trochanter (local pain) were significantly lower than at the ilio-tibial band (radiated pain). There was no correlation between PPT measurements and visual analog scales. Despite the acceptable sensitivity and specificity of pressure algometer, because of low positive predictive value and large interindividual variability, pressure algometer has a limited value as a screening test.

    Conclusions: The examination of tenderness associated with GTP is facilitated by the used algometer. It is the intraindividual body-side PPT differences that yield the most sensitive measurement for the assessment of deep pain. A cut-off value of 0.8 can be used for diagnostic purposes. Interindividual differences might be considerable and could mask pathologic diagnostic findings.

  • 31.
    Skoglund, Charlotte
    et al.
    Departments of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Chen, Qi
    Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Franck, Johan
    Departments of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Attention-deficit/hyperactivity disorder and risk for substance use disorders in relatives2015In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 77, no 10, p. 880-886Article in journal (Refereed)
    Abstract [en]

    Background: Previous research indicates that attention-deficit/hyperactivity disorder (ADHD) is highly associated with substance use disorders (SUD). However, these studies have failed to clarify the nature of the overlap. The main aim of this study was to explore whether the overlap between ADHD and SUD could be explained by shared genetic and environmental factors or by harmful effects of ADHD medication.

    Methods: We employed a matched cohort design across different levels of family relatedness recorded from 1973-2009. By linking longitudinal Swedish national registers, 62,015 ADHD probands and first-degree and second-degree relatives were identified and matched 1:10 with control subjects without ADHD and their corresponding relatives. Any record of SUD was defined by discharge diagnoses of the International Classification of Diseases or a purchase of any drug used in the treatment of SUD.

    Results: First-degree relatives of ADHD probands were at elevated risk for SUD (odds ratios 2.2 and 1.8) compared with relatives of control subjects. The corresponding relative risk in second-degree relatives was substantially lower (odd ratios 1.4 and 1.4). The familial aggregation patterns remained similar for first-degree and second-degree relatives after excluding individuals with coexisting disorders such as schizophrenia, bipolar disorder, depression, and conduct disorder.

    Conclusions: Our findings suggest that the co-occurrence of ADHD and SUD is due to genetic factors shared between the two disorders, rather than to a general propensity for psychiatric disorders or harmful effects of ADHD medication.

  • 32.
    Sundelin, Heléne E. K.
    et al.
    Department of Pediatrics, University Hospital, Linköping, Sweden .
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Hultman, Christina M.
    Departments of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Tomson, Torbjörn
    Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
    Autism and epilepsy: A population-based nationwide cohort study2016In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 87, no 2, p. 192-197Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the risk of autism spectrum disorder (ASD) in individuals with epilepsy and in their first-degree relatives to determine shared etiology.

    Methods: Through the Swedish Patient Register, we identified 85,201 individuals with epilepsy, as well as all their siblings (n = 80,511) and offspring (n = 98,534). Each individual with epilepsy was compared with 5 controls, matched for age, sex, calendar period, and county, while siblings and offspring were compared with siblings and offspring of controls. We excluded siblings and offspring with epilepsy. Using Cox regression, we calculated hazard ratios (HRs) for future diagnosis of ASD. Logistic regression was applied to calculate odds ratios (ORs) for prior diagnosis of ASD.

    Results: During follow-up, 1,381 (1.6%) individuals with epilepsy and 700 (0.2%) controls were diagnosed with ASD. Individuals with epilepsy were therefore at increased risk of future ASD (HR 10.49, 95% confidence interval [CI] 9.55-11.53), with the highest risk seen in individuals diagnosed with epilepsy in childhood. Both siblings (HR 1.62, 95% CI 1.43-1.83) and offspring (HR 1.64, 95% CI 1.46-1.84) of epilepsy patients were at increased risk of ASD. The risk in the offspring was particularly high in mothers with epilepsy (HR 1.91; 95% CI 1.63-2.23). Epilepsy was also associated with a prior diagnosis of ASD (OR 4.56, 95% CI 4.02-5.18).

    Conclusions: Individuals with epilepsy are at increased risk of ASD, especially if epilepsy appears in childhood. Further, ASD is more common in the siblings and offspring of individuals with epilepsy, suggesting shared etiology.

