| 1. |
- Bjorvatn Saevik, Åse, et al.
(författare)
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Potential Transcriptional Biomarkers to Guide Glucocorticoid Replacement in Autoimmune Addison's Disease
- 2021
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Ingår i: Journal of the Endocrine Society. - : Endocrine Society. - 2472-1972. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundNo reliable biomarkers exist to guide glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD), leading to overtreatment with alarming and persistent side effects or undertreatment, which could be fatal.ObjectiveTo explore changes in gene expression following different GC replacement doses as a means of identifying candidate transcriptional biomarkers to guide GC replacement in AAD.MethodsStep 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. In 3 of the most highly upregulated genes, we performed real-time PCR (rt-PCR) to compare gene expression levels before and 3, 4, and 6 hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD.ResultsStep 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and levels of ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression.ConclusionsWe introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.
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| 2. |
- Björnsdottir, Sigridur
(författare)
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Addison's disease : epidemiological and clinical studies
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Addison’s disease (AD) is a potentially life-threatening condition that often presents with vague and nonspecific symptoms. Patients with AD have increased mortality risk. Data on parity and pregnancy outcome in women with AD are limited. Furthermore, there are no data on fracture risk or drug prescription patterns in patients with AD. Continuous subcutaneous hydrocortisone infusion (CSHI) is a novel treatment modality, but it has not yet been established whether the circadian hormone profiles and insulin sensitivity differ in patients on CSHI compared with conventional oral hydrocortisone treatment (OHC). The four studies in this thesis aim to enhance knowledge and clinical management of patients with AD. Parity and pregnancy outcome: In all, 1188 women with AD were retrospectively evaluated. Women with AD had a reduced overall parity compared with controls (P < 0.001). Adjusted odds ratios (ORs) (95% confidence interval, CI) for infants born to mothers with deliveries ≤ 3 years before diagnosis of AD were 2.40 (1.27-4.53) for preterm birth, 3.50 (1.83-6.67) for low birth weight and 1.74 (1.02-2.96) for caesarean section. In comparison with controls, women who gave birth after their AD diagnosis were at increased risk for both caesarean delivery (adjusted OR, 2.35, 95% CI; 1.68-3.27) and preterm delivery (adjusted OR, 2.61, 95% CI; 1.69-4.05). No differences were found in risks of congenital malformations or infant death. Hip fracture risk: Totally, 3219 patients with AD were retrospectively evaluated. Patients with AD had a higher risk of hip fracture (hazard ratio, HR 1.8, 95% CI; 1.6-2.1; p < 0.001) than matched controls. The increased risk was independent of age at diagnosis, sex and calendar period. A positive association between hip fracture and undiagnosed AD was noted with the highest risk estimates during the last year before AD diagnosis (OR 2.8, 95% CI; 1.8-4.2). Drug prescription patterns:We identified 1305 patients with both a diagnosis of AD and on combination treatment with hydrocortisone/cortisone acetate and fludrocortisone. The yearly prevalence of AD increased from 12.2 to 13.1 (Pfor trend = .062); incidence varied between 0.5 and 0.6 (Pfor trend = .131) per 100 000 person-years during the period 2005-2009. Patients with AD received more prescribed drugs than controls. Both before and after AD diagnosis, patients used more gastrointestinal medications, antianemic preparations, lipid-modifying agents, antibiotics for systemic use, hypnotics and sedatives and drugs for obstructive airway disease (pvalues < 0.05). Notably, an increased prescription of several antihypertensive drugs and highceiling diuretics was observed after AD diagnosis. Circadian hormone profiles and insulin sensitivity:CSHI provided a more physiological circadian cortisol curve, including a late night cortisol surge, than OHC treatment. CSHI yielded a normalization of adrenocorticotropic hormone (ACTH) levels and showed a more normal circadian variation than OHC. CSHI prevented a continuous decrease in glucose during the night. No difference in insulin sensitivity was observed between the two treatment arms. The expected growth hormone (GH) peak during nighttime was more pronounced for CSHI, which, together with the higher insulin-like growth factor type 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) levels, suggest a more anabolic status. Conclusion: This thesis demonstrates that both undiagnosed and diagnosed AD entail increased risks of unfavorable pregnancy outcome, hip fractures and altered drug prescription patterns compared to controls. In addition, parity is reduced in patients diagnosed with AD. This raises concerns about the conventional replacement therapy. CSHI is a safe and reliable mode of glucocorticoid replacement and might become a treatment option in selected patients.
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| 3. |
- Björnsdottir, Sigridur, et al.
