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1.
  • Dalin, Frida, et al. (författare)
  • Clinical and immunological characteristics of autoimmune addison disease : A nationwide swedish multicenter study
  • 2017
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - Oxford University Press. - 0021-972X. ; 102:2, s. 379-389
  • Tidskriftsartikel (refereegranskat)abstract
    • Context: Studies of the clinical and immunological features of autoimmune Addison disease (AAD) are needed to understand the disease burden and increased mortality. Objective: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles, and cardiovascular risk factors. Design, Setting, and Participants: A cross-sectional, population-based study that included 660 AAD patients from the Swedish Addison Registry (2008-2014). When analyzing the cardiovascular risk factors, 3594 individuals from the population-based survey in Northern Sweden, MONICA (monitoring of trends and determinants of cardiovascular disease), served as controls. Main Outcome Measures: The endpoints were the prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined. Results: The proportion of 21-hydroxylase autoantibody-positive patients was 83%, and 62% of patients had ≥1 associated autoimmune diseases, more frequently coexisting in females (P < 0.0001). AAD patients had a lower body mass index (P < 0.0001) and prevalence of hypertension (P = 0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of the patients, with a mean dose of 28.1 ± 8.5 mg/d. The mean hydrocortisone equivalent dose normalized to the body surface was 14.8±4.4 mg/m2/d. A greater hydrocortisone equivalent dose was associated with a greater incidence of hypertension (P = 0.046). Conclusions: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients did not have an increased prevalence of overweight, hypertension, type 2 diabetes mellitus, or hyperlipidemia. However, high glucocorticoid replacement doses could be a risk factor for hypertension.
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2.
  • Eriksson, Daniel, et al. (författare)
  • Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden.
  • 2018
  • Ingår i: Scientific reports. - 2045-2322. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.
  •  
3.
  • Eriksson, Daniel, et al. (författare)
  • Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1
  • 2018
  • Ingår i: The Journal of clinical endocrinology and metabolism. - Oxford University Press. - 1945-7197. ; 103:1, s. 179-186
  • Tidskriftsartikel (refereegranskat)abstract
    • Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.
4.
  • Eriksson, D, et al. (författare)
  • Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
  • 2016
  • Ingår i: Journal of Internal Medicine. - 0954-6820 .- 1365-2796. ; 286:6, s. 595-608
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>BACKGROUND:</strong> Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology.</p><p><strong>METHODS:</strong> To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls.</p><p><strong>RESULTS:</strong> We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10(-15) , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex.</p><p><strong>CONCLUSION:</strong> Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.</p>
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5.
  • Bäcklund, Nils, et al. (författare)
  • Reference intervals of salivary cortisol and cortisone and their diagnostic accuracy in Cushing's syndrome
  • 2020
  • Ingår i: European journal of endocrinology. - Society of the European Journal of Endocrinology. - 1479-683X. ; 182:6, s. 569-582
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The challenge of diagnosing Cushing's syndrome (CS) calls for high precision biochemical screening. This study aimed to establish robust reference intervals for, and compare the diagnostic accuracy of, salivary cortisol and cortisone in late-night samples and after a low-dose (1 mg) dexamethasone suppression test (DST). Design and methods: Saliva samples were collected at 08:00 and 23:00 h, and at 08:00 h, after a DST, from 22 patients with CS and from 155 adult reference subjects. We also collected samples at 20:00 and 22:00 h from 78 of the reference subjects. Salivary cortisol and cortisone were analysed with liquid chromatography-tandem mass spectrometry. The reference intervals were calculated as the 2.5th and 97.5th percentiles of the reference population measurements. Diagnostic accuracies of different tests were compared, based on areas under the receiver-operating characteristic curves. Results: The upper reference limits of salivary cortisol and cortisone at 23:00 h were 3.6 nmol/L and 13.5 nmol/L, respectively. Using these reference limits, CS was detected with a sensitivity (95% CI) of 90% (70-99%) and specificity of 96% (91-98%) for cortisol, and a 100% (84-100%) sensitivity and 95% (90-98%) specificity for cortisone. After DST, cortisol and cortisone upper reference limits were 0.79 nmol/L and 3.5 nmol/L, respectively. CS was detected with 95% (75-100%) sensitivity and 96% (92-99%) specificity with cortisol, and 100% (83-100%) sensitivity and 94% (89-97%) specificity with cortisone. No differences in salivary cortisol or cortisone levels were found between samples collected at 22:00 and 23:00 h. Conclusion: Salivary cortisol and cortisone in late-night samples and after DST showed high accuracy for diagnosing CS, salivary cortisone being slightly, but significantly better.
