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Sökning: WFRF:(Juréus Anders)

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  • Musliner, Katherine L., et al. (författare)
  • Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia With Risk for Depression in the Danish Population
  • 2019
  • Ingår i: JAMA psychiatry. - Chicago : American Medical Association. - 2168-6238. ; 76:5, s. 516-525
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored.OBJECTIVE: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis.DESIGN SETTING AND PARTICIPANTS: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018.EXPOSURES: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium.MAIN OUTCOMES AND MEASURES: The main outcome was first depressive episode (international Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency).RESULTS: Of 34 573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (beta =-.07; SE =.02; P =.002).CONCLUSIONS AND RELEVANCE: Polygenic ability for MD is associated with first depress on in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.
  • Stahl, Eli A, et al. (författare)
  • Genome-wide association study identifies 30 loci associated with bipolar disorder
  • 2019
  • Ingår i: Nature Genetics. - 1061-4036. ; 51:5, s. 793-803
  • Tidskriftsartikel (refereegranskat)abstract
    • Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
  • Forsberg, Anton, et al. (författare)
  • Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients
  • 2013
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - Springer-Verlag New York. - 1619-7070. ; 40:4, s. 580-593
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD).METHODS: In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [(11)C]AZD2995 and [(11)C]AZD2184 in three healthy control subjects and seven AD patients.RESULTS: AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [(3)H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [(11)C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [(11)C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus.CONCLUSION: Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [(11)C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [(11)C]AZD2995. However, the very low nonspecific binding of [(11)C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.
  • Juréus, Anders, et al. (författare)
  • Characterization of AZD4694, a novel fluorinated Abeta plaque neuroimaging PET radioligand
  • 2010
  • Ingår i: Journal of neurochemistry. - 1471-4159. ; 114:3, s. 784-794
  • Tidskriftsartikel (refereegranskat)abstract
    • Positron emission tomography (PET) radioligands that bind selectively to β-amyloid plaques (Aβ) are promising imaging tools aimed at supporting the diagnosis of Alzheimer’s disease and the evaluation of new drugs aiming to modify amyloid plaque load. For extended clinical use, there is a particular need for PET tracers labeled with fluorine-18, a radionuclide with 110 min half-life allowing for central synthesis followed by wide distribution. The development of fluorinated radioligands is, however, challenging because of the lipophilic nature of aromatic fluorine, rendering fluorinated ligands more prone to have high non-specific white matter binding. We have here developed the new benzofuran-derived radioligand containing fluorine, AZD4694 that shows high affinity for β-amyloid fibrils in vitro (Kd = 2.3 ± 0.3 nM). In cortical sections from human Alzheimer’s disease brain [3H]AZD4694 selectively labeled β-amyloid deposits in gray matter, whereas there was a lower level of non-displaceable binding in plaque devoid white matter. Administration of unlabeled AZD4694 to rat showed that it has a pharmacokinetic profile consistent with good PET radioligands, i.e., it quickly entered and rapidly cleared from normal rat brain tissue. Ex vivo binding data in aged Tg2576 mice after intravenous administration of [3H]AZD4694 showed selective binding to β-amyloid deposits in a reversible manner. In Tg2576 mice, plaque bound [3H]AZD4694 could still be detected 80 min after i.v. administration. Taken together, the preclinical profile of AZD4694 suggests that fluorine-18 labeled AZD4694 may have potential for PET-visualization of cerebral β-amyloid deposits in the living human brain.
  • Thornton, Laura M, et al. (författare)
  • The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods.
  • 2018
  • Ingår i: Contemporary clinical trials. - 1559-2030. ; 74, s. 61-69
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research.ANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H.Blood samples and clinical information were collected from 13,363 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable.Our multi-pronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection. ANGI is a registered clinical trial: clinicaltrials.govNCT01916538; https://clinicaltrials.gov/ct2/show/NCT01916538?cond=Anorexia+Nervosa&draw=1&rank=3.
  • Wanngren, Johanna, et al. (författare)
  • Second generation γ-secretase modulators exhibit different modulation of Notch β and Aβ production.
  • 2012
  • Ingår i: The Journal of biological chemistry. - 1083-351X. ; 287:39, s. 32640-50
  • Tidskriftsartikel (refereegranskat)abstract
    • The γ-secretase complex is an appealing drug target when the therapeutic strategy is to alter amyloid-β peptide (Aβ) aggregation in Alzheimer disease. γ-Secretase is directly involved in Aβ formation and determines the pathogenic potential of Aβ by generating the aggregation-prone Aβ42 peptide. Because γ-secretase mediates cleavage of many substrates involved in cell signaling, such as the Notch receptor, it is crucial to sustain these pathways while altering the Aβ secretion. A way of avoiding interference with the physiological function of γ-secretase is to use γ-secretase modulators (GSMs) instead of inhibitors of the enzyme. GSMs modify the Aβ formation from producing the amyloid-prone Aβ42 variant to shorter and less amyloidogenic Aβ species. The modes of action of GSMs are not fully understood, and even though the pharmacology of GSMs has been thoroughly studied regarding Aβ generation, knowledge is lacking about their effects on other substrates, such as Notch. Here, using immunoprecipitation followed by MALDI-TOF MS analysis, we found that two novel, second generation GSMs modulate both Notch β and Aβ production. Moreover, by correlating S3-specific Val-1744 cleavage of Notch intracellular domain (Notch intracellular domain) to total Notch intracellular domain levels using immunocytochemistry, we also demonstrated that Notch intracellular domain is not modulated by the compounds. Interestingly, two well characterized, nonsteroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drug), R-flurbiprofen and sulindac sulfide, affect only Aβ and not Notch β formation, indicating that second generation GSMs and nonsteroidal anti-inflammatory drug-based GSMs have different modes of action regarding Notch processing.
