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  • Hukic, Dzana Sudic, et al. (författare)
  • Cognitive Manic Symptoms in Bipolar Disorder Associated with Polymorphisms in the DAOA and COMT Genes
  • 2013
  • Ingår i: PLoS ONE. - Public Library of Science. - 1932-6203. ; 8:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Bipolar disorder is characterized by severe mood symptoms including major depressive and manic episodes. During manic episodes, many patients show cognitive dysfunction. Dopamine and glutamate are important for cognitive processing, thus the COMT and DAOA genes that modulate the expression of these neurotransmitters are of interest for studies of cognitive function. Methodology: Focusing on the most severe episode of mania, a factor was found with the combined symptoms of talkativeness, distractibility, and thought disorder, considered a cognitive manic symptoms (CMS) factor. 488 patients were genotyped, out of which 373 (76%) had talkativeness, 269 (55%) distractibility, and 372 (76%) thought disorder. 215 (44%) patients were positive for all three symptoms, thus showing CMS (Table 1). As population controls, 1,044 anonymous blood donors (ABD) were used. Case-case and case-control design models were used to investigate genetic associations between cognitive manic symptoms in bipolar 1 disorder and SNPs in the COMT and DAOA genes. Results: The finding of this study was that cognitive manic symptoms in patients with bipolar 1 disorder was associated with genetic variants in the DAOA and COMT genes. Nominal association for DAOA SNPs and COMT SNPs to cognitive symptoms factor in bipolar 1 disorder was found in both allelic (Table 2) and haplotypic (Table 3) analyses. Genotypic association analyses also supported our findings. However, only one association, when CMS patients were compared to ABD controls, survived correction for multiple testing by max (T) permutation. Data also suggested interaction between SNPs rs2391191 in DAOA and rs5993883 in COMT in the case-control model. Conclusion: Identifying genes associated with cognitive functioning has clinical implications for assessment of prognosis and progression. Our finding are consistent with other studies showing genetic associations between the COMT and DAOA genes and impaired cognition both in psychiatric disorders and in the general population.
  • Backlund, Lena, et al. (författare)
  • Cognitive manic symptoms associated with the P2RX7 gene in bipolar disorder.
  • 2011
  • Ingår i: Bipolar disorders. - 1399-5618. ; 13:5-6, s. 500-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Several genetic loci have been suggested to be associated with bipolar disorder but results have been inconsistent. Studying associations between bipolar symptoms and candidate genes may better expose this relationship. Here we investigate the association between bipolar key symptoms and the P2RX7 gene. Methods: Key symptoms of mania were rated in two sets of medicated bipolar disorder patients (n = 171 and n = 475) at two specialized outpatient clinics for affective disorders and three regular psychiatric outpatient units in Sweden. The relationships between all manic symptoms according to DSM-IV were entered in a principal component analysis. We used a case-case model to reduce the genetic heterogeneity and tested associations between four factors related to manic symptoms and their association to four single nucleotide polymorphisms in the P2RX7 gene. Results: The combination of the cognitive symptoms, distractibility, talkativeness, and thought disorder was significantly associated with rs1718119 in the P2RX7 gene in Set 1 [odds ratio (OR) = 1.78; p = 0.011]. The association was re-tested in the second set (OR = 1.42; p = 0.009). In the total sample, the association was even stronger (OR = 1.49; p < 0.001). None of the other factors was associated with the P2RX7 gene. Within the first factor, the distractibility symptom accounted for a significant portion of the association to rs1718119 (p = 0.016). Conclusion: There is an association between specific symptoms of bipolar disorder and the P2RX7 gene. This finding may open up new approaches to elucidating the neurobiology behind bipolar symptoms.