  • 33.
    Thelin, Eric
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Johannesson, Louise
    Karolinska Institute, Stockholm, Sweden.
    Bellander, Bo-Michael
    Karolinska Institute, Stockholm, Sweden.
    The temporal profiles in serum concentrations of the biomarker S100B in the first 48 hours after traumatic brain injury correspond to outcome2011In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 28, no 5, p. A20-A20Article in journal (Refereed)
    Abstract [en]

    Background: Traumatic brain injury (TBI) is one of the leading causes of death and disability. An early and accurate assessment of the affected patient suffering from TBI is important to promptly decide upon treatment strategies. Serum levels of the protein S100B are elevated in patients suffering from TBI, and has been proposed as a good addition to other clinical variables when calculating outcome. Different temporal patterns of the serum levels of S100B have been shown. The aim of this study was to analyze the different patterns, with a focus on outcome and other factors related to co-morbidity in patients suffering from TBI.

    Methods: In all, 265 patients suffering from TBI admitted to the neuro-intensive care unit, having three consecutive serum samples of S100B within the first 72 h after trauma were included.

    Results: S100B AUC, S100 peak serum level, and increasing serum levels of S100B significantly presence of traumatic subarachnoid hemorrhage, early cerebral ischemia and signs of increasing intracranial hematomas are statistically significant (p<0.05) to high and increasing levels of S100B. Using a multi-nomial logit regression analysis, increased age (p<0.01), early cerebral ischemia (p<0.05), and increased S100B AUC statistically significantly affected mortality (p<0.01).

    Conclusion: The temporal profile of S100B is unique for every patient after TBI, and statistically correlates with S100B AUC, one of the factors that correlates strongly with mortality and morbidity, and thereby may promptly provide the physician with an important tool in clinical decision-making.

  • 34.
    Thelin, Eric Peter
    et al.
    Department of Clinical Neuroscience, Section for Neurosurgery, Karolinska University Hospital Solna, Stockholm, Sweden.
    Johannesson, Louise
    Department of Economics, Stockholm University, Stockholm, Sweden.
    Nelson, David
    Department of Physiology and Pharmacology, Section of Anesthesiology and Intensive Care, Karolinska University Hospital Solna, Stockholm, Sweden.
    Bellander, Bo-Michael
    Department of Clinical Neuroscience, Section for Neurosurgery, Karolinska University Hospital Solna, Stockholm, Sweden.
    S100B Is an Important Outcome Predictor in Traumatic Brain Injury2013In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 30, no 7, p. 519-528Article in journal (Refereed)
    Abstract [en]

    The objective of the study was to examine how S100B, a biomarker of traumatic brain injury (TBI), contributes to outcome prediction after adjusting for known parameters, including age, Glasgow Coma Scale (GCS), pupil reaction, and computed tomography (CT) variables; to examine which parameters have the best correlation to elevated serum levels of S100B; and to investigate when to sample S100B to achieve the strongest association to outcome. This retrospective study included 265 patients with TBI admitted to the neurointensive care unit, Karolinska University Hospital Solna, Stockholm, Sweden. Univariate and multivariate proportional odds regressions were performed to determine parameters most closely related to outcome, and how S100B adds to prediction accuracy. Age (p < 0.0001), pupil reaction (p < 0.0001), and levels of S100B (p < 0.0001) had the strongest statistical correlation to outcome. The area under curve of S100B, the first 48 h after trauma, yielded an additional explained variance of 6.6% in excess of known outcome parameters, including age, GCS, pupil reaction, and CT variables, themselves exhibiting an explained variance of 29.3%. S100B adds substantial information regarding patient outcome, in excess of that provided by known parameters. Only CT variables were found to be significant predictors of increased levels of S100B in uni- and multivariate analysis. Early samples of S100B, within 12 h after trauma, appear to have little prognostic value, and S100B should likely be sampled 12-36 h following trauma to best enhance TBI outcome prediction.

  • 35.
    Tobe, Brian T. D.
    et al.
    Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla CA, USA; Department of Psychiatry, Veterans Administration Medical Center, La Jolla CA, USA .
    Venizelos, Nikolaos
    Örebro University, School of Health Sciences. Department of Cinical Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Snyder, Evan Y.
    Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla CA, USA; Department of Pediatrics, University of California, San Diego, La Jolla CA, USA.
    Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 22, p. E4462-E4471, article id 1700111114Article in journal (Refereed)
    Abstract [en]

    The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active non-phosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2: CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the " lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknown-might reveal otherwise inscrutable intracellular pathogenic pathways.

