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  • 101.
    Agathangelidis, Andreas
    et al.
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Ljungström, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Scarfo, Lydia
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Fazi, Claudia
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Gounari, Maria
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy;Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Pandzic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stamatopoulos, Kostas
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Tonon, Giovanni
    IRCCS Ist Sci San Raffaele, Funct Genom Canc Unit, Div Expt Oncol, Milan, Italy.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 5, p. 865-873Article in journal (Refereed)
    Abstract [en]

    Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we per-formed whole-genome sequencing in 11 individuals with monoclonal B-cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia (>10 years without progression from initial diagnosis). All three entities were indistinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not frequently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lym phocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unreported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

  • 102. Agathangelidis, Andreas
    et al.
    Vardi, Anna
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Stereotyped B-cell receptors in chronic lymphocytic leukemia2014In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, no 10, p. 2252-2261Article, review/survey (Refereed)
    Abstract [en]

    Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IGs) has proved to be a particularly fruitful field in chronic lymphocytic leukemia (CLL), not only for understanding disease pathogenesis but also for discriminating clinical subgroups with markedly distinct course and outcome. Of utmost importance was the identification of quasi-identical BcR IGs among unrelated patients with CLL, fittingly coined as "stereotypy," that set the wheels in motion for unraveling the role of antigen(s) in the selection and expansion of the leukemic clones. The categorization of CLL clones into "subsets" according to shared BcR IG structural characteristics provided a compartmentalized view of this otherwise heterogeneous disease, which eventually led to defining strikingly homogeneous groups of patients in terms of: (i) functional properties of the clonal BcR IGs, e. g. BcR reactivity and signaling; (ii) clonal genetic landscape, e. g. genomic aberrations, gene expression/methylation profiles, microRNA signatures; and (iii) clinical course and outcome. The remarkable restriction of the CLL IG gene repertoire, resulting to a great degree from the high impact of BcR IG stereotypy, may also prompt speculations regarding CLL ontogenesis. Overall, the BcR IG molecule justifiably lies at the heart of CLL clinical research, holding the promise of subset-tailored therapies.

  • 103.
    Ager, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Solli, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    The PhonicStick: A Swedish Study: How do children age 5 and 6 handle the PhonicStick and will the use of it affect their phonological awareness?2009Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Phonological awareness is the ability to recognise, identify and manipulate components in words. Phonological awareness is an important part of the early literacy learning, although researchers disagree on how the connection arises. In the United Kingdom, synthetic phonics is a recommended way to teach literacy and the Jolly Phonics is a common approach within this method. In Sweden, mostly synthetic but also analytic methods are used for literacy teaching. The PhonicStick is developed as a communication device for impaired people and is based on the Jolly Phonics. In this study, the PhonicStick was being tested on children aged 5 and 6 years in mainstream pre-school classes to evaluate the use of it and its use for improvement of phonological awareness. The participating children were randomly divided into a test and a control group. All children were pre- and post-tested to analyse the possible improvement of parts of the phonological awareness. The test group went through three PhonicStick sessions, including different games and tests. The results from the pre- and post-tests of phonological awareness showed no significant differences between the test and control group. However, four out of five PhonicStick tests showed a significant improvement between session 1 and session 3. This shows that the children in the study were able to handle the PhonicStick after only three sessions, including remembering phonics the without visual information and producing words including two or three phonics.

  • 104. Aghajanova, L.
    et al.
    Altmae, S.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Giudice, L. C.
    Stanniocalcin-1 in Human Endometrium2015In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 103, no 2, p. E6-E7Article in journal (Other academic)
  • 105. Aghajanova, Lusine
    et al.
    Mahadevan, S
    Altmäe, Signe
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Regan, L
    Sebire, N
    Dixon, P
    Fisher, R A
    Van den Veyver, I B
    No evidence for mutations in NLRP7, NLRP2 or KHDC3L in women with unexplained recurrent pregnancy loss or infertility2015In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 30, no 1, p. 232-238Article in journal (Refereed)
    Abstract [en]

    STUDY QUESTION: Are mutations in NLRP2/7 (NACHT, LRR and PYD domains-containing protein 2/7) or KHDC3L (KH Domain Containing 3 Like) associated with recurrent pregnancy loss (RPL) or infertility?

    SUMMARY ANSWER: We found no evidence for mutations in NLRP2/7 or KHDC3L in unexplained RPL or infertility.

    WHAT IS KNOWN ALREADY: Mutations in NLRP7 and KHDC3L are known to cause biparental hydatidiform moles (BiHMs), a rare form of pregnancy loss. NLRP2, while not associated with the BiHM pathology, is known to cause recurrent Beckwith Weidemann Syndrome (BWS).

    STUDY DESIGN, SIZE, AND DURATION: Ninety-four patients with well characterized, unexplained infertility were recruited over a 9-year period from three IVF clinics in Sweden. Blood samples from 24 patients with 3 or more consecutive miscarriages of unknown etiology were provided by the Recurrent Miscarriage Clinic at St Mary's Hospital, London, UK.

    PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were recruited into both cohorts following extensive clinical studies. Genomic DNA was isolated from peripheral blood and subject to Sanger sequencing of NLRP2, NLRP7 and KHDC3L. Sequence electropherograms were analyzed by Sequencher v5.0 software and variants compared with those observed in the 1000 Genomes, single nucleotide polymorphism database (dbSNP) and HapMap databases. Functional effects of non-synonymous variants were predicted using Polyphen-2 and sorting intolerant from tolerant (SIFT).

    MAIN RESULTS AND THE ROLE OF CHANCE: No disease-causing mutations were identified in NLRP2, NLRP7 and KHDC3L in our cohorts of unexplained infertility and RPL.

    LIMITATIONS, REASONS FOR CAUTION: Due to the limited patient size, it is difficult to conclude if the low frequency single nucleotide polymorphisms observed in the present study are causative of the phenotype. The design of the present study therefore is only capable of detecting highly penetrant mutations.

    WIDER IMPLICATIONS OF THE FINDINGS: The present study supports the hypothesis that mutations in NLRP7 and KHDC3L are specific for the BiHM phenotype and do not play a role in other adverse reproductive outcomes. Furthermore, to date, mutations in NLRP2 have only been associated with the imprinting disorder BWS in offspring and there is no evidence for a role in molar pregnancies, RPL or unexplained infertility.

    STUDY FUNDING/COMPETING INTERESTS: This study was funded by the following sources: Estonian Ministry of Education and Research (Grant SF0180044s09), Enterprise Estonia (Grant EU30020); Mentored Resident research project (Department of Obstetrics and Gynecology, Baylor College of Medicine); Imperial NIHR Biomedical Research Centre; Grant Number C06RR029965 from the National Center for Research Resources (NCCR; NIH). No competing interests declared.

  • 106.
    Aghanavesi, Somayeh
    et al.
    Dalarna Univ, Falun, Sweden.
    Memedi, Mevludin
    Örebro Univ, Örebro, Sweden.
    Dougherty, Mark
    Dalarna Univ, Falun, Sweden.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Westin, Jerker
    Dalarna Univ, Falun, Sweden.
    Verification of a Method for Measuring Parkinson's Disease Related Temporal Irregularity in Spiral Drawings2017In: Sensors, ISSN 1424-8220, E-ISSN 1424-8220, Vol. 17, no 10, article id 2431Article in journal (Refereed)
    Abstract [en]

    -value = 0.02). Test-retest reliability of TIS was good with Intra-class Correlation Coefficient of 0.81. When assessing changes in relation to treatment, TIS contained some information to capture changes from Off to On and wearing off effects. However, the correlations between TIS and clinical scores (UPDRS and Dyskinesia) were weak. TIS was able to differentiate spiral drawings drawn by patients in an advanced stage from those drawn by healthy subjects, and TIS had good test-retest reliability. TIS was somewhat responsive to single-dose levodopa treatment. Since TIS is an upper limb high-frequency-based measure, it cannot be detected during clinical assessment.

  • 107. Agnafors, S.
    et al.
    Sydsjö, G.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Bladh, M.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Svedin, C.
    Behaviour problems in children-a longitudinal study of genetic and environmental factors2015In: European Child and Adolescent Psychiatry, ISSN 1018-8827, E-ISSN 1435-165X, Vol. 24, p. S35-S35Article in journal (Other academic)
  • 108.
    Agnafors, Sara
    et al.
    Linkoping Univ, Fac Hlth Sci, IKE, Div Child & Adolescent Psychiat, S-58185 Linkoping, Sweden.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Bladh, Marie
    Linkoping Univ, Div Obstet & Gynecol IKE, Fac Hlth Sci, S-58185 Linkoping, Sweden.
    Sydsjö, Gunilla
    Linkoping Univ, Div Obstet & Gynecol IKE, Fac Hlth Sci, S-58185 Linkoping, Sweden.
    Dekeyser, Linda
    Linkoping Univ, Div Obstet & Gynecol IKE, Fac Hlth Sci, S-58185 Linkoping, Sweden.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Svedin, Carl-Göran
    Linkoping Univ, Fac Hlth Sci, IKE, Div Child & Adolescent Psychiat, S-58185 Linkoping, Sweden.
    Effect of gene, environment and maternal depressive symptoms on pre-adolescence behavior problems: a longitudinal study2013In: Child and Adolescent Psychiatry and Mental Health, ISSN 1753-2000, E-ISSN 1753-2000, Vol. 7, article id 10Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Depression is a common and disabling condition with a high relapse frequency. Maternal mental health problems and experience of traumatic life events are known to increase the risk of behavior problems in children. Recently, genetic factors, in particular gene-by-environment interaction models, have been implicated to explain depressive etiology. However, results are inconclusive.

    METHODS:

    Study participants were members of the SESBiC-study. A total of 889 mothers and their children were followed during the child's age of 3 months to 12 years. Information on maternal depressive symptoms was gathered postpartum and at a 12 year follow-up. Mothers reported on child behavior and traumatic life events experienced by the child at age 12. Saliva samples were obtained from children for analysis of 5-HTTLPR and BDNF Val66Met polymorphisms.

    RESULTS:

    Multivariate analysis showed a significant association between maternal symptoms of depression and anxiety, and internalizing problems in 12-year-old children (OR 5.72, 95% CI 3.30-9.91). Furthermore, carriers of two short alleles (s/s) of the 5-HTTLPR showed a more than 4-fold increased risk of internalizing problems at age 12 compared to l/l carriers (OR 4.73, 95% CI 2.14-10.48). No gene-by-environment interaction was found and neither depressive symptoms postpartum or traumatic experiences during childhood stayed significant in the final model.

    CONCLUSIONS:

    Concurrent maternal symptoms of depression and anxiety are significant risk factors for behavior problems in children, which need to be taken into account in clinical practice. Furthermore, we found a main effect of 5-HTTLPR on internalizing symptoms in 12-year-old children, a finding that needs to be confirmed in future studies.