  • Gothefors, Dan, et al. (författare)
  • Swedish clinical guidelines-Prevention and management of metabolic risk in patients with severe psychiatric disorders
  • 2010
  • Ingår i: Nordic Journal of Psychiatry. - Informa Healthcare. - 1502-4725. ; 64:5, s. 294-302
  • Tidskriftsartikel (refereegranskat)abstract
    • Individuals with severe psychiatric disorders are more likely than the population at large to develop metabolic derangements such as overweight and diabetes. Cardiovascular disease is also more frequently seen in this group. Contributing factors may include inappropriate diet or lack of physical activity, but antipsychotic medication may also play a role. Seven Swedish specialist medical societies have collaborated in formulating a set of concise clinically applicable guidelines-reproduced here in modified form-for the prevention and management of metabolic risk in this patient group. The importance of implementation is emphasized.
  • Owe-Larsson, Björn, et al. (författare)
  • Increased plasma levels of thioredoxin-1 in patients with first episode psychosis and long-term schizophrenia.
  • 2011
  • Ingår i: Progress in neuro-psychopharmacology & biological psychiatry. - 1878-4216. ; 35:4, s. 1117-21
  • Tidskriftsartikel (refereegranskat)abstract
    • Excessive level of radicals and/or dysfunctional antioxidant response, oxidative stress, is implicated in the pathogenesis of schizophrenia. A condition of oxidative stress has been detected in the brain, peripheral tissues and fluids including plasma. Plasma thioredoxin-1 (Trx1) is well characterized and a putative marker for oxidative stress and recently shown to be increased in plasma at the onset of schizophrenia. The present study aimed to explore whether Trx1 can be used as a marker to identify schizophrenic patients at the time-point when patients have their first episode of psychosis as compared to patients with long-term schizophrenia and mentally healthy patients, respectively. Plasma samples obtained from 18 patients at first episode of psychosis, from 49 long-term schizophrenic patients and from 20 mentally healthy controls (admitted with minor physical injury to the general ward) where analyzed by ELISA for Trx1. The patients with first episode of psychosis were diagnosed at least 6months later and shown to constitute various psychotic syndromes, including schizophrenia, or affective disorder. The concentration of Trx1 in the patients with first episode of psychosis was 1.5±1.0ng/ml and 0.8±0.6ng/ml in controls. In the long-term schizophrenic patients the plasma concentration was 1.5±0.7. The differences between the groups of acute psychotic or long-term schizophrenia patients to controls were significant (p<0.016 and p<0.001, respectively). Our data indicate that Trx1 may not be used as an early marker to identify schizophrenic patients in a mixed population of first episode psychotic patients. Further, Trx1 did not discriminate with reliable accuracy patients with psychotic disorder from mentally healthy controls on an individual basis due to overlap in levels of Trx1. However, our observations show that psychotic patients in general are in a significant long-term condition of oxidative stress, with possible implications for the profound morbidity and mortality found in this patient population.
  • Westman, Jeanette, et al. (författare)
  • Cardiovascular mortality in bipolar disorder: a population-based cohort study in Sweden
  • 2013
  • Ingår i: BMJ Open. - British Medical Journal Publishing Group. - 2044-6055. ; 3:4, s. 002373-002373
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To estimate the cardiovascular mortality among persons with bipolar disorder in Sweden compared to the general population. Design Population register-based cohort study with a 20-year follow-up. Setting Sweden. Participants The entire population of Sweden (n=10.6 million) of whom 17101 persons were diagnosed with bipolar disorder between 1987 and 2006. Main outcome measures Mortality rate ratios (MRR), excess mortality (excess deaths), cardiovascular disorder (CVD) and specifically cerebrovascular disease, coronary heart disease, acute myocardial infarction, sudden cardiac deaths and hospital admission rate ratio (ARR). Results Persons with bipolar disorder died of CVD approximately 10years earlier than the general population. One third (38%) of all deaths in persons with bipolar disorder were caused by CVD and almost half (44%) by other somatic diseases, whereas suicide and other external causes accounted for less than a fifth of all deaths (18%). Excess mortality of both CVD (n=824) and other somatic diseases (n=988) was higher than that of suicide and other external causes (n=675 deaths). MRRs for cerebrovascular disease, coronary heart disease and acute myocardial infarction were twice as high in persons with bipolar disorder compared to the general population. Despite the increased mortality of CVD, hospital admissions (ARR) for CVD treatment were only slightly increased in persons with bipolar disorder when compared to the general population. Conclusions The increased cardiovascular mortality in persons with bipolar disorder calls for renewed efforts to prevent and treat somatic diseases in this group. Specifically, our findings further imply that it would be critical to ensure that persons with bipolar disorder receive the same quality care for CVD as persons without bipolar disorder.