  • 36.
    Tseli, Elena
    et al.
    Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Stockholm, Sweden.
    Grooten, Wilhelmus Johannes Andreas
    Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Stockholm, Sweden; Functional Area Occupational Therapy and Physiotherapy, Allied Health Professionals Function, Karolinska University Hospital, Stockholm, Sweden.
    Stålnacke, Britt-Marie
    Department of Community Medicine and Rehabilitation, Rehabilitation Medicine, Umeå University, Umeå, Sweden; Department of Clinical Sciences, Department of Rehabilitation Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
    Boersma, Katja
    Örebro University, School of Law, Psychology and Social Work.
    Enthoven, Paul
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Gerdle, Björn
    Pain and Rehabilitation Centre, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Äng, Björn Olov
    Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Stockholm, Sweden; Functional Area Occupational Therapy and Physiotherapy, Allied Health Professionals Function, Karolinska University Hospital, Stockholm, Sweden; School of Education, Health and Social Studies, Dalarna University, Falun, Sweden.
    Predictors of multidisciplinary rehabilitation outcomes in patients with chronic musculoskeletal pain: protocol for a systematic review and meta-analysis2017In: Systematic Reviews, E-ISSN 2046-4053, Vol. 6, no 1, article id 199Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chronic musculoskeletal pain is a major public health problem. Early prediction for optimal treatment results has received growing attention, but there is presently a lack of evidence regarding what information such proactive management should be based on. This study protocol, therefore, presents our planned systematic review and meta-analysis on important predictive factors for health and work-related outcomes following multidisciplinary rehabilitation (MDR) in patients with chronic musculoskeletal pain.

    METHODS: We aim to perform a synthesis of the available evidence together with a meta-analysis of published peer-reviewed original research that includes predictive factors preceding MDR. Included are prospective studies of adults with benign, chronic (> 3 months) musculoskeletal pain diagnoses who have taken part in MDR. In the studies, associations between personal and rehabilitation-based factors and the outcomes of interest are reported. Outcome domains are pain, physical functioning including health-related quality of life, and work ability with follow-ups of 6 months or more. We will use a broad, explorative approach to any presented predictive factors (demographic, symptoms-related, physical, psychosocial, work-related, and MDR-related) and these will be analyzed through (a) narrative synthesis for each outcome domain and (b) if sufficient studies are available, a quantitative synthesis in which variance-weighted pooled proportions will be computed using a random effects model for each outcome domain. The strength of the evidence will be evaluated using the Grading of Recommendations, Assessment, Development and Evaluation.

    DISCUSSION: The strength of this systematic review is that it aims for a meta-analysis of prospective cohort or randomized controlled studies by performing an extensive search of multiple databases, using an explorative study approach to predictive factors, rather than building on single predictor impact on the outcome or on predefined hypotheses. In this way, an overview of factors central to MDR outcome can be made and will help strengthen the evidence base and inform a wide readership including health care practitioners and policymakers.

    SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016025339.

  • 37.
    Tucker, P.
    et al.
    Stockholm University, Stockholm, Sweden.
    Bejerot, Eva
    Stockholm University, Stockholm, Sweden.
    Åkerstedt, T.
    Stockholm University, Stockholm, Sweden.
    Sleep quality as a mediator in the relationship between doctors' worktime control and patient safety2012In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 21, no Suppl. 1, p. 273-273Article in journal (Other academic)
    Abstract [en]

    Objective: Poorer worktime control is associated with greater sleep disturbances. The fatigue that results from poor quality sleep may pose a threat job performance. Thus the current study seeks to determine whether the relationship between doctors' worktime control and their perceptions of the risk of medical error is mediated by sleep quality.