  • 109. Agnafors, Sara
    et al.
    Svedin, Carl Göran
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Bladh, Marie
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Sydsjö, Gunilla
    A Biopsychosocial Approach to Risk and Resilience on Behavior in Children Followed from Birth to Age 122017In: Child Psychiatry and Human Development, ISSN 0009-398X, E-ISSN 1573-3327, Vol. 48, no 4, p. 584-596Article in journal (Refereed)
    Abstract [en]

    An increasing prevalence of mental health problems calls for more knowledge into factors associated with resilience. The present study used multiple statistical methodologies to examine a biopsychosocial model of risk and resilience on preadolescence behavior. Data from 889 children and mothers from a birth cohort were used. An adversity score was created by combining maternal symptoms of depression, psychosocial risk and children's experiences of life events. The proposed resilience factors investigated were candidate genetic polymorphisms, child temperament, social functioning, and maternal sense of coherence. The l/l genotype of the serotonin transporter linked polymorphic region was associated with lower internalizing scores, but not mainly related to the level of adversity. An easy temperament was associated with resilience for children exposed to high adversity. Social functioning was found to be promotive independent of the risk level. The results support a multiple-level model of resilience indicating effects, though small, of both biological and psychosocial factors.

  • 110.
    Agnafors, Sara
    et al.
    Linkoping Univ, Dept Clin & Expt Med, Fac Hlth Sci, Div Child & Adolescent Psychiat, SE-58185 Linkoping, Sweden..
    Sydsjö, Gunilla
    Linkoping Univ, Div Obstet & Gynaecol, Dept Clin & Expt Med, Fac Hlth Sci, SE-58185 Linkoping, Sweden..
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Bladh, Marie
    Linkoping Univ, Div Obstet & Gynaecol, Dept Clin & Expt Med, Fac Hlth Sci, SE-58185 Linkoping, Sweden..
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Svedin, Carl Göran
    Linkoping Univ, Dept Clin & Expt Med, Fac Hlth Sci, Div Child & Adolescent Psychiat, SE-58185 Linkoping, Sweden..
    Early predictors of behavioural problems in pre-schoolers: a longitudinal study of constitutional and environmental main and interaction effects2016In: BMC Pediatrics, ISSN 1471-2431, E-ISSN 1471-2431, Vol. 16, article id 76Article in journal (Refereed)
    Abstract [en]

    Background: The early environment is important for child development and wellbeing. Gene-by-environment studies investigating the impact of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the Brain Derived Neurotrophic Factor (BDNF) Val66Met polymorphisms by life events on mental health and behaviour problems have been inconclusive. Methodological differences regarding sample sizes, study population, definitions of adversities and measures of mental health problems obstacle their comparability. Furthermore, very few studies included children. The aim of this study was to examine the associations between a broad range of risk factors covering pregnancy and birth, genetic polymorphism, experience of multiple life events and psychosocial environment, and child behaviour at age 3, using a comparably large, representative, population-based sample. Methods: A total of 1,106 children, and their mothers, were followed from pregnancy to age 3. Information on pregnancy and birth-related factors was retrieved from the Medical Birth Register. Questionnaires on depressive symptoms, child behaviour and child experiences of life events were filled in by the mothers. Child saliva samples were used for genotyping the 5-HTTLPR and BDNF Val66Met polymorphisms. Multiple logistic regression was used to investigate the association between psychological scales and genetic polymorphisms. Results: Symptoms of postpartum depression increased the risk of both internalizing and externalizing problems. Experience of multiple life events was also a predictor of behavioural problems across the scales. No gene-by-environment or gene-by-gene-by-environment interactions were found. Children of immigrants had an increased risk of internalizing problems and parental unemployment was significantly associated with both internalizing and externalizing type of problems. Conclusion: This study shows the importance of the psychosocial environment for psychosocial health in preschool children, and adds to the literature of null-findings of gene-by-environment effects of 5-HTTLPR and BDNF in children.

  • 111.
    Agosti, F.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Cordisco Gonzalez, S.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Martinez Damonte, V.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Tolosa, M. J.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Di Siervi, N.
    Univ Buenos Aires, CONICET, ININFA, Inst Invest Farmacol, Buenos Aires, DF, Argentina..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Davio, C.
    Univ Buenos Aires, CONICET, ININFA, Inst Invest Farmacol, Buenos Aires, DF, Argentina..
    Perello, M.
    CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina.;Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol, IMBICE,Neurophysiol Lab, La Plata, Buenos Aires, Argentina..
    Raingo, J.
    Univ La Plata, CONICET, Multidisciplinary Inst Cell Biol IMBICE, Electrophysiol Lab, La Plata, Buenos Aires, Argentina.;CIC, Comis Invest Prov Buenos Aires, La Plata, Buenos Aires, Argentina..
    Melanocortin 4 Receptor Constitutive Activity Inhibits L-Type Voltage-Gated Calcium Channels In Neurons2017In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 346, p. 102-112Article in journal (Refereed)
    Abstract [en]

    The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain nuclei playing a crucial role in the regulation of energy balance controlling the homeostasis of the organism. It displays both agonist-evoked and constitutive activity, and moreover, it can couple to different G proteins. Most of the research on MC4R has been focused on agonist-induced activity, while the molecular and cellular basis of MC4R constitutive activity remains scarcely studied. We have previously shown that neuronal N-type voltage-gated calcium channels (Ca(V)2.2) are inhibited by MC4R agonist-dependent activation, while the Ca-V subtypes that carry L- and P/Q-type current are not. Here, we tested the hypothesis that MC4R constitutive activity can affect Ca-V, with focus on the channel subtypes that can control transcriptional activity coupled to depolarization (L-type, Ca(V)1.2/1.3) and neurotransmitter release (N- and P/Q-type, Ca(V)2.2 and Ca(V)2.1). We found that MC4R constitutive activity inhibits specifically Ca(V)1.2/1.3 and Ca(V)2.1 subtypes of Ca-V. We also explored the signaling pathways mediating this inhibition, and thus propose that agonist-dependent and basal MC4R activation modes signal differentially through G(s) and G(i/o) pathways to impact on different Ca-V subtypes. In addition, we found that chronic incubation with MC4R endogenous inverse agonist, agouti and agouti-related peptide (AgRP), occludes Ca-V inhibition in a cell line and in amygdaloid complex cultured neurons as well. Thus, we define new mechanisms of control of the main mediators of depolarization-induced calcium entry into neurons by a GPCR that displays constitutive activity.

  • 112. Agosti, Francina
    et al.
    Lopez Soto, Eduardo J.
    Cabral, Agustina
    Castrogiovanni, Daniel
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perello, Mario
    Raingo, Jesica
    Melanocortin 4 receptor activation inhibits presynaptic N-type calcium channels in amygdaloid complex neurons2014In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 40, no 5, p. 2755-2765Article in journal (Refereed)
    Abstract [en]

    The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor involved in food intake and energy expenditure regulation. MC4R activation modifies neuronal activity but the molecular mechanisms by which this regulation occurs remain unclear. Here, we tested the hypothesis that MC4R activation regulates the activity of voltage-gated calcium channels and, as a consequence, synaptic activity. We also tested whether the proposed effect occurs in the amygdala, a brain area known to mediate the anorexigenic actions of MC4R signaling. Using the patch-clamp technique, we found that the activation of MC4R with its agonist melanotan II specifically inhibited 34.5 +/- 1.5% of N-type calcium currents in transiently transfected HEK293 cells. This inhibition was concentration-dependent, voltage-independent and occluded by the G(s) pathway inhibitor cholera toxin. Moreover, we found that melanotan II specifically inhibited 25.9 +/- 2.0% of native N-type calcium currents and 55.4 +/- 14.4% of evoked inhibitory postsynaptic currents in mouse cultured amygdala neurons. Invivo, we found that the MC4R agonist RO27-3225 increased the marker of cellular activity c-Fos in several components of the amygdala, whereas the N-type channel blocker conotoxin GVIA increased c-Fos expression exclusively in the central subdivision of the amygdala. Thus, MC4R specifically inhibited the presynaptic N-type channel subtype, and this inhibition may be important for the effects of melanocortin in the central subdivision of the amygdala.

  • 113.
    Agoston, Denes V.
    et al.
    Uniformed Serv Univ Hlth Sci, Dept Anat, Bethesda, MD 20814 USA.;Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Sköld, Mattias K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Editorial: When Physics Meets Biology; Biomechanics and Biology of traumatic Brain injury2016In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 7, article id 91Article in journal (Other academic)
  • 114.
    Agrasada, Grace V.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Postnatal Peer Counseling on Exclusive Breastfeeding of Low-birthweight Filipino Infants: Results of a Randomized Controlled Trial2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In a Manila hospital, 204 mothers were randomized into three groups: two intervention groups receiving home-based counseling visits, one of them (n=68) by counselors trained to use a locally developed, two-tiered program of breastfeeding counseling, and the other by counselors trained in general childcare (n=67), were compared with a control group of mothers (n=69) who did not receive any counseling. All infants were scheduled for seven visits to the hospital for follow-up. During hospital visits, maternal and infant body measurements were made and an independent interviewer asked the mothers individually to recall how the infant had been fed. One study physician, blind to participant groups, was consulted at all scheduled and unscheduled infant visits.

    At six months, 44% of the breastfeeding-counseled mothers, 7% of the childcare-counseled mothers and none of the mothers in the control group were exclusively breastfeeding. Twenty- four mothers breastfed exclusively during the first six months, of whom 22 received breastfeeding counseling and 2 had no breastfeeding counseling. Among 24 infants who were exclusively breastfed from birth to six months there were no episodes of diarrhea. All infants had gained in weight, length and head circumference. Mean maternal weight loss at six months was similar whether her breastfeeding was exclusive or partial.

    The reasons why mothers without breastfeeding counseling introduced non-breast milk feeding before six months reflected lack of knowledge and support. Breastfeeding support during the first six months focusing on how to prevent and solve breastfeeding problems, particularly during the first two weeks, will enable mothers to choose to breastfeed exclusively up to six months.

    This study has provided fundamental evidence of successful intervention by breastfeeding counseling to achieve six months of exclusive breastfeeding among term, low-birthweight infants. The locally developed training program in breastfeeding counseling, which successfully prepared volunteers to counsel mothers at home, could be incorporated into primary health care in the Philippines. Mothers who received breastfeeding counseling appreciated how this helped them to achieve their breastfeeding goals for the first six months. Improved breastfeeding practices as a result of breastfeeding counseling provided infants with protection from diarrhea and respiratory infections, contributing to their health and development.