  • Amare, Azmeraw T, et al. (författare)
  • Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study.
  • 2018
  • Ingår i: JAMA psychiatry. - 2168-6238. ; 75:1, s. 65-74
  • Tidskriftsartikel (refereegranskat)abstract
    • Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.
  • Backlund, Lena, et al. (författare)
  • P2RX7: Expression Responds to Sleep Deprivation and Associates with Rapid Cycling in Bipolar Disorder Type 1
  • 2012
  • Ingår i: Plos One. - 1932-6203. ; 7:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Context: Rapid cycling is a severe form of bipolar disorder with an increased rate of episodes that is particularly treatment-responsive to chronotherapy and stable sleep-wake cycles. We hypothesized that the P2RX7 gene would be affected by sleep deprivation and be implicated in rapid cycling. Objectives: To assess whether P2RX7 expression is affected by total sleep deprivation and if variation in P2RX7 is associated with rapid cycling in bipolar patients. Design: Gene expression analysis in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and case-case and case-control SNP/haplotype association analyses in patients. Participants: Healthy volunteers at the sleep research center, University of California, Irvine Medical Center (UCIMC), USA (n = 8) and Swedish outpatients recruited from specialized psychiatric clinics for bipolar disorder, diagnosed with bipolar disorder type 1 (n = 569; rapid cycling: n = 121) and anonymous blood donor controls (n = 1,044). Results: P2RX7 RNA levels were significantly increased during sleep deprivation in PBMCs from healthy volunteers (p = 2.3*10(-9)). The P2RX7 rs2230912_A allele was more common (OR = 2.2, p = 0.002) and the ACGTTT haplotype in P2RX7 (rs1718119 to rs1621388) containing the protective rs2230912_G allele (OR = 0.45-0.49, p = 0.003-0.005) was less common, among rapid cycling cases compared to non-rapid cycling bipolar patients and blood donor controls. Conclusions: Sleep deprivation increased P2RX7 expression in healthy persons and the putatively low-activity P2RX7 rs2230912 allele A variant was associated with rapid cycling in bipolar disorder. This supports earlier findings of P2RX7 associations to affective disorder and is in agreement with that particularly rapid cycling patients have a more vulnerable diurnal system.
  • Boden, Robert, et al. (författare)
  • A comparison of cardiovascular risk factors for ten antipsychotic drugs in clinical practice
  • 2013
  • Ingår i: Neuropsychiatric Disease and Treatment. - 1176-6328 .- 1178-2021. ; 9, s. 371-377
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>It is well known that abdominal obesity, dyslipidemia, and insulin resistance are highly prevalent in patients receiving maintenance treatment with antipsychotics, but there is limited knowledge about the association between cardiovascular risk factors and treatment with antipsychotic drugs. In this naturalistic study we investigated a sample of 809 antipsychotic-treated patients from Swedish psychosis outpatient teams. Cardiovascular risk factors (eg, metabolic syndrome, homeostasis model assessment of insulin resistance, and low-density lipoprotein values) were measured, and their associations to current antipsychotic pharmacotherapy were studied. Ten antipsychotic drugs were compared in a stepwise logistic regression model. For the patients, the presence of the components of metabolic syndrome ranged from 35% for hyperglycemia to 64% for elevated waist circumference. Hypertriglyceridemia was associated with clozapine (odds ratio [OR] = 1.81, 95% confidence interval [CI] 1.08-3.04), reduced high-density lipoprotein with both clozapine and olanzapine (OR = 1.73, 95% CI 1.01-2.97; and OR = 2.03, 95% CI 1.32-3.13), hypertension with perphenazine (OR = 2.00, 95% CI 1.21-3.59), and hyperglycemia inversely with ziprasidone (OR = 0.21, 95% CI 0.05-0.89) and positively with haloperidol (OR = 2.02, 95% CI 1.18-3.48). There were no significant relationships between any of the antipsychotic drugs and increased waist circumference, homeostasis model assessment of insulin resistance, or low-density lipoprotein levels. In conclusion, treatment with antipsychotic drugs is differentially associated with cardiovascular risk factors, even after adjusting for waist circumference, sex, age, and smoking.</p>
  • Carlsson, Axel C., et al. (författare)