    Method: A representative sample of doctors in Sweden (N = 1534) completed a questionnaire about working conditions, wellbeing and patient safety (response rate 53.1%). Worktime control was measured by two items which asked respondents: (1) whether they could influence their work hours; and (2) whether they had access to flexitime (response options ‘‘yes’’, ‘‘yes, to some extent’’ and ‘‘no’’). Concerns about patient safety were measured by two items which asked respondents: (1) how much they worried about the risk of making mistakes (five response options from ‘‘no, never’’ to ‘‘yes, constantly’’); and (2) how often they felt that their workload increased the risk of malpractice (four response options from ‘‘daily’’ to ‘‘less than once a month’’). Sleep quality was measured by the Karolinska Sleep Quality Index (KSQI), calculated as the mean score of responses to four items which asked participants how often they had experienced each of the following sleep symptoms in the last three months: difficulty falling asleep, repeated awakenings with difficulty falling back to sleep, too early (final) awakening and interrupted / restless sleep (range of possible scores: 1 – Never; 5 – Always/5 times or more per week).

    Results: There were significant associations between both worktime control measures, both patient safety measures and scores on the KSQI. Mediation analyses (Sobel test for mediation) indicated that the associations between each worktime control measure and each patient safety measure were mediated by sleep quality (P < 0.0001 in each case).

    Conclusion: Worktime control allows doctors to optimise the fit between the demands of their work schedule, and their own personal needs and circumstances. In doing so, it facilitates sleep and recovery between duty periods, thereby enhancing job performance and promoting patient safety.

  • 38.
    Vrettou, Maria
    et al.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Nillson, Kent W.
    Västerås Centre for Clinical Research, Uppsala University, Västerås, Sweden.
    Tuvblad, Catherine
    Department of Psychology, University of Southern California, Los Angeles, United States.
    Rehn, Mattias
    Västerås Centre for Clinical Research, Uppsala University, Västerås, Sweden.
    Andershed, Anna-Karin
    Örebro University, School of Law, Psychology and Social Work.
    Wallén-Mackenzie, Åsa
    Department of Organismal Biology, Uppsala University, Uppsala, Sweden.
    Andershed, Henrik
    Örebro University, School of Law, Psychology and Social Work.
    Nylander, Ingrid
    Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
    Comasco, Erika
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    VGLUT2 genotype interacts with environmental experiences to predict alcohol misuse in young adults2016In: ISBRA ESBRA World Congress on Alcohol an Alcoholism, Berlin, Germany, 2016Conference paper (Other academic)
    Abstract [en]

    The heritability of alcohol use disorder (AUD) ranges between 40 to 60%, as demonstrated by twin studies. Environmental factors are hence of importance for the developmental trajectory of the disorder. Gene-by-environment interactions indeed influence neuroplasticity and determine the individual’s susceptibility or resilience to AUD. Lately, a role of Vesicular Glutamate Transporter 2 (VGLUT2)-mediated neurotransmission has been indicated in studies of addiction- and alcohol-related phenotypes. We previously demonstrated an association between the single nucleotide polymorphism (SNP) rs2290045 in the VGLUT2 gene and alcohol dependence as well as showed an interaction effect between voluntary ethanol drinking and early life stress on Vglut2 expression in the ventral tegmental area of outbred rats. In the present study, using a population-based, cross-sectional and retrospective design, we aimed to investigate the association between two candidate VGLUT2 SNPs, rs1900586 and rs2290045, and aversive as well as supportive environmental factors on alcohol misuse in young adults. A total of 2,500 (52.6% females) individuals (mean age: 22.15 years) were included in the study. Aversive life events (i.e., physical violence, verbal aggression, witnessing violence) and parent-child relationship (i.e., early: until 18 years of age; lifetime: until present) were self-reported. Alcohol misuse was assessed using the AUD Identification Test (AUDIT). Preliminary results showed no main genotype effects on drinking profile. Multivariable analyses revealed that SNP rs1900586 interacted with exposure to verbal aggression and early parent-child relationship in respect to AUDIT scores. Male carriers of the major (T) allele reported higher AUDIT scores when exposed to verbal aggression and poor early parent-child relationship than the C carriers exposed to the same environment, while the opposite pattern was noted in the presence of supportive parent-child relationship. In individuals with symptoms of dependence or harmful alcohol use, SNP rs1900586 interacted with exposure to physical violence and parent-child relationship (early and lifetime) in both sexes. The same interaction effect was detected for SNP rs2290045 in females. These preliminary findings provide the first evidence that VGLUT2 genotype moderates the environmental sensitivity to alcohol misuse among young adults and call for further investigation in independent cohorts, including clinical samples.