    List of papers
    1. Postnatal peer counselling on exclusive breastfeeding of low-birthweight infants: a randomized, controlled trial
    Open this publication in new window or tab >>Postnatal peer counselling on exclusive breastfeeding of low-birthweight infants: a randomized, controlled trial
    2005 In: Acta Paediatrica, Vol. 94, p. 1109-1115Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93829 (URN)
    Available from: 2005-11-22 Created: 2005-11-22Bibliographically approved
    2. Training peer counselors in supporting mothers of term, low birth weight infants to exclusively breastfeed
    Open this publication in new window or tab >>Training peer counselors in supporting mothers of term, low birth weight infants to exclusively breastfeed
    2005 (English)In: Asia Pacific Family Medicine, ISSN 1444-1683, E-ISSN 1447-056X, Vol. 4, no 1Article in journal (Refereed) Published
    Abstract [en]

    Aim:      This article describes a locally developed, two-tiered program of counseling training, aimed at supporting mothers of term, low birth weight infants to exclusively breastfeed from birth to 6 months. Methods:      An invitation to attend a mother–child health seminar was sent to 13 health centers in Metropolitan Manila. Level One training consisted of a three-day seminar on postpartum mother–child care conducted by the health staff of the Philippine General Hospital. Level Two of the training, conducted by a certified breastfeeding counselor, consisted of a 40-hour instructional program which used interactive didactics and practical skill workshops which taught the counselors how to prevent and manage breastfeeding problems. Result:      Thirty of 37 (81%) women passed Level One training. Fourteen of these 30 women (46.7%) decided to proceed to Level Two training. Eight of the 14 women who had the longest breastfeeding experience were chosen to undergo the Level Two training. All eight women completed the training. Six of the eight (75%) had satisfactory post-training assessment; the remaining two were re-trained and were subsequently assessed to be fit for counseling work. An assessment of post-training competencies showed that counseling knowledge and skills were improved by the training. Further, the intervention demonstrated a 56.6% exclusive breastfeeding rate at six months compared to the national prevalence rate of 1.4%. Conclusion:      This training program has increased breastfeeding counseling knowledge as established by increased correct breastfeeding information and appropriate counseling skills observed after the women completed the training.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93830 (URN)
    Available from: 2005-11-22 Created: 2005-11-22 Last updated: 2017-12-14Bibliographically approved
    3. When and why Filipino mothers of term low birth weight infants stop breastfeeding exclusively
    Open this publication in new window or tab >>When and why Filipino mothers of term low birth weight infants stop breastfeeding exclusively
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-93831 (URN)
    Available from: 2005-11-22 Created: 2005-11-22 Last updated: 2010-01-13Bibliographically approved
    4. Exclusive breastfeeding of low birth weight infants for the first six months: infant morbidity and maternal and infant anthropometry
    Open this publication in new window or tab >>Exclusive breastfeeding of low birth weight infants for the first six months: infant morbidity and maternal and infant anthropometry
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-93832 (URN)
    Available from: 2005-11-22 Created: 2005-11-22 Last updated: 2010-01-13Bibliographically approved
  • 115.
    Agrawal, Sumit
    et al.
    Western Univ, Dept Otolaryngol Head & Neck Surg, London, ON, Canada.
    Schart-Moren, Nadine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Ladak, Hanif M.
    Western Univ, Dept Otolaryngol Head & Neck Surg, London, ON, Canada;Western Univ, Dept Med Biophys, London, ON, Canada;Western Univ, Dept Elect & Comp Engn, London, ON, Canada.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    The secondary spiral lamina and its relevance in cochlear implant surgery2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 1, p. 9-18Article in journal (Refereed)
    Abstract [en]

    Objective: We used synchrotron radiation phase contrast imaging (SR-PCI) to study the 3D microanatomy of the basilar membrane (BM) and its attachment to the spiral ligament (SL) (with a conceivable secondary spiral lamina [SSL] or secondary spiral plate) at the round window membrane (RWM) in the human cochlea. The conception of this complex anatomy may be essential for accomplishing structural preservation at cochlear implant surgery.

    Material and methods: Sixteen freshly fixed human temporal bones were used to reproduce the BM, SL, primary and secondary osseous spiral laminae (OSL), and RWM using volume-rendering software. Confocal microscopy immunohistochemistry (IHC) was performed to analyze the molecular constituents.

    Results: SR-PCI reproduced the soft tissues including the RWM, Reissner's membrane (RM), and the BM attachment to the lateral wall (LW) in three dimensions. A variable SR-PCI contrast enhancement was recognized in the caudal part of the SL facing the scala tympani (ST). It seemed to represent a SSL allied to the basilar crest (BC). The SSL extended along the postero-superior margin of the round window (RW) and immunohistochemically expressed type II collagen.

    Conclusions: Unlike in several mammalian species, the human SSL is restricted to the most basal portion of the cochlea around the RW. It anchors the BM and may influence its hydro-mechanical properties. It could also help to shield the BM from the RW. The microanatomy should be considered at cochlear implant surgery.

  • 116.
    Agrogiannis, Nikolaos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rozen, Shai
    Reddy, Gangadasu
    Audolfsson, Thorir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rodriguez Lorenzo, Andres
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Vastus lateralis vascularized nerve graft in facial nerve reconstruction: An anatomical cadaveric study and clinical implications2015In: Microsurgery, ISSN 0738-1085, E-ISSN 1098-2752, Vol. 35, no 2, p. 135-139Article in journal (Refereed)
  • 117. Aguilar, Carlos
    et al.
    Edholm, Kaijsa
    Simmons, Andrew
    Cavallin, Lena
    Muller, Susanne
    Skoog, Ingmar
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Axelsson, Rimma
    Wahlund, Lars-Olof
    Westman, Eric
    Automated CT-based segmentation and quantification of total intracranial volume2015In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 25, no 11, p. 3151-3160Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To develop an algorithm to segment and obtain an estimate of total intracranial volume (tICV) from computed tomography (CT) images.

    MATERIALS AND METHODS: Thirty-six CT examinations from 18 patients were included. Ten patients were examined twice the same day and eight patients twice six months apart (these patients also underwent MRI). The algorithm combines morphological operations, intensity thresholding and mixture modelling. The method was validated against manual delineation and its robustness assessed from repeated imaging examinations. Using automated MRI software, the comparability with MRI was investigated. Volumes were compared based on average relative volume differences and their magnitudes; agreement was shown by a Bland-Altman analysis graph.

    RESULTS: We observed good agreement between our algorithm and manual delineation of a trained radiologist: the Pearson's correlation coefficient was r = 0.94, tICVml[manual] = 1.05 × tICVml[automated] - 33.78 (R(2) = 0.88). Bland-Altman analysis showed a bias of 31 mL and a standard deviation of 30 mL over a range of 1265 to 1526 mL.

    CONCLUSIONS: tICV measurements derived from CT using our proposed algorithm have shown to be reliable and consistent compared to manual delineation. However, it appears difficult to directly compare tICV measures between CT and MRI.

    KEY POINTS: • Automated estimation of tICV is in good agreement with manual tracing. • Consistent tICV estimations from repeated measurements demonstrate the robustness of the algorithm. • Automatically segmented volumes seem less variable than those from manual tracing. • Unbiased and automated tlCV estimation is possible from CT.

  • 118.
    Agustsson, Atli
    et al.
    Univ Iceland, Sch Hlth Sci, Res Ctr Movement Sci, Reykjavik, Iceland..
    Sveinsson, Thorarinn
    Univ Iceland, Sch Hlth Sci, Res Ctr Movement Sci, Reykjavik, Iceland..
    Rodby-Bousquet, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Lund Univ, Orthopaed, Dept Clin Sci Lund, Lund, Sweden..
    The effect of asymmetrical limited hip flexion on seating posture, scoliosis and windswept hip distortion2017In: Research in Developmental Disabilities, ISSN 0891-4222, E-ISSN 1873-3379, Vol. 71, p. 18-23Article in journal (Refereed)
    Abstract [en]

    Background: Postural asymmetries with seating problems are common in adults with cerebral palsy.

    Aims: To analyse the prevalence of asymmetrical limited hip flexion (< 90) in adults with CP, and to evaluate the association between asymmetrical limited hip flexion and postural asymmetries in the sitting position.

    Methods and procedures: Cross-sectional data of 714 adults with CP, 16-73 years, GMFCS level I -V, reported to CPUP, the Swedish cerebral palsy national surveillance program and quality registry, from 2013 to 2015. Hip range of motion was analysed in relation to pelvic obliquity, trunk asymmetry, weight distribution, scoliosis and windswept hip distortion.

    Outcomes and results: The prevalence of asymmetrical limited hip flexion increased as GMFCS level decreased. Of adults at GMFCS level V, 22% had asymmetrical limited hip flexion (< 90). The odds of having an oblique pelvis (OR 2.6, 95% CI:1.6-2.1), an asymmetrical trunk (OR 2.1, 95% CI:1.1-4.2), scoliosis (OR 3.7, 95% CI:1.3-9.7), and windswept hip distortion (OR 2.6, 95% CI:1.2-5.4) were higher for adults with asymmetrical limited hip flexion compared with those with bilateral hip flexion > 90 degrees.

    Conclusions and implications: Asymmetrical limited hip flexion affects the seating posture and is associated with scoliosis and windswept hip distortion.

  • 119.
    Agyemang, Amanda
    et al.
    Kravis Childrens Hosp, Icahn Sch Med Mt Sinai, Jaffe Food Allergy Inst, Div Allergy & Immunol,Dept Pediat, New York, NY USA.
    Saf, Sarah
    Kravis Childrens Hosp, Icahn Sch Med Mt Sinai, Jaffe Food Allergy Inst, Div Allergy & Immunol,Dept Pediat, New York, NY USA;Hop Enfants Armand Trousseau, Ctr Asthme & Allergies, Dept Allergol, Paris, France.
    Sifers, Travis
    Kravis Childrens Hosp, Icahn Sch Med Mt Sinai, Jaffe Food Allergy Inst, Div Allergy & Immunol,Dept Pediat, New York, NY USA.
    Mishoe, Michelle
    Kravis Childrens Hosp, Icahn Sch Med Mt Sinai, Jaffe Food Allergy Inst, Div Allergy & Immunol,Dept Pediat, New York, NY USA.
    Borres, Magnus P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research. Thermo Fisher Sci, Uppsala, Sweden.
    Sampson, Hugh A.
    Kravis Childrens Hosp, Icahn Sch Med Mt Sinai, Jaffe Food Allergy Inst, Div Allergy & Immunol,Dept Pediat, New York, NY USA.
    Nowak-Wegrzyn, Anna
    Kravis Childrens Hosp, Icahn Sch Med Mt Sinai, Jaffe Food Allergy Inst, Div Allergy & Immunol,Dept Pediat, New York, NY USA.
    Utilizing boiled milk sIgE as a predictor of baked milk tolerance in cow's milk allergic children2019In: Journal of Allergy and Clinical Immunology: In Practice, ISSN 2213-2198, E-ISSN 2213-2201, Vol. 7, no 6, p. 2049-2051Article in journal (Refereed)
  • 120.
    Ahlgren, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Studies on Prediction of Axillary Lymph Node Status in Invasive Breast Cancer2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Breast cancer is the most common malignancy among females in Sweden. Axillary lymph-node dissection is a standard procedure in the management of breast cancer, aiming at obtaining prognostic information for adjuvant therapy decisions. Axillary dissection entails considerable morbidity. The aims of this study were to establish more selective surgical approaches and to investigate angiogenesis, a potential predictor for lymph-node metastases and prognosis.