  • Borgegård, Tomas, et al. (författare)
  • Alzheimers Disease: : Presenilin 2-Sparing gamma-Secretase Inhibition Is a Tolerable A beta Peptide-Lowering Strategy
  • 2012
  • Ingår i: Journal of Neuroscience. - Society for Neuroscience. - 0270-6474. ; 32:48, s. 17297-17305
  • Tidskriftsartikel (refereegranskat)abstract
    • gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in Alzheimers disease (AD). Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A beta production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1(PS1) over PS2 subclass of gamma-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain A beta levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious gamma-secretase targeting strategy for AD.
  • Charney, Alexander W, et al. (författare)
  • Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases.
  • 2018
  • Ingår i: Biological psychiatry. - 1873-2402.
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood.Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis.CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden.CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
  • Juréus, Anders, 1970- (författare)
  • Galanin :  Studies by Modification of the Ligand and the Receptor
  • 1998
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • This thesis is devoted to the deeper understanding of the molecular details of the interaction between the neuropeptide galanin and its target protein, the G-protein coupled 7TM galanin receptor. The enzymatic control of galanin degradation and second messenger systems triggered by galanin receptor activation are also studied.Galanin analogs with substitutions of amino acids by units of L-Ala residues have been developed as selective ligands to galanin receptor subtypes in the rat hypothalamus and in the rat jejunum. It is shown that galanin receptors in the jejunum require also the C-terminal segment KHGLT25-29for receptor recognition in contrast to receptors in the hypothalamus which only interact with the N-terminal portion (1-13) of galanin.It is confirmed that the N-terminal portion (1-13) of galanin is essential for receptor recognition in the rat hypothalamus and that the C-terminus of the ligand can be extended with sequences of amino acids or other organic structures to increase the affinity of the N-terminal (1-13) fragment of galanin. It is also concluded that a minimum motif required for galanin receptor recognition should contain the indol structure of a Trp residue and the aromatic side chain of a Tyr residue plus one additional bulky highly hydrophobic structure as well as some positively charged structures.The galanin binding domains of the receptor, GalR1 have been studied by site directed mutagenesis and a structural model for the interaction of the major pharmacophores of galanin is proposed. The charged N-terminus of galanin is suggested to interact with Phe115 in TM III by cation-p interaction, the Trp2 residue of galanin is proposed to interact with a pair of His residues located at the top of TM VI and the Tyr9 of galanin is interacting with another phenylalanine, Phe282 in the EC III of the receptor. One of the two histidine residues (264,267); His267is believed not only to be important for ligand binding but also is stabilising the active conformation of the GalR1 receptor, important for the G-protein coupling of the agonist occupied receptor.It is shown that galanin binding sites are present at significantly higher numbers in the ventral part of the rat hippocampus compared to the dorsal area. Furthermore it is determined that the efficiency of the inhibitory coupling to basal and forskolin stimulated cAMP production by galanin receptors is 250 fold less potent in the dorsal region of the rat hippocampus. The differences in regulation of adenylate cyclase suggests an unequal receptor subtype distribution in the dorsal and ventral hippocampus with higher levels of Gicoupled GalR1 receptors in the ventral segments of the hippocampal formation.An internally quenched fluorescent substrate for galanin degrading enzymes has been developed and used for purification of a galanin inactivating 70 kDa membrane associated metallo-endopeptidase from bovine spinal cord. The enzyme that has a inhibitor profile different from NEP-24.11 primarily cleaves galanin between Trp2 and Thr3 and recognises both galanin and the galanin mimicking fluorescent artificial substrate with high affinity. This cleavage generates products that are inactive at both GalR1 and GalR2 receptors.
  • Juréus, Jan, et al. (författare)
  • The natural course of spontaneous osteonecrosis of the knee (SPONK) A 1-to 27-year follow-up of 40 patients
  • 2013
  • Ingår i: Acta Orthopaedica. - Taylor & Francis. - 1745-3682. ; 84:4, s. 410-414
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose Spontaneous osteonecrosis of the knee (SPONK) is a painful lesion in the elderly, frequently leading to osteoarthritis and subsequent knee surgery. We evaluated the natural course and long-term consequences of SPONK in terms of need for major knee surgery. Methods Between 1982 and 1988, 40 consecutive patients were diagnosed with SPONK. The short-term outcome has been reported previously (1991). After 1-7 years, 10 patients had a good radiographic outcome and 30 were considered failures, developing osteoarthritis. In 2012, all 40 of the patients were matched with the Swedish Knee Arthroplasty Register (SKAR) and their medical records were reviewed to evaluate the long-term need for major knee surgery. Results At the 2012 review, 33 of the 40 patients had died. The mean follow-up time from diagnosis to surgery, death, or end of study was 9 (1-27) years. 17 of 40 patients had had major knee surgery with either arthroplasty (15) or osteotomy (2). All operated patients but 1 were in the radiographic failure group and had developed osteoarthritis in the study from 1991. 6 of 7 patients with large lesions (> 40% of the AP radiographic view of the condyle) at the time of the diagnosis were operated. None of the 10 patients with a lesion of less than 20% were ever operated. Interpretation It appears that the size of the osteonecrotic lesion can be used to predict the outcome. Patients showing early signs of osteoarthritis or with a large osteonecrosis have a high risk of later major knee surgery.
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