  • 39.
    Vumma, Ravi
    et al.
    Örebro University, School of Health and Medical Sciences.
    Johansson, Jessica
    Örebro University, School of Health and Medical Sciences.
    Lewander, Tommy
    Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University Hospital.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Functional characterization of tryptophan transport in human fibroblast cellsManuscript (Other (popular science, discussion, etc.))
  • 40.
    Vumma, Ravi
    et al.
    Department of Chemistry and Biomedical Sciences, Faculty of Health and Life Sciences, Linnaeus University, Kalmar, Sweden.
    Johansson, Jessica
    Örebro University, School of Health Sciences.
    Venizelos, Nikolaos
    Örebro University, School of Medical Sciences.
    Proinflammatory Cytokines and Oxidative Stress Decrease the Transport of Dopamine Precursor Tyrosine in Human Fibroblasts2017In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 75, no 4, p. 178-184Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Proinflammatory cytokines and oxidative stress responses have been extensively implicated in the pathophysiology of neuropsychiatric disorders over the past 2 decades. Moreover, disturbed transport of the dopamine precursor (i.e., the amino acid tyrosine) has been demonstrated, in different studies, across fibroblast cell membranes obtained from neuropsychiatric patients. However, the role and influences of proinflammatory cytokines and oxidative stress, and the reasons for disturbed tyrosine transport in neuropsychiatric disorders, are still not evaluated.

    AIMS: The present study aimed to assess the role of proinflammatory cytokines and oxidative stress, indicated in many neuropsychiatric disorders, in tyrosine transportation, by using human skin-derived fibroblasts.

    METHODS: Fibroblasts obtained from a healthy control were used in this study. Fibroblasts were treated with proinflammatory cytokines (IL-1β, IFN-γ, IL-6, TNF-α), their combinations, and oxidative stress, optimized for concentrations and incubation time, to analyze the uptake of 14C-tyrosine compared to untreated controls.

    RESULTS AND CONCLUSION: This study demonstrates that proinflammatory cytokines and oxidative stress decrease the transport of tyrosine (47% and 33%, respectively), which can alter dopamine synthesis. The functionality of the tyrosine transporter could be a new potential biomarker to target for discovering new drugs to counteract the effects of proinflammatory cytokines and oxidative stress in the pathophysiology of neuropsychiatric disorders.

  • 41.
    Walum, Hasse
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Neiderhiser, Jenae M.
    Department of Psychology, Pennsylvania State University, Philadelphia PA, United States .
    Reiss, David
    Yale Child Study Center, Yale University, New Haven CT, United States.
    Ganiban, Jody M.
    Department of Psychology, George Washington University, Washington DC, United States .
    Spotts, Erica L.
    Division of Behavioral and Social Research, National Institute on Aging, Bethesda MD, United States.
    Pedersen, Nancy L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Anckarsäter, Henrik
    Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden .
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Westberg, Lars
    Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior2012In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 71, no 5, p. 419-426Article in journal (Refereed)
    Abstract [en]

    Background: In specific vole and primate species the neuropeptide oxytocin plays a central role in the regulation of pair-bonding behavior. Here we investigate the extent to which genetic variants in the oxytocin receptor gene (OXTR) are associated with pair-bonding and related social behaviors in humans.

    Methods: We first genotyped twelve single nucleotide polymorphisms (SNPs) in the TOSS (Twin and Offspring Study in Sweden) (n = 2309) and the TCHAD (Swedish Twin Study of Child and Adolescent Development) (n = 1240), comprising measures of self-reported pair-bonding behavior. In the TOSS sample we further investigated one of the SNPs for measures of marital status and quality. Moreover, in the TCHAD sample we explored the longitudinal relationship between precursors of pair-bonding during childhood and subsequent behavior in romantic relationships. Finally, in the TCHAD study and in the Child and Adolescent Twin Study of Sweden (CATSS) (n = 1771), the association between the same SNP and childhood behaviors was investigated.