    Clinical nodal status, tumour size and S-phase were associated with nodal metastases in cohort of 1145 women. The proportion of nodal metastases was 13% in the subgroup with the lowest risk.

    In a study from two registries, 675 and 1035 breast cancers ≤10 mm diagnosed by screening mammography had nodal metastases in 6,5% and 7%, respectively. Clinically detected cancers had a risk of 16% and 14%, respectively.

    In a study on 415 women, a 5-node biopsy of the axilla had a sensitivity of 97,3% and a false negative rate of 2,7% in comparison with axillary dissection.

    Six sections from 21 breast cancers were analysed for microvessel density (MVD). The inter-section variation contributed more to the total variance than inter-tumour variation, 45,0% and 37,3%, respectively.

    In a cohort of 315 women, breast cancers with high MVD more frequently had p53 mutations (27,1%) compared with cases with low MVD (18,4%). This difference was not statistically significant (p=0,075). p53 mutations were associated with a worse outcome, whereas MVD was not.

    In conclusion, women with screening detected ≤10 mm breast cancers have a low risk of lymph node metastases and some may not need axillary dissection in the future. The 5-node biopsy could be an alternative to axillary dissection. MVD is associated with methodological weaknesses and routine use is not recommended.

  • 121.
    Ahlgren, Kerstin M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    von Euler, Henrik
    Sundberg, Katarina
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedhammar, Åke
    Andersson, Göran
    Hansson-Hamlin, Helene
    Lernmark, Åke
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e105473-Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS:

    Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.

    METHODS:

    Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.

    RESULTS:

    None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.

    CONCLUSIONS/INTERPRETATIONS:

    Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.

  • 122.
    Ahlgren, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Molecular Radionuclide Imaging Using Site-specifically Labelled Recombinant Affibody Molecules: Preparation and Preclinical Evaluation2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Radionuclide molecular imaging is an emerging multidisciplinary technique that is used in modern medicine to visualise diseases at cellular and molecular levels. This thesis is based on five papers (I-V) and focuses on the development of site-specific radiolabelled recombinant anti-HER2 Affibody molecules and preclinical evaluations in vitro and in vivo of the labelled conjugates. This work is part of a preclinical development of an Affibody molecule-based tracer for molecular imaging of HER2 expressing tumours.

    Papers I and II report the evaluation of the Affibody molecule ZHER2:2395-C, site-specifically labelled with the radiometals 111In (for SPECT) and 57Co (as a surrogate for 55Co, suitable for PET applications) using a thiol reactive DOTA derivative as a chelator. Both conjugates demonstrated very suitable biodistribution properties, enabling high contrast imaging just a few hours after injection.

    Papers III and IV report the development and optimization of a technique for site-specific labelling of ZHER2:2395-C with 99mTc using an N3S chelating peptide sequence. 99mTc-ZHER2:2395-C demonstrated high and specific tumour uptake and rapid clearance of non-bound tracer from the blood, resulting in high tumour-to-non-tumour ratios shortly after injection, enabling high contrast imaging. In addition, in the study described in paper IV, freeze-dried kits previously developed for 99mTc-labelling were optimised, resulting in the development of a kit in which all the reagents and protein needed for labelling of ZHER2:2395-C with 99mTc were contained in a single vial.

    Paper V reports the evaluation of an anti-HER2 Affibody molecule, ABY-025, with a fundamentally re-engineered scaffold. Despite the profound re-engineering, the biodistribution pattern of 111In-ABY-025 was very similar to that of two variants of the parental molecule.

    It seems reasonable to believe that these results will also be applicable to Affibody molecules towards other targets. Hopefully, this work will also be helpful in the development of other small proteinaceous tracers.

    List of papers
    1. Evaluation of maleimide derivative of DOTA for site-specific labeling of recombinant affibody molecules
    Open this publication in new window or tab >>Evaluation of maleimide derivative of DOTA for site-specific labeling of recombinant affibody molecules
    Show others...
    2008 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 19, no 1, p. 235-243Article in journal (Refereed) Published
    Abstract [en]

    Affibody molecules are a new class of small (7 kDa) scaffold affinity proteins, which demonstrate promising properties as agents for in vivo radionuclide targeting. The Affibody scaffold is cysteine-free and therefore independent of disulfide bonds. Thus, a single thiol group can be engineered into the protein by introduction of one cysteine. Coupling of thiol-reactive bifunctional chelators can enable site-specific labeling of recombinantly produced Affibody molecules. In this study, the use of 1,4,7,10-tetraazacyclododecane-1,4,7-tris-acetic acid-10-maleimidoethylacetamide (MMA-DOTA) for 111 In-labeling of anti-HER2 Affibody molecules His 6-Z HER2:342-Cys and Z HER2:2395-Cys has been evaluated. The introduction of a cysteine residue did not affect the affinity of the proteins, which was 29 pM for His 6-Z HER2:342-Cys and 27 pM for Z HER2:2395-Cys, comparable with 22 pM for the parental Z HER2:342. MMA-DOTA was conjugated to DTT-reduced Affibody molecules with a coupling efficiency of 93% using a 1:1 molar ratio of chelator to protein. The conjugates were labeled with 111 In to a specific radioactivity of up to 7 GBq/mmol, with preserved binding for the target HER2. In vivo, the non-His-tagged variant 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys demonstrated appreciably lower liver uptake than its His-tag-containing counterpart. In mice bearing HER2-expressing LS174T xenografts, 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys showed specific and rapid tumor localization, and rapid clearance from blood and nonspecific compartments, leading to a tumor-to-blood-ratio of 18 +/- 8 already 1 h p.i. Four hours p.i., the tumor-to-blood ratio was 138 +/- 8. Xenografts were clearly visualized already 1 h p.i.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-104530 (URN)10.1021/bc700307y (DOI)000252520300030 ()18163536 (PubMedID)
    Available from: 2009-05-29 Created: 2009-05-28 Last updated: 2017-12-13Bibliographically approved
    2. Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys61]-ZHER2:2395-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors
    Open this publication in new window or tab >>Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys61]-ZHER2:2395-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors
    2010 (English)In: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 12, no 1, p. 54-62Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: Imaging using positron emission tomography (PET) in the field of nuclear medicine is becoming increasingly important. The aim of this study was to develop a method for labeling of affibody molecules with radiocobalt for PET applications. PROCEDURES: The human epidermal growth factor receptors type 2 (HER2) binding affibody molecule DOTA-Z(2395)-C was radiolabeled with (57)Co (used as a surrogate of (55)Co). The binding specificity and cellular processing of the labeled compound was studied in vitro followed by in vivo characterization in normal and tumor-bearing mice. Furthermore, a comparative biodistribution study was performed with a (111)In-labeled counterpart. RESULTS: DOTA-Z(2395)-C was successfully labeled with radiocobalt with nearly quantitative yield. The compound displayed good retention on cells over time and high tumor accumulation of radioactivity in animal studies. Imaging studies showed clear visualization of HER2-positive tumors. Furthermore, the radiocobalt label provided better tumor-to-organ ratios than (111)In. CONCLUSIONS: Radiocobalt is a promising label for affibody molecules for future PET applications.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122173 (URN)10.1007/s11307-009-0238-8 (DOI)000273479300008 ()19557480 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2017-12-12Bibliographically approved
    3. Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine
    Open this publication in new window or tab >>Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine
    Show others...
    2009 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 50, no 5, p. 781-789Article in journal (Refereed) Published
    Abstract [en]

    The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Small (7 kDa) high-affinity anti-HER2 Affibody molecules may be suitable tracers for SPECT visualization of HER2-expressing tumors. The use of generator-produced (99m)Tc as a label would facilitate the prompt translation of anti-HER2 Affibody molecules into use in clinics. METHODS: A C-terminal cysteine was introduced into the Affibody molecule Z(HER2:342) to enable site-specific labeling with (99m)Tc. Two recombinant variants, His(6)-Z(HER2:342)-Cys (dissociation constant [K(D)], 29 pM) and Z(HER2:2395)-Cys, lacking a His tag (K(D), 27 pM), were labeled with (99m)Tc in yields exceeding 90%. The binding specificity and the cellular processing of Affibody molecules were studied in vitro. Biodistribution and gamma-camera imaging studies were performed in mice bearing HER2-expressing xenografts. RESULTS: (99m)Tc-His(6)-Z(HER2:342)-Cys was capable of targeting HER2-expressing SKOV-3 xenografts in SCID mice, but the liver radioactivity uptake was high. A series of comparative biodistribution experiments indicated that the presence of the His tag caused elevated accumulation in the liver. (99m)Tc-Z(HER2:2395)-Cys, not containing a His tag, showed low uptake in the liver and high and specific uptake in HER2-expressing xenografts. Four hours after injection, the radioactivity uptake values (percentage of injected activity per gram of tissue [%IA/g]) were 6.9 +/- 2.5 (mean +/- SD) %IA/g in LS174T xenografts (moderate level of HER2 expression) and 15 +/- 3 %IA/g in SKOV-3 xenografts (high level of HER2 expression). The corresponding tumor-to-blood ratios were 88 +/- 24 and 121 +/- 24, respectively. Both LS174T and SKOV-3 xenografts were clearly visualized with a clinical gamma-camera 1 h after injection of (99m)Tc-Z(HER2:2395)-Cys. CONCLUSION: The Affibody molecule (99m)Tc-Z(HER2:2395)-Cys is a promising tracer for SPECT visualization of HER2-expressing tumors.

    Keywords
    Affibody molecule, technetium, imaging, HER2, C-terminal cysteine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122172 (URN)10.2967/jnumed.108.056929 (DOI)000272487900017 ()19372467 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2017-12-12Bibliographically approved
    4. Kit formulation for 99mTc-labeling of recombinant anti-HER2 Affibody molecules with a C-terminally engineered cysteine
    Open this publication in new window or tab >>Kit formulation for 99mTc-labeling of recombinant anti-HER2 Affibody molecules with a C-terminally engineered cysteine
    2010 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 37, no 5, p. 539-546Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Molecular imaging of HER2-expression in malignant tumors provides potentially important information for patient management. Affibody molecules have shown to be suitable tracers for imaging applications using SPECT or PET. Results from an earlier evaluation of the application of site specific 99mTc-labeling on the Affibody molecule, ZHER2:2395-C, were favorable.

    Methods: As a preparation for clinical application of this tracer we have developed and evaluated a robust single-vial freeze-dried kit, allowing labeling of the Affibody molecule, ZHER2:2395-C, with 99mTc.