  • High prevalence of diagnosis of diabetes, depression, anxiety, hypertension, asthma and COPD in the total population of Stockholm, Sweden a challenge for public health
  • 2013
  • Ingår i: BMC Public Health. - 1471-2458 .- 1471-2458. ; 13, s. 670
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Background: There is limited knowledge on the prevalence of disease in total populations. Such studies have historically been difficult to conduct but the development of health data registers has facilitated large-scale studies on recorded diagnoses in entire regions. The aim of this study was to analyze the prevalence of diagnosis of six common diseases in the Swedish capital region. Methods: The study population included all living persons who resided in Stockholm County, Sweden, on December 31st 2011 (N = 2 093 717). Information on all consultations between 2007 and 2011 was obtained from primary health care, specialist outpatient care and inpatient care. Prevalence was defined as the proportion of individuals with a recorded diagnosis of diabetes, depression, anxiety disorders, hypertension, asthma and chronic obstructive pulmonary disease during the five year period, respectively. Analyses were done by age and gender. Results: Hypertension had the highest five-year prevalence (12.2%), followed by depression (6.6%), diabetes mellitus (6.2%), asthma (5.9%), anxiety disorders/phobia (4.8%), and COPD (1.8%). Diabetes was more common in men (5.3% of women and 7.1% of men) while depression (8.7% in women and 4.4% in men) and anxiety (6.3% in women and 3.4% in men) were considerably more common in women. Smaller gender differences were also found for hypertension (13.0% in women and 11.4% in men), asthma (6.4% in women and 5.4% in men) and COPD (2.1% in women and 1.6% in men). Diabetes, hypertension and COPD increased markedly with age, whereas anxiety, depression and asthma were fairly constant in individuals above 18 years. During one year of observation, more than half of all patients had only been diagnosed in primary health care, with hypertension being the diagnosis with the largest proportion of patients only identified in primary health care (70.6%). Conclusion: The prevalence of common diseases in the population can be estimated by combining data gathered during consecutive years from primary care, specialist outpatient care and inpatient care. However, accuracy of disease prevalence is highly dependent on the quality of the data. The high prevalence of the six diagnoses analysed in this study calls for preventive action to minimize suffering and costs to society.</p>
  • Clapham, Eric, et al. (författare)
  • Suicide Ideation and Behavior as Risk Factors for Subsequent Suicide in Schizophrenia : A Nested Case-Control Study
  • 2019
  • Ingår i: Journal of Suicide and Life-threatening Behaviour. - WILEY. - 0363-0234 .- 1943-278X. ; 49:4, s. 996-1005
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Objective To investigate suicide ideation and behavior as risk factors for suicide in schizophrenia during varying time periods. Method Cases were 84 patients who died by suicide within 5 years from diagnosis in a source population of patients discharged for the first time from psychiatric hospitals in Stockholm County, Sweden, with a schizophrenia spectrum diagnosis. One control was individually matched with each suicide case. Data were retrieved from clinical records in a blind fashion. Thoughts of death, thoughts of suicide, suicide plan, and suicide attempt during varying time periods were investigated as risk factors for subsequent completed suicide. Results In adjusted analyses, thoughts of suicide, suicide plan, and suicide attempt were significantly associated with subsequent completed suicide in the following year. The highest suicide risk was found within a year following suicide attempt (adjusted OR 9.9, 95% confidence interval 2.5-39.0). The association between suicide ideation and behavior and subsequent suicide declined over time. Conclusions Several types of suicide ideation and behavior were associated with suicide, and the association was stronger for suicidal behavior. The clinical significance of suicidal communication appears highest during the following month or/and year. Many suicides occurred without recorded short-term suicidal communication.</p>
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