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6.
  • Dahlqvist, Julia R., et al. (författare)
  • MRI in Neuromuscular Diseases: An Emerging Diagnostic Tool and Biomarker for Prognosis and Efficacy
  • 2020
  • Ingår i: Annals of Neurology. - WILEY. - 0364-5134 .- 1531-8249.
  • Forskningsöversikt (refereegranskat)abstract
    • <p>There is an unmet need to identify biomarkers sensitive to change in rare, slowly progressive neuromuscular diseases. Quantitative magnetic resonance imaging (MRI) of muscle may offer this opportunity, as it is noninvasive and can be carried out almost independent of patient cooperation and disease severity. Muscle fat content correlates with muscle function in neuromuscular diseases, and changes in fat content precede changes in function, which suggests that muscle MRI is a strong biomarker candidate to predict prognosis and treatment efficacy. In this paper, we review the evidence suggesting that muscle MRI may be an important biomarker for diagnosis and to monitor change in disease severity. ANN NEUROL 2020</p>
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7.
  • Dahlqvist, Martin, et al. (författare)
  • Complex magnetism in nanolaminated Mn<sub>2</sub>GaC
  • 2014
  • Annan publikation (övrigt vetenskapligt)abstract
    • <p>We have used first-principles calculations and Heisenberg Monte Carlo simulations to search for the magnetic ground state of Mn<sub>2</sub>GaC, a recently synthesized magnetic nanolaminate. We have, independent on method, identified a range of low energy collinear as well as non-collinear magnetic configurations, indicating a highly frustrated magnetic material with several nearly degenerate magnetic states. An experimentally obtained magnetization of only 0.29 per Mn atom in Mn<sub>2</sub>GaC may be explained by canted spins in an antiferromagnetic configuration of ferromagnetically ordered sub-layers with alternating spin orientation, denoted AFM[0001]<img src="http://www.diva-portal.org/cgi-bin/mimetex.cgi?%5Csmal%5Ctext%7BA%7D%5Catop%5Ctext%7B4%7D" />. Furthermore, low temperature X-ray diffraction show a new basal plane peak appearing upon a magnetic transition, which is consistent with the here predicted change in inter-layer spacing for the AFM[0001]<img src="http://www.diva-portal.org/cgi-bin/mimetex.cgi?%5Csmal%5Ctext%7BA%7D%5Catop%5Ctext%7B4%7D" /> configuration.</p>
  •  
8.
  • Dalin, Frida, et al. (författare)
  • Clinical and immunological characteristics of Autoimmune Addison's disease : a nationwide Swedish multicenter study
  • 2017
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - 0021-972X .- 1945-7197. ; 102:2, s. 379-389
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>CONTEXT:</strong> Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.</p><p><strong>OBJECTIVE:</strong> To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.</p><p><strong>DESIGN, SETTING AND PARTICIPANTS:</strong> Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.</p><p><strong>MAIN OUTCOME MEASURE:</strong> Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.</p><p><strong>RESULTS:</strong> Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p&lt;0.0001). AAD patients had lower BMI (p&lt;0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).</p><p><strong>CONCLUSIONS:</strong> Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.</p>
  •  
9.
  • Dalin, Frida, et al. (författare)
  • Clinical and immunological characteristics of Autoimmune Addison's disease : a nationwide Swedish multicenter study.
  • 2017
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - Oxford University Press. - 0021-972X .- 1945-7197. ; 102:2, s. 379-389
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>CONTEXT:</strong> Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.</p><p><strong>OBJECTIVE:</strong> To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.</p><p><strong>DESIGN, SETTING AND PARTICIPANTS:</strong> Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.</p><p><strong>MAIN OUTCOME MEASURE:</strong> Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.</p><p><strong>RESULTS:</strong> Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p&lt;0.0001). AAD patients had lower BMI (p&lt;0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).</p><p><strong>CONCLUSIONS:</strong> Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.</p>
  •  
10.
  • Eriksson, Daniel, et al. (författare)
  • Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addisons disease in Sweden
  • 2018
  • Ingår i: Scientific Reports. - NATURE PUBLISHING GROUP. - 2045-2322 .- 2045-2322. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Autoimmune Addisons disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.</p>
  •  
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