    Results: The composition of the kit (containing glucoheptonate, EDTA and tin(II)-chloride), as well as the protein amount and the pertechnetate volume were optimized for a high labeling yield (> 90 %) and minimal presence of reduced hydrolyzed technetium colloids (< 1 %). The specificity to HER2 receptors, the binding competence and the stability in PBS and murine serum were verified in vitro. The shelf-life was also evaluated in vitro, showing no reduction in labeling yield or binding capacity to HER2-expressing cells after over 400 days of storage of the single-vial freeze-dried kit.

    Conclusions: ZHER2:2395-C labeled with 99mTc using the lyophilized kit was stable and resulted in a favorable biodistribution in an in vivo evaluation in normal NMRI mice.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122175 (URN)10.1016/j.nucmedbio.2010.02.009 (DOI)000279412400002 ()20610158 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2017-12-12Bibliographically approved
    5. Targeting of HER2-Expressing Tumors Using 111In-ABY-025, a Second-Generation Affibody Molecule with a Fundamentally Reengineered Scaffold
    Open this publication in new window or tab >>Targeting of HER2-Expressing Tumors Using 111In-ABY-025, a Second-Generation Affibody Molecule with a Fundamentally Reengineered Scaffold
    Show others...
    2010 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 51, no 7, p. 1131-1138Article in journal (Refereed) Published
    Abstract [en]

    Overexpression of HER2 in breast carcinomas predicts response to trastuzumab therapy. Affibody molecules based on a non-immunoglobulin scaffold have demon-strated high potential for in vivo molecular imaging of HER2-expressing tumors. Re-engineering of the molecular scaffold has led to a second generation of optimized Affibody molecules, having a surface distinctly different from the parental protein domain from staphylococcal protein A. The new tracer showed further increased melting point, stability and overall hydrophilicity compared to the parental molecule, and was shown to be more amenable for chemical peptide synthesis. The goal of this study was to assess potential effects of this extensive re-engineering on HER2 targeting, using ABY-025, a DOTA conjugated variant of the novel tracer.

    Methods: 111In-ABY-025 was compared with previously evaluated parent HER2-binding Affibody tracers in vitro and in vivo. The in vivo behavior was further evaluated in mice bearing SKOV-3 xenografts, in rats and in cynomolgus macaques.

    Results: 111In-ABY-025 bound specifically to HER2 in vitro and in vivo. Direct comparison with the previous generation of HER2-binding tracers showed that ABY-025 retained excellent targeting properties. Rapid blood clearance was shown in mice, rats and macaques. A highly specific tumor uptake of 16.7 ± 2.5 %IA/g was seen at 4 h after injection. The tumor-to-blood ratio was 6.3 at 0.5 h, 88 at 4 h, and increased up to 3 days after injection. Gamma camera imaging of tumors was already possible 0.5 h after injection. Furthermore, repeated i.v. administration of ABY-025 did not induce antibody formation in rats.

    Conclusions: The biodistribution of 111In-ABY-025 was in remarkably good agreement with the parent tracers, despite profound re-engineering of the non-binding surface. The molecule displayed rapid blood clearance in all species investigated and excellent targeting capacity in tumor bearing mice, leading to high tumor-to-organ-ratios and high contrast imaging shortly after injection.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122176 (URN)10.2967/jnumed.109.073346 (DOI)000279430900021 ()20554729 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2017-12-12Bibliographically approved
  • 123. Ahlgrim, C.
    et al.
    Gutermuth, J.
    Onell, A.
    Borres, Magnus P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Schaeffner, I
    Darsow, U.
    Pfab, F.
    Brockow, K.
    Ring, J.
    Behrendt, H.
    Jakob, T.
    Huss-Marp, J.
    Comparison of Molecular Multiplex and Singleplex Analysis of IgE to Grass Pollen Allergens in Untreated German Grass Pollen-Allergic Patients2015In: Journal of investigational allergology & clinical immunology, ISSN 1018-9068, E-ISSN 1698-0808, Vol. 25, no 3, p. 190-195Article in journal (Refereed)
    Abstract [en]

    Background: The ImmunoCAP ISAC 112 platform is the only commercially available molecular allergy IgE multiplex test. Data on the comparison of this rather novel test with the molecular singleplex ImmunoCAP IgE platform are lacking. Objective:To compare the multiplex ISAC 112 platform and the singleplex ImmunoCAP platform in regard to IgE to grass pollen allergens in untreated grass pollen allergic patients in Germany. Methods: Serum samples from 101 adults with grass pollen allergy were analyzed for specific IgE (sIgE) to 8 allergenic molecules from timothy grass pollen and to the 112 allergenic molecules included in the ISAC panel. The results for the multiplex and singleplex tests were subsequently analyzed statistically. Results: Comparison of sIgE to grass pollen allergens detected by ISAC 112 and the singleplex ImmunoCAP assay revealed the following correlation coefficients: 0.88 (rPhl p1), 0.96 (rPhl p2), 0.70 (nPhl p4), 0.94 (rPhl p5b), 0.92 (rPhl p6), 0.85 (rPhl p11), and 0.78 (rPhl p12). Conclusion: Molecular testing with ISAC 112 correlates well with the ImmunoCAP platform for respective molecular timothy grass pollen allergens.

  • 124.
    Ahlin, Cecilia
    et al.
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Lundgren, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Embretsen-Varro, Elin
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Jirstrom, Karin
    Lund Univ, Dept Pathol & Oncol, Lund, Sweden..
    Blomqvist, Carl
    Orebro Univ, Dept Oncol, Orebro, Sweden.;Univ Helsinki, Dept Oncol, Helsinki, Finland..
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers2017In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 164, no 3, p. 667-678Article in journal (Refereed)
    Abstract [en]

    Cyclin D1 has a central role in cell cycle control and is an important component of estrogen regulation of cell cycle progression. We have previously shown that high cyclin D expression is related to aggressive features of ER-positive but not ER-negative breast cancer. The aims of the present study were to validate this differential ER-related effect and furthermore explore the relationship between cyclin D overexpression and CCND1 gene amplification status in a node-negative breast cancer case-control study. Immunohistochemical nuclear expression of cyclin D1 (n = 364) and amplification of the gene CCND1 by fluorescent in situ hybridization (n = 255) was performed on tissue microarray sections from patients with T1-2N0M0 breast cancer. Patients given adjuvant chemotherapy were excluded. The primary event was defined as breast cancer death. Breast cancer-specific survival was analyzed in univariate and multivariable models using conditional logistic regression. Expression of cyclin D1 above the median (61.7%) in ER breast cancer was associated with an increased risk for breast cancer death (OR 3.2 95% CI 1.5-6.8) also when adjusted for tumor size and grade (OR 3.1). No significant prognostic impact of cyclin D1 expression was found among ER-negative cases. Cyclin D1 overexpression was significantly associated to high expression of the proliferation markers cyclins A (rho 0.19, p = 0.006) and B (rho 0.18, p = 0.003) in ER-positive tumors, but not in ER-negative cases. There was a significant association between CCND1 amplification and cyclin D1 expression (p = 0.003), but CCND1 amplification was not statistically significantly prognostic (HR 1.4, 95% CI 0.4-4.4). We confirmed our previous observation that high cyclin D1 expression is associated to high proliferation and a threefold higher risk of death from breast cancer in ER-positive breast cancer.

  • 125. Ahlin, Erik
    et al.
    Elshafei, Amir
    Nur, Musa
    El Safi, Sayda Hassan
    Ronnelid, Johan
    Elghazali, Gehad
    Retraction: Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese patients with Leishmania donovani infection (vol 51, pg 579, 2011)2014In: Revista Brasileira de Reumatologia, ISSN 0482-5004, E-ISSN 1809-4570, Vol. 54, no 3, p. 255-255Article in journal (Refereed)
  • 126.
    Ahlinder, Linnea
    et al.
    Swedish Def Res Agcy, FOI, Cementvagen 20, SE-90182 Umea, Sweden..
    Lindstrom, Susanne Wiklund
    Swedish Def Res Agcy, FOI, Cementvagen 20, SE-90182 Umea, Sweden..
    Lejon, Christian
    Swedish Def Res Agcy, FOI, Cementvagen 20, SE-90182 Umea, Sweden..
    Geladi, Paul
    Swedish Univ Agr Sci, Dept Forest Biomat & Technol, SE-90183 Umea, Sweden..
    Österlund, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Noise Removal with Maintained Spatial Resolution in Raman Images of Cells Exposed to Submicron Polystyrene Particles2016In: NANOMATERIALS, ISSN 2079-4991, Vol. 6, no 5, article id UNSP 83Article in journal (Refereed)
    Abstract [en]

    The biodistribution of 300 nm polystyrene particles in A549 lung epithelial cells has been studied with confocal Raman spectroscopy. This is a label-free method in which particles and cells can be imaged without using dyes or fluorescent labels. The main drawback with Raman imaging is the comparatively low spatial resolution, which is aggravated in heterogeneous systems such as biological samples, which in addition often require long measurement times because of their weak Raman signal. Long measurement times may however induce laser-induced damage. In this study we use a super-resolution algorithm with Tikhonov regularization, intended to improve the image quality without demanding an increased number of collected pixels. Images of cells exposed to polystyrene particles have been acquired with two different step lengths, i.e., the distance between pixels, and compared to each other and to corresponding images treated with the super-resolution algorithm. It is shown that the resolution after application of super-resolution algorithms is not significantly improved compared to the theoretical limit for optical microscopy. However, to reduce noise and artefacts in the hyperspectral Raman images while maintaining the spatial resolution, we show that it is advantageous to use short mapping step lengths and super-resolution algorithms with appropriate regularization. The proposed methodology should be generally applicable for Raman imaging of biological samples and other photo-sensitive samples.

  • 127.
    Ahlqvist, E.
    et al.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Karajamaki, A.
    Vaasa Cent Hosp, Primary Hlth Care, Vaasa, Finland..
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Storm, P.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Dorkhan, M.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Vikman, P.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Prasad, R. B.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Aly, D. Mansour
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Shaat, N.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Lindholm, E.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Tuomi, T.
    Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Rosengren, A. H.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Groop, L.
    Lund Univ, Ctr Diabet, Malmo, Sweden.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland..
    Clustering of diabetes into novel subgroups provides improved prediction of outcome2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, p. S117-S117Article in journal (Other academic)
  • 128.
    Ahlqvist, Emma
    et al.
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Storm, Petter
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Käräjämäki, Annemarie
    Department of Primary Health Care, Vaasa Central Hospital, Finland.
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Dorkhan, Mozhgan
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Carlsson, Annelie
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, SE-22185 Lund, Sweden.
    Vikman, Petter
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Prasad, Rashmi
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Mansour Aly, Dina
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Almgren, Peter
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Wessman, Ylva
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Shaat, Nael
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Spegel, Peter
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Mulder, Hindrik
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Lindholm, Eero
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Melander, Olle
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Hansson, Ola
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Malmqvist, Ulf
    Clinical Research and Trial Center, Lund University Hospital, Sweden.
    Lernmark, Åke
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Lahti, Kaj
    Department of Primary Health Care, Vaasa Central Hospital, Finland.
    Forsén, Tom
    Department of Primary Health Care, Vaasa Central Hospital, Finland.
    Tuomi, Tiinamaija
    Abdominal Center, Endocrinology, Helsinki University Central Hospital; Research Program for Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
    Rosengren, Anders
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Groop, Leif
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables2018In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 6, no 5, p. 361-369Article in journal (Refereed)
    Abstract [en]

     Background

    Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis.