    Results: One SNP (rs7632287) in OXTR was associated with traits reflecting pair-bonding in women in the TOSS and TCHAD samples. In girls the rs7632287 SNP was further associated with childhood social problems, which longitudinally predicted pair-bonding behavior in the TCHAD sample. This association was replicated in the CATSS sample in which an association between the same SNP and social interaction deficit symptoms from the autism spectrum was detected.

    Conclusion: These results suggest an association between variation in OXTR and human pair-bonding and other social behaviors, possibly indicating that the well-described influence of oxytocin on affiliative behavior in voles could also be of importance for humans.

  • 42.
    Wang, Ruoli
    et al.
    Department of Mechanics, Royal Institute of Technology, Stockholm, Sweden.
    Thur, Charlotte K.
    Department of Molecular Medicine and Surgery, Section of Orthopaedics and Sports Medicine, Karolinska Institutet, Stockholm, Sweden.
    Gutierrez-Farewik, Elena M.
    Department of Mechanics, Royal Institute of Technology, Stockholm, Sweden; Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Wretenberg, Per
    Department of Molecular Medicine and Surgery, Section of Orthopaedics and Sports Medicine, Karolinska Institute Solna, Stockholm, Sweden.
    Broström, Eva
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    One year follow-up after operative ankle fractures: a prospective gait analysis study with a multi-segment foot model2010In: Gait & Posture, ISSN 0966-6362, E-ISSN 1879-2219, Vol. 31, no 2, p. 234-240Article in journal (Refereed)
    Abstract [en]

    Ankle fractures are one of the most common lower limb traumas. Several studies reported short- and long-term post-operative results, mainly determined by radiographic and subjective functional evaluations. Three-dimensional gait analysis with a multi-segment foot model was used in the current study to quantify the inter-segment foot motions in 18 patients 1 year after surgically treated ankle fractures. Data were compared to that from gender- and age-matched healthy controls. The correlations between Olerud/Molander ankle score and kinematics were also evaluated. Patients with ankle fractures showed less plantarflexion and smaller range of motion in the injured talocrural joint, which were believed to be a sign of residual joint stiffness after surgery and immobilization. Moreover, the forefoot segment had smaller sagittal and transverse ranges of motion, less plantarflexion and the hallux segment had less dorsiflexion and smaller sagittal range of motion. The deviations found in the forefoot segment may contribute to the compensation mechanisms of the injured ankle joint. Findings of our study show that gait analysis with a multi-segment foot model provides a quantitative and objective way to perform the dynamic assessment of post-operative ankle fractures, and makes it possible to better understand not only how the injured joint is affected, but also the surrounding joints.

  • 43.
    Weiss, Rüdiger J.
    et al.
    Department of Molecular Medicine and Surgery, Section of Orthopaedics and Sports Medicine, Karolinska Institutet, Stockholm, Sweden.
    Wretenberg, Per
    Department of Molecular Medicine and Surgery, Section of Orthopaedics and Sports Medicine, Karolinska Institute, Solna, Stockholm, Sweden.
    Stark, André
    Department of Molecular Medicine and Surgery, Section of Orthopaedics and Sports Medicine, Karolinska Institutet, Stockholm, Sweden.
    Palmblad, Karin
    Department of Women and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Per
    Department of Medicine, Section of Rheumatology, Karolinska Institutet, Stockholm, Sweden.
    Gröndal, Lollo
    Department of Molecular Medicine and Surgery, Section of Orthopaedics and Sports Medicine, Karolinska Institutet, Stockholm, Sweden.
    Broström, Eva
    Department of Women and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Gait pattern in rheumatoid arthritis2008In: Gait & Posture, ISSN 0966-6362, E-ISSN 1879-2219, Vol. 28, no 2, p. 229-234Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to analyse kinematic and kinetic gait changes in rheumatoid arthritis (RA) patients in comparison to healthy controls and to examine whether levels of functional disability (Health Assessment Questionnaire (HAQ)-scores) were associated with gait parameters. Using a three-dimensional motion analysis system, kinematic and kinetic gait parameters were measured in 50 RA patients and 37 healthy controls. There was a significant reduction in joint motions, joint moments and work in the RA cohort compared with healthy controls. The following joint motions were decreased: hip flexion-extension range (Delta6 degrees ), hip abduction (Delta4 degrees ), knee flexion-extension range (Delta8 degrees ) and ankle plantarflexion (Delta10 degrees ). The following joint moments were reduced: hip extensor (Delta0.30Nm/kg) and flexor (Delta0.20Nm/kg), knee extensor (Delta0.11Nm/kg) and flexor (Delta0.13Nm/kg), and ankle plantarflexor (Delta0.44Nm/kg). Work was lower in hip positive work (Delta0.07J/kg), knee negative work (Delta0.08J/kg) and ankle positive work (Delta0.15J/kg). Correlations were fair although significant between HAQ and hip flexion-extension range, hip abduction, knee flexion-extension range, hip abductor moment, stride length, step length and single support (r=-0.30 to -0.38, p<0.05). Our findings suggest that RA patients have overall less joint movement and specifically restricted joint moments and work across the large joints of the lower limbs during walking than healthy controls. There were only fair associations between levels of functional disability and gait parameters. The findings of this study help to improve the understanding how RA affects gait changes in the lower limbs.