    Methods

    We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations.

    Findings

    We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes.

    Interpretation

    We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.

  • 129.
    Ahlroth Pind, Caroline
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Gunnbjörnsdottír, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. National University Hospital of Iceland, Reykjavik, Iceland.
    Bjerg, A
    Karolinska Inst, Stockholm, Sweden.
    Järvholm, B
    Umeå Univ, Umeå, Sweden.
    Lundbäck, B
    Univ Gothenburg, Gothenburg, Sweden.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Middelveld, R
    Karolinska Inst, Stockholm, Sweden.
    Nilsson Sommar, J
    Umeå Univ, Umeå, Sweden.
    Norbäck, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Patient-reported signs of dampness at home may be a risk factor for chronic rhinosinusitis: A cross-sectional study2017In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 47, no 11, p. 1383-1389Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: An association between dampness at home and respiratory conditions has been convincingly demonstrated in children. Fewer studies have been performed in adults, and data are lacking for chronic rhinosinusitis (CRS). With a prevalence of 10.9% in Europe, CRS imposes a significant burden on quality of life, as well as economy.

    OBJECTIVE: Our aim was to study CRS and other respiratory conditions in relation to dampness at home in a representative sample of adults.

    METHODS: The Swedish GA2 LEN questionnaire was answered by 26 577 adults (16-75 years) and included questions on respiratory symptoms, smoking, education and environmental exposure. CRS was defined according to the EP3 OS criteria. Dampness was defined as reporting water damage, floor dampness or visible moulds in the home during the last 12 months. The dampness score was ranked from 0 to 3, counting the number of signs of dampness reported.

    RESULTS: Dampness at home was reported by 11.3% and was independently related to respiratory conditions after adjustment for demographic and socio-economic factors and smoking: CRS odds ratio (OR) 1.71; allergic rhinitis OR 1.24; current asthma OR 1.21; wheeze OR 1.37; nocturnal dyspnoea OR 1.80; nocturnal coughing OR 1.34; and chronic bronchitis OR 1.64. The risk of CRS and most of the other respiratory conditions was further elevated in subjects reporting multiple signs of dampness.

    CONCLUSIONS AND CLINICAL RELEVANCE: This study demonstrated an independent association between dampness at home and CRS in adults. The high burden of this and the other respiratory conditions studied is a strong argument in favour of countering indoor dampness by improving building standards.

  • 130.
    Ahlsson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Akerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Schijven, Dick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olivier, Jocelien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Univ Groningen, Dept Behav Physiol, Groningen, Netherlands.;Karolinska Inst, Ctr Gender Med, Stockholm, Sweden..
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Gene Expression in Placentas From Nondiabetic Women Giving Birth to Large for Gestational Age Infants2015In: Reproductive Sciences, ISSN 1933-7191, E-ISSN 1933-7205, Vol. 22, no 10, p. 1281-1288Article in journal (Refereed)
    Abstract [en]

    Gestational diabetes, obesity, and excessive weight gain are known independent risk factors for the birth of a large for gestational age (LGA) infant. However, only 1 of the 10 infants born LGA is born by mothers with diabetes or obesity. Thus, the aim of the present study was to compare placental gene expression between healthy, nondiabetic mothers (n = 22) giving birth to LGA infants and body mass index-matched mothers (n = 24) giving birth to appropriate for gestational age infants. In the whole gene expression analysis, only 29 genes were found to be differently expressed in LGA placentas. Top upregulated genes included insulin-like growth factor binding protein 1, aminolevulinate synthase 2, and prolactin, whereas top downregulated genes comprised leptin, gametocyte-specific factor 1, and collagen type XVII 1. Two enriched gene networks were identified, namely, (1) lipid metabolism, small molecule biochemistry, and organismal development and (2) cellular development, cellular growth, proliferation, and tumor morphology.

  • 131.
    Ahlsson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Kaijser, Magnus
    Clincial Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Adami, Johanna
    Clincial Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lundgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Palme, Mårten
    Department of Economics, Stockholm University, Stockholm, Sweden.
    School performance after preterm birth2015In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 26, no 1, p. 106-111Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: An increased risk of poor school performance for children born preterm has been shown in many studies, but whether this increase is attributable to preterm birth per se or to other factors associated with preterm birth has not been resolved. METHODS: We used data from the Swedish Medical Birth Register, the Longitudinal Integration Database for Sickness Insurance and Labor Market Study, the Swedish Multigeneration Register, and the National School Register to link records comprising the Swedish birth cohorts from 1974 through 1991. Linear regression was used to assess the association between gestational duration and school performance, both with and without controlling for parental and socioeconomic factors. In a restricted analysis, we compared siblings only with each other. RESULTS: Preterm birth was strongly and negatively correlated with school performance. The distribution of school grades for children born at 31-33 weeks was on average 3.85 (95% confidence interval = -4.36 to -3.35) centiles lower than for children born at 40 weeks. For births at 22-24 weeks, the corresponding figure was -23.15 (-30.32 to -15.97). When taking confounders into account, the association remained. When restricting the analysis to siblings, however, the association between school performance and preterm birth after week 30 vanished completely, whereas it remained, less pronounced, for preterm birth before 30 weeks of gestation. CONCLUSIONS: Our study suggests that the association between school performance and preterm birth after 30 gestational weeks is attributable to factors other than preterm birth per se.

  • 132. Ahlstedt, J.
    et al.
    Orbom, A.
    Akesson, A.
    Frejd, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Strand, S.
    Tran, T.
    Simultaneous dual-radionuclide SPECT-imaging of HER2 expression using 99mTc-Affibody/111In-trastuzumab2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S274-S274, article id OP522Article in journal (Other academic)
  • 133.
    Ahlsten, G
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Nowinski, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Mikrocefali och makrocefali2017In: Barnneurologi / [ed] Martin Jägervall och Johan Lundgren, Studentlitteratur AB, 2017, 1, p. 223-228Chapter in book (Other academic)
  • 134.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, Alaska Sci Ctr, Anchorage, AK 99508 USA.
    Bonnedahl, Jonas
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Kalmar Cty Council, Dept Infect Dis, Kalmar, Sweden.
    Woksepp, Hanna
    Kalmar Cty Hosp, Res Sect, Dept Dev & Publ Hlth, Kalmar, Sweden.
    Hernandez, Jorge
    Kalmar Cty Hosp, Dept Clin Microbiol, Kalmar, Sweden.
    Reed, John A.
    US Geol Survey, Alaska Sci Ctr, Anchorage, AK 99508 USA.
    Tibbitts, Lee
    US Geol Survey, Alaska Sci Ctr, Anchorage, AK 99508 USA.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Douglas, David C.
    US Geol Survey, Alaska Sci Ctr, Juneau, AK USA.
    Ramey, Andrew M.
    US Geol Survey, Alaska Sci Ctr, Anchorage, AK 99508 USA.
    Satellite tracking of gulls and genomic characterization of faecal bacteria reveals environmentally mediated acquisition and dispersal of antimicrobial-resistant Escherichia coli on the Kenai Peninsula, Alaska2019In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 28, no 10, p. 2531-2545Article in journal (Refereed)
    Abstract [en]

    Gulls (Larus spp.) have frequently been reported to carry Escherichia coli exhibiting antimicrobial resistance (AMR E. coli); however, the pathways governing the acquisition and dispersal of such bacteria are not well described. We equipped 17 landfill-foraging gulls with satellite transmitters and collected gull faecal samples longitudinally from four locations on the Kenai Peninsula, Alaska to assess: (a) gull attendance and transitions between sites, (b) spatiotemporal prevalence of faecally shed AMR E. coli, and (c) genomic relatedness of AMR E. coli isolates among sites. We also sampled Pacific salmon (Oncorhynchus spp.) harvested as part of personal-use dipnet fisheries at two sites to assess potential contamination with AMR E. coli. Among our study sites, marked gulls most commonly occupied the lower Kenai River (61% of site locations) followed by the Soldotna landfill (11%), lower Kasilof River (5%) and upper Kenai River (<1%). Gulls primarily moved between the Soldotna landfill and the lower Kenai River (94% of transitions among sites), which were also the two locations with the highest prevalence of AMR E. coli. There was relatively high spatial and temporal variability in AMR E. coli prevalence in gull faeces and there was no evidence of contamination on salmon harvested in personal-use fisheries. We identified E. coli sequence types and AMR genes of clinical importance, with some isolates possessing genes associated with resistance to as many as eight antibiotic classes. Our findings suggest that gulls acquire AMR E. coli at habitats with anthropogenic inputs and subsequent movements may represent pathways through which AMR is dispersed.

  • 135.
    Ahlström, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ekström, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sjöholm, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Strand, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, E.
    Antaros Med, Molndal, Sweden..
    Hagmar, P.
    Antaros Med, Molndal, Sweden..
    Malmberg, Filip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Registration-based automated lesion detection and therapy evaluation of tumors in whole body PET-MR images2017In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no S5, article id 78PArticle in journal (Other academic)
  • 136.
    Ahlström, Isabell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy.
    Hellström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy.
    Emtner, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotheraphy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Anens, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy.
    Reliability of the Swedish version of the Exercise Self-Efficacy Scale (S-ESES): a test-retest study in adults with neurological disease2015In: Physiotherapy Theory and Practice, ISSN 0959-3985, E-ISSN 1532-5040, Vol. 31, no 3, p. 194-199Article in journal (Refereed)
    Abstract [en]

    Objective: To examine the test-retest reliability of the Swedish translated version of the Exercise Self-Efficacy Scale (S-ESES) in people with neurological disease and to examine internal consistency.

    Design: Test-retest study.

    Subjects: A total of 30 adults with neurological diseases including: Parkinson's disease; Multiple Sclerosis; Cervical Dystonia; and Charcot Marie Tooth disease.

    Method: The S-ESES was sent twice by surface mail. Completion interval mean was 16 days apart. Weighted kappa, intraclass correlation coefficient 2,1 [ICC (2,1)], standard error of measurement (SEM), also expressed as a percentage value (SEM%), and Cronbach's alpha were calculated.

    Results: The relative reliability of the test-retest results showed substantial agreement measured using weighted kappa (MD = 0.62) and a very high-reliability ICC (2,1) (0.92). Absolute reliability measured using SEM was 5.3 and SEM% was 20.7. Excellent internal consistency was shown, with an alpha coefficient of 0.91 (test 1) and 0.93 (test 2).