  • 44.
    Westin, Jerker
    et al.
    Academy of Industry and Society, Computer Science, Dalarna University, Borlänge, Sweden; Department of Medical Sciences, Biomedical Informatics and Engineering, Uppsala University, Uppsala, Sweden.
    Ghiamati, Samira
    Academy of Industry and Society, Computer Science, Dalarna University, Borlänge, Sweden.
    Memedi, Mevludin
    Academy of Industry and Society, Computer Science, Dalarna University, Borlänge, Sweden.
    Nyholm, Dag
    Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
    Johansson, Anders
    Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
    Dougherty, Mark
    Academy of Industry and Society, Computer Science, Dalarna University, Borlänge, Sweden.
    Groth, Torgny
    Department of Medical Sciences, Biomedical Informatics and Engineering, Uppsala University, Uppsala, Sweden.
    A new computer method for assessing drawing impairment in Parkinson's disease2010In: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 190, no 1, p. 143-148Article in journal (Refereed)
    Abstract [en]

    A test battery, consisting of self-assessments and motor tests (tapping and spiral drawing tasks) was used on 9482 test occasions by 62 patients with advanced Parkinson's disease (PD) in a telemedicine setting. On each test occasion, three Archimedes spirals were traced. A new computer method, using wavelet transforms and principal component analysis processed the spiral drawings to generate a spiral score. In a web interface, two PD specialists rated drawing impairment in spiral drawings from three random test occasions per patient, using a modification of the Bain & Findley 10-category scale. A standardised manual rating was defined as the mean of the two raters’ assessments. Bland-Altman analysis was used to evaluate agreement between the spiral score and the standardised manual rating. Another selection of spiral drawings was used to estimate the Spearman rank correlations between the raters (r = 0.87), and between the mean rating and the spiral score (r = 0.89). The 95% confidence interval for the method's prediction errors was ±1.5 scale units, which was similar to the differences between the human raters. In conclusion, the method could assess PD-related drawing impairments well comparable to trained raters.

  • 45. Wigerius, Michael
    et al.
    Melik, Wessam
    Elväng, Annelie
    Johansson, Magnus
    Södertörns högskola, Huddinge, Sweden.
    Rac1 and Scribble are targets for the arrest of neurite outgrowth by TBE virus NS52010In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 44, no 3, p. 260-271Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) causes extensive CNS disease in humans known as TBE, however, relatively little is known of the molecular mechanisms for its progress. Here, we now show that TBEV produces defects in neuronal development of PC12 cells through a function of the viral NS5 protein. The methyltransferase domain of NS5 is critical and sufficient for restriction of nerve growth factor induced neurite outgrowth. This effect is reversed by expression of NS5 mutants unable to bind Scribble and unexpectedly, in Scribble depleted cells with binding-competent NS5. Furthermore, we also demonstrate that the Rho GTPase Rac1 and the guanine nucleotide-exchange factor, betaPIX are outcompeted by NS5 for binding to Scribble, linking to effects on neurite outgrowth by TBEV. Together, these findings provide the first experimental evidence that Rac1 and betaPIX are indirect targets of NS5 acting through the multifunctional polarity protein Scribble to oppose neuronal differentiation. In conclusion, our results offer a potential mechanism by which TBEV alters neuronal circuitry and opens new avenues for therapeutic interventions.

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