    Conclusion: The S-ESES is recommended for use in research and in clinical work for people with neurological diseases. The low-absolute reliability, however, indicates a limited ability to measure changes on an individual level.

  • 137.
    Ahlsvik, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Rossinen, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Barnmorskors erfarenheter av att stödja och bemöta förstföderskor med förlossningsrädsla2018Independent thesis Advanced level (degree of Master (One Year)), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background: Fear of childbirth in pregnant women waiting for their first child is affecting both mother and child. That is why it is important for the midwife’s in the antenatal care to pay attention to fear of childbirth in time and also to help the women in the best possible way. Fear of childbirth is a problem that increases which can result in complicated deliveries and sections which costs a lot of money for the community.

     

    Aim: The aim of this study was to investigate midwife’s experience of supporting and responding to fear of childbirth in nulliparous women and to study what has caused the fear.

     

    Method: We conducted a qualitative interview study with 11 midwives working at antenatal clinics in mid Sweden. The interviews were analyzed with manifest content analysis.

     

    Result: Four categories were found: Different ways to communicate fear, the content of the fear, influence factor and to help and support women with fear of childbirth.  Thirteen subcategories were created and formed the categories: Expresses the fear with words, no words, thoughts about disaster, control loss, pain, complications, past experiences, abuse, mental illness, external impact, difficult to reach the woman, a challenge and strengthening the woman's self-esteem.

     

    Conclusion: Most nulliparous women express their fear of childbirth early in pregnancy, but not everyone dares to talk about it. Controll loss is described as the main motive for fear. The most common cause of fear of childbirth today is due to external factors such as media and influences from friends and family. Also today's situation of maternity ward affects women's fear of childbirth. It could be a challenge to be able to support and respond to the woman in the best way.

  • 138.
    Ahmad, Abdulbaghi
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Childhood trauma and posttraumatic stress disorder: A developmental and cross-cultural approach1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis aims to identify child-specific cross-cultural protecting and vulnerability factors regarding traumatic experiences and posttraumatic stress reactions. Children between 6-18 years were interviewed from three different socio-cultural backgrounds. In Iraqi Kurdistan, 20 participants in a mass-escape tragedy (MET), 54 orphans and 45 survivors of the genocide operation "Anfal" were interviewed. In Sweden, a sample of 32 Kurdistanian refugee children and a comparable Swedish sample were included. The frequencies of posttraumatic stress disorder (PTSD) were 20%, 43%. 87%, 9,7% and 12.5% respectively.

    The relatively low frequencies of PTSD in the follow-up sample 2 months, 4 months, 14 months and 26 months after the MET suggest the child functioning in a complete, authoritative family, as a protecting factor. The significant of this developmentally based child-specific functioning level within the supportive family system can also explain the fluctuating PTSD-related symptom scores in this sample parallel to the changes in the socio-economic situation in the region. The over time decrease in behavioural problems among fostercare orphans and their low PTSD frequencies as compared with the increase in behavioural problems and the high PTSD frequencies among orphanage samples further support this suggestion. Child trauma scores and captivity duration predicted for PTSD in "Anfal" survivors, irrespective of parents' trauma scores and PTSD or fathers re-union with the family, suggesting child-specific vulnerability more than contagion effect. Despite PTSD, children in Kurdistan performed high functioning levels, probably indicating a child-specific manifestation of hypervigilance. The Kurdistanian refugee sample revealed lower lifetime reexperiencing PTSD symptom scores than the Swedish sample, indicating a healing effect on the former coming to Sweden and a resilience deficit for the later growing up in a highly sheltered society.

    There are more similarities than differences between children from Kurdistan and Sweden in reporting traumatic experiences and exhibiting posttraumatic stress symptoms. Developmentally based child characteristics have a determinant role as protective or vulnerability factors in childhood trauma and PTSD, even if socio-cultural factors also play a role.

  • 139.
    Ahmad, Abdulbaghi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Introducing child mental health in the medical curriculum in Duhok2009In: Duhok Medical Journal, ISSN 2071-7326, Vol. 3, no 1, p. 12-24Article in journal (Refereed)
    Abstract [en]

    Background Child mental health and child and adolescent psychiatry is increasinglybecoming an indicator for any modern society to bring up child perspectives preparing forprosperous future. This field was lacking as an own medical speciality in the Middle Eastuntil the establishment of the Department of Child Mental Health at the College of Medicine,University of Duhok in 20 September 2001.

    Objectives To build up local competence in Child Mental Health, and to introduce Child andAdolescent Psychiatry as a modern subject in the curriculums at the College of Medicine,University of Duhok, in the Kurdistan region of Iraq.

    Methods The Department of Child Mental Health (CMH) was established at the College ofMedicine, University of Duhok, in collaboration with the Department of Neuroscience, Childand Adolescent Psychiatry at the Uppsala University in Sweden. Education programs aredelivered from the Uppsala University in Sweden to the College of Medicine, University ofDuhok in Iraqi Kurdistan, at three levels; community-based education, undergraduate medicaleducation, and postgraduate education to achieve High Diploma (Master) degree, adjusted tothe local system in Kurdistan.

    Results The CMH is a unit belonged to the pediatrics at the College of Medicine, and havinglinks to the Directorates of Health, Education and Social Care in Duhok. Lectures in Childand Adolescent Psychiatry are delivered to the fifth year medicine students one week inautumn to be followed by another week of teaching in clinical case discussions in springevery year. The final examination consisting of the means of scores collected during the firsttheory and the second clinical courses compose 20% of the final pediatric examination. Thepostgraduate program consists of two-year education, after one-year pediatric residency, toobtain specialist competence in the subject.

    Conclusions Transferring up-to-date knowledge on modern subjects from advancedinternational universities to the universities in Iraq is necessary and possible if modernteaching methods are effectively utilized. The CMH is proved to be a good example ofsuccessful collaboration, making the College of Medicine at the University of Duhok as thefirst school of medicine in the Middle East having Child and Adolescent Psychiatry as anobligatory teaching subject.

  • 140.
    Ahmad, Abdulbaghi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Krisbearbeningsprogram för flyktingbarn2015In: Tidskriften för svensk psykiatri, ISSN 1653-8579Article in journal (Refereed)
  • 141.
    Ahmad, Abdulbaghi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Larsson, Bo
    Sundelin Wahlsten, Viveka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    EMDR treatment for children with PTSD: Results of a randomized controlled trial2007In: Nordic Journal of Psychiatry, ISSN 0803-9488, E-ISSN 1502-4725, Vol. 61, no 5, p. 349-354Article in journal (Refereed)
    Abstract [en]

    The objective of the study was to examine the efficacy of EMDR treatment for children with post-traumatic stress disorder ( PTSD) compared with untreated children in a waiting list control group (WLC) participating in a randomized controlled superiority trial (RCT). Thirty-three 6-16-year-old children with a DSM-IV diagnosis of PTSD were randomly assigned to eight weekly EMDR sessions or the WLC group. The Posttraumatic Stress Symptom Scale for Children (PTSS-C scale) was used in interviews with children to evaluate their symptoms and outcome. Post-treatment scores of the EMDR group were significantly lower than the WLC indicating improvement in total PTSS-C scores, PTSD-related symptom scale, and the subscales re-experiencing and avoidance among subjects in the EMDR group, while untreated children improved in PTSD-non-related symptom scale. The improvement in re-experiencing symptoms proved to be the most significant between-group difference over time. The results of the present exploratory study including a limited number of children with PTSD are encouraging and warrant further controlled studies of larger samples of children suffering from PTSD.

  • 142.
    Ahmad, Abdulbaghi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Sofi, MA
    Department of Psychiatry Erbil University Hospital Erbil, Iraqi Kurdistan, IQ .
    Sundelin Wahlsten, Viveka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    von Knorring, Anne-Liis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Posttraumatic stress disorder in children after the military operation "Anfal" in Iraqi Kurdistan2000In: European Child and Adolescent Psychiatry, ISSN 1018-8827, E-ISSN 1435-165X, Vol. 9, no 4, p. 235-243Article in journal (Refereed)
    Abstract [en]

     Five years after the military operation “Anfal” in Iraqi Kurdistan, 45 families were randomly selected among the survivors in two displacement camps. The Posttraumatic Stress Symptoms for Children (PTSS-C) and the Harvard Trauma Questionnaire (HTQ) were administered to the oldest child and the caregiver in each family, respectively. Posttraumatic stress disorder (PTSD) was reported in 87% of children and 60% of their caregivers. While childhood PTSD was only significantly predicted by child trauma score and the duration of captivity, it was neither predicted by maternal PTSD nor did it disappear after the reunion with the PTSD-free father. However, the small sample size makes the results hypotheses rather than conclusive.

  • 143.
    Ahmad, Abdulbaghi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    von Knorring, Anne-Liis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sundelin Wahlsten, Viveka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Traumatic experiences and post-traumatic stress disorder in Kurdistanian children and their parents in homeland and exile: An epidemiological approach2008In: Nordic Journal of Psychiatry, ISSN 0803-9488, E-ISSN 1502-4725, Vol. 62, no 6, p. 457-463Article in journal (Refereed)
    Abstract [en]

    The prevalence and correlates of post-traumatic stress disorder (PTSD) were assessed in random samples of school-aged Kurdistanian children and their parents in homeland and exile. Of the 376 eligible children at the two sites, 312 children and their parents (293 mothers and 248 fathers) completed the Harvard-Uppsala Trauma Questionnaire and Posttraumatic Stress Symptom interviews for children, and Harvard Trauma Questionnaire for parents. Unlike their children, fathers showed significantly higher PTSD frequencies in exile than in the homeland. The fathers' PTSD negatively correlated with the living standard and fathers' education, while child PTSD mostly correlated with maternal education and living in exile. Living in exile seems to have a negative impact on fathers' post-traumatic reactions, despite its positive influence on children. High drop-outs in exile limit the conclusions.

  • 144.
    Ahmad, Shafqat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Harvard Med Sch, Div Prevent Med, Brigham & Womens Hosp, Boston, MA 02115 USA;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.
    Ahluwalia, Tarunveer S.
    Steno Diabet Ctr Copenhagen, Gentofte, Denmark.
    Editorial: The Role of Genetic and Lifestyle Factors in Metabolic Diseases2019In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 10, article id 475Article in journal (Other academic)
  • 145.
    Ahmad, Shafqat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Harvard Med Sch, Prevent Med Div, Brigham & Womens Hosp, Boston, MA 02115 USA;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.
    Fatima, Syeda Sadia
    Aga Khan Univ, Dept Biol & Biomed Sci, Karachi, Pakistan.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Smith, Caren E.
    Tufts Univ, Res Ctr Aging, Jean Mayer US Dept Agr, Nutr & Genom Lab, Boston, MA 02111 USA.
    Gene Lifestyle Interactions With Relation to Obesity, Cardiometabolic, and Cardiovascular Traits Among South Asians2019In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 10, article id 221Article, review/survey (Refereed)
    Abstract [en]

    The rapid rise of obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) during the last few decades among South Asians has been largely attributed to a major shift in lifestyles including physical inactivity, unhealthy dietary patterns, and an overall pattern of sedentary lifestyle. Genetic predisposition to these cardiometabolic risk factors may have interacted with these obesogenic environments in determining the higher cardiometabolic disease prevalence. Based on the premise that gene-environment interactions cause obesity and cardiometabolic diseases, we systematically searched the literature and considered the knowledge gaps that future studies might ful fill. We identified only seven published studies that focused specifically on gene-environment interactions for cardiometabolic traits in South Asians, most of which were limited by relatively small sample and lack of replication. Some studies reported that the differences in metabolic response to higher physical activity and low caloric diet might be modified by genetic risk related to these cardiometabolic traits. Although studies on gene lifestyle interactions in cardiometabolic traits report significant interactions, future studies must focus on more precise assessment of lifestyle factors, investigation of a larger set of genetic variants and the application of powerful statistical methods to facilitate translatable approaches. Future studies should also be integrated with findings both using mechanistic studies through laboratory settings and randomized clinical trials for clinical outcomes.

  • 146.
    Ahmad, Shafqat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Harvard Med Sch, Brigham & Womens Hosp, Prevent Med Div, Boston, MA 02215 USA;Harvard Med Sch, Brigham & Womens Hosp, Ctr Lipid Metabol, 900 Commonwealth Ave, Boston, MA 02215 USA;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA;Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02215 USA.
    Moorthy, M. Vinayaga
    Harvard Med Sch, Brigham & Womens Hosp, Prevent Med Div, Boston, MA 02215 USA;Harvard Med Sch, Brigham & Womens Hosp, Ctr Lipid Metabol, 900 Commonwealth Ave, Boston, MA 02215 USA.
    Demler, Olga, V
    Harvard Med Sch, Brigham & Womens Hosp, Prevent Med Div, Boston, MA 02215 USA;Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02215 USA.
    Hu, Frank B.
    Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA 02215 USA.
    Ridker, Paul M.
    Harvard Med Sch, Brigham & Womens Hosp, Prevent Med Div, Boston, MA 02215 USA;Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02215 USA.
    Chasman, Daniel, I
    Harvard Med Sch, Brigham & Womens Hosp, Prevent Med Div, Boston, MA 02215 USA.
    Mora, Samia
    Harvard Med Sch, Brigham & Womens Hosp, Prevent Med Div, Boston, MA 02215 USA;Harvard Med Sch, Brigham & Womens Hosp, Ctr Lipid Metabol, 900 Commonwealth Ave, Boston, MA 02215 USA;Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02215 USA.
    Assessment of Risk Factors and Biomarkers Associated With Risk of Cardiovascular Disease Among Women Consuming a Mediterranean Diet2018In: JAMA NETWORK OPEN, ISSN 2574-3805, Vol. 1, no 8, article id e185708Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Higher Mediterranean diet (MED) intake has been associated with lower risk of cardiovascular disease (CVD), but limited data are available about the underlying molecular mechanisms of this inverse disease association in human populations.

    OBJECTIVE To better characterize the relative contribution of traditional and novel factors to the MED-related risk reduction in CVD events in a US population.

    DESIGN, SETTING, AND PARTICIPANTS Using a prospective cohort design, baseline MED intake was assessed in 25 994 initially healthy US women in theWomen's Health Study who were followed up to 12 years. Potential mediating effects of a panel of 40 biomarkers were evaluated, including lipids, lipoproteins, apolipoproteins, inflammation, glucose metabolism and insulin resistance, branched-chain amino acids, small-molecule metabolites, and clinical factors. Baseline study information and samples were collected between April 30, 1993, and January 24, 1996. Analyses were conducted between August 1, 2017, and October 30, 2018.

    EXPOSURES Intake of MED is a 9-category measure of adherence to a Mediterranean dietary pattern. Participants were categorized into 3 levels based on their adherence to the MED.

    MAIN OUTCOMES AND MEASURES Incident CVD confirmed through medical records and the proportion of CVD risk reduction explained by mediators.

    RESULTS Among 25 994women (mean [SD] age, 54.7 [7.1] years), those with low, middle, and upper MED intakes composed 39.0%, 36.2%, and 24.8% of the study population and experienced 428 (4.2%), 356 (3.8%), and 246 (3.8%) incident CVD events, respectively. Compared with the reference group who had low MED intake, CVD risk reductions were observed for the middle and upper groups, with respective HRs of 0.77 (95% CI, 0.67-0.90) and 0.72 (95% CI, 0.61-0.86) (P for trend < .001). The largest mediators of the CVD risk reduction of MED intake were biomarkers of inflammation (accounting for 29.2% of the MED-CVD association), glucose metabolism and insulin resistance (27.9%), and body mass index (27.3%), followed by blood pressure (26.6%), traditional lipids (26.0%), high-density lipoprotein measures (24.0%) or very low-density lipoprotein measures (20.8%), with lesser contributions from low-density lipoproteins (13.0%), branched-chain amino acids (13.6%), apolipoproteins (6.5%), or other small-molecule metabolites (5.8%).

    CONCLUSIONS AND RELEVANCE In this study, higher MED intake was associated with approximately one-fourth relative risk reduction in CVD events, which could be explained in part by known risk factors, both traditional and novel.

  • 147.
    Ahmadi, Z.
    et al.
    Lund Univ, Lund, Sweden..
    Sundh, J.
    Univ Orebro, Orebro, Sweden..
    Bornefalk Hermansson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ekström, M.
    Lund Univ, Lund, Sweden..
    Does Long-Term Oxygen Therapy 24 H/day Improve Survival Compared To 15 H/day In Hypoxemic Chronic Obstructive Pulmonary Disease?2016In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 193Article in journal (Refereed)
  • 148. Ahmadi, Zainab
    et al.
    Bornefalk-Hermansson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Franklin, Karl A.
    Midgren, Bengt
    Ekstrom, Magnus P.
    Hypo- and hypercapnia predict mortality in oxygen-dependent chronic obstructive pulmonary disease: a population-based prospective study2014In: Respiratory research (Online), ISSN 1465-9921, E-ISSN 1465-993X, Vol. 15, p. 30-Article in journal (Refereed)
    Abstract [en]

    Background: The prognostic role of the arterial blood gas tension of carbon dioxide (PaCO2) in severe Chronic Obstructive Pulmonary Disease (COPD) remains unknown. The aim of this study was to estimate the association between PaCO2 and mortality in oxygen-dependent COPD. Methods: National prospective study of patients starting long-term oxygen therapy (LTOT) for COPD in Sweden between October 1, 2005 and June 30, 2009, with all-cause mortality as endpoint. The association between PaCO2 while breathing air, PaCO2 (air), and mortality was estimated using Cox regression adjusted for age, sex, arterial blood gas tension of oxygen (PaO2), World Health Organization performance status, body mass index, comorbidity, and medications. Results: Of 2,249 patients included, 1,129 (50%) died during a median 1.1 years (IQR 0.6-2.0 years) of observation. No patient was lost to follow-up. PaCO2 (air) independently predicted adjusted mortality (p < 0.001). The association with mortality was U-shaped, with the lowest mortality at approximately PaCO2 (air) 6.5 kPa and increased mortality at PaCO2 (air) below 5.0 kPa and above 7.0 kPa. Conclusion: In oxygen-dependent COPD, PaCO2 (air) is an independent prognostic factor with a U-shaped association with mortality.

  • 149.
    Ahmadi, Zainab
    et al.
    Univ Lund Hosp, Div Resp Med & Allergol, Dept Clin Sci, SE-22100 Lund, Sweden..
    Lundstrom, Staffan
    Stockholms Sjukhem Fdn, Palliat Care Serv, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala Univ, Dept Med Sci Resp Med & Allergol, Uppsala, Sweden..
    Strang, Peter
    Stockholms Sjukhem Fdn, Palliat Care Serv, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Emtner, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy.
    Currow, David C.
    Flinders Univ S Australia, Discipline Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Palliat Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Support Serv, Adelaide, SA 5001, Australia..
    Ekström, Magnus
    Univ Lund Hosp, Div Resp Med & Allergol, Dept Clin Sci, SE-22100 Lund, Sweden.;Flinders Univ S Australia, Discipline Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Palliat Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Support Serv, Adelaide, SA 5001, Australia..
    End-of-life care in oxygen-dependent COPD and cancer: a national population-based study2015In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 46, no 4, p. 1190-1193Article in journal (Refereed)
  • 150.
    Ahmadi, Zainab
    et al.
    Lund Univ, Div Resp Med & Allergol, Dept Clin Sci, Lund, Sweden.
    Sundh, Josefin
    Univ Orebro, Sch Med Sci, Dept Resp Med, Orebro, Sweden.
    Bornefalk-Hermansson, Anna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Ekström, Magnus
    Lund Univ, Div Resp Med & Allergol, Dept Clin Sci, Lund, Sweden.
    Long-Term Oxygen Therapy 24 vs 15 h/day and Mortality in Chronic Obstructive Pulmonary Disease2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, article id e0163293Article in journal (Refereed)
    Abstract [en]

    Long-term oxygen therapy (LTOT) >= 15 h/day improves survival in hypoxemic chronic obstructive pulmonary disease ( COPD). LTOT 24 h/day is often recommended but may pose an unnecessary burden with no clear survival benefit compared with LTOT 15 h/day. The aim was to test the hypothesis that LTOT 24 h/day decreases all-cause, respiratory, and cardiovascular mortality compared to LTOT 15 h/day in hypoxemic COPD. This was a prospective, observational, population-based study of COPD patients starting LTOT between October 1, 2005 and June 30, 2009 in Sweden. Overall and cause-specific mortality was analyzed using Cox and Fine-Gray regression, controlling for age, sex, prescribed oxygen dose, PaO2 (air), PaCO2 (air), Forced Expiratory Volume in one second (FEV1), WHO performance status, body mass index, comorbidity, and oral glucocorticoids. A total of 2,249 included patients were included with a median follow-up of 1.1 years (interquartile range, 0.6-2.1). 1,129 (50%) patients died and no patient was lost to follow-up. Higher LTOT duration analyzed as a continuous variable was not associated with any change in mortality rate (hazard ratio [HR] 1.00; (95% confidence interval [CI], 0.98 to 1.02) per 1 h/day increase above 15 h/day. LTOT exactly 24 h/day was prescribed in 539 (24%) patients and LTOT 15-16 h/day in 1,231 (55%) patients. Mortality was similar between the groups for all-cause, respiratory and cardiovascular mortality. In hypoxemic COPD, LTOT 24 h/day was not associated with a survival benefit compared with treatment 15-16 h/day. A design for a registry-based randomized trial (R-RCT) is proposed.

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