(författare)
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Addison's Disease in Women Is a Risk Factor for an Adverse Pregnancy Outcome
- 2010
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 95:12, s. 5249-5257
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Tidskriftsartikel (refereegranskat)abstract
- Context: Autoimmune Addison's disease(AAD) tends to affect young and middle-aged women. It is not known whether the existence of undiagnosed or diagnosed AAD influences the outcome of pregnancy. Objective: The aim of the study was to compare the number of children and pregnancy outcomes in individuals with AAD and controls. Design and Setting: We conducted a population-based historical cohort study in Sweden. Patients: Through the Swedish National Patient Register and the Total Population Register, we identified 1,188 women with AAD and 11,879 age-matched controls who delivered infants between 1973 and 2006. Main Outcome Measures: We measured parity and pregnancy outcome. Results: Adjusted odds ratios (ORs) for infants born to mothers with deliveries 3 yr or less before the diagnosis of AAD were 2.40 [95% confidence interval (Cl), 1.27-4.53] for preterm birth (<= 37 wk), 3.50 (95% Cl, 1.83-6.67) for low birth weight (<2500 g), and 1.74 (95% Cl, 1.02-2.96) for cesarean section. Compared to controls, women who gave birth after their AAD diagnosis were at increased risk of both cesarean delivery (adjusted OR, 2.35; 95% Cl, 1.68-3.27) and preterm delivery (adjusted OR, 2.61; 95% Cl, 1.69-4.05). Stratifying by isolated AAD and concomitant type 1 diabetes and/or autoimmune thyroid disease in the mother did not essentially influence these risks. There were no differences in risks of congenital malformations or infant death. Women with AAD had a reduced overall parity compared to controls (P < 0.001). Conclusion: Clinically undiagnosed and diagnosed AAD both entail increased risks of unfavorable pregnancy outcomes. AAD also influences the number of childbirths.
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| 4. |
- Björnsdottir, Sigridur, et al.
(författare)
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Risk of Hip Fracture in Addison's Disease : A Population-based Cohort Study
- 2011
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 270:2, s. 187-195
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The results of studies of bone mineral density (BMD) in Addison's disease (AD) are inconsistent. There are no published data on hip fracture risk in patients with AD. In this study we compare hip fracture risk in adults with and without AD. Design: A population-based cohort study. Methods: Through the Swedish National Patient Register and the Total Population Register, we identified 3,219 patients without prior hip fracture who were diagnosed with AD at the age of ≥30 years during the period 1964-2006, and 31,557 age- and sex-matched controls. Time to hip fracture was measured. Results: We observed 221 hip fractures (6.9%) in patients with AD and 846 (2.7%) in the controls. Patients with AD had a higher risk of hip fracture (hazard ratio (HR) = 1.8; 95% confidence interval (CI), 1.6-2.1; p < 0.001). This risk increase was independent of sex and age at or calendar period of diagnosis. Risk estimates did not change with adjustment for type 1 diabetes, autoimmune thyroid disease, rheumatoid arthritis or coeliac disease. Women diagnosed with AD ≤50 years old had the highest risk of hip fracture (HR = 2.7; 95% CI, 1.6-4.5). We found a positive association between hip fracture and undiagnosed AD (odds ratio (OR) = 2.4; 95% CI, 2.1- 3.0) with the highest risk estimates in the last year before AD diagnosis (OR = 2.8; 95% CI, 1.8-4.2). Conclusion: Both clinically undiagnosed and diagnosed AD were associated with hip fractures, with the highest relative risk seen in women diagnosed with AD ≤50 years of age.
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| 5. |
- Björnsdóttir, Sigridur, et al.
(författare)
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The effect of the ‘Gait keeper’ mutation in the DMRT3 gene on gaiting ability in Icelandic horses
- 2014
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Ingår i: Journal of Animal Breeding and Genetics. - : Wiley. - 0931-2668 .- 1439-0388. ; 131, s. 415-425
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Tidskriftsartikel (refereegranskat)abstract
- A nonsense mutation in DMRT3 (‘Gait keeper' mutation) has a predominant effect on gaiting ability in horses, being permissive for the ability to perform lateral gaits and having a favourable effect on speed capacity in trot. The DMRT3 mutant allele (A) has been found in high frequency in gaited breeds and breeds bred for harness racing, while other horse breeds were homozygous for the wild-type allele (C). The aim of this study was to evaluate further the effect of the DMRT3 nonsense mutation on the gait quality and speed capacity in the multigaited Icelandic horse and demonstrate how the frequencies of the A- and C- alleles have changed in the Icelandic horse population in recent decades. It was confirmed that homozygosity for the DMRT3 nonsense mutation relates to the ability to pace. It further had a favourable effect on scores in breeding field tests for the lateral gait t€olt, demonstrated by better beat quality, speed capacity and suppleness. Horses with the CA genotype had on the other hand significantly higher scores for walk, trot, canter and gallop, and they performed better beat and suspension in trot and gallop. These results indicate that the AA genotype reinforces the coordination of ipsilateral legs, with the subsequent negative effect on the synchronized movement of diagonal legs compared with the CA genotype. The frequency of the A-allele has increased in recent decades with a corresponding decrease in the frequency of the C-allele. The estimated frequency of the A-allele in the Icelandic horse population in 2012 was 0.94. Selective breeding for lateral gaits in the Icelandic horse population has apparently altered the frequency of DMRT3 genotypes with a predicted loss of the C-allele in relatively few years. The results have practical implications for breeding and training of Icelandic horses and other gaited horse breeds.
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| 6. |
- Dalin, Frida, 1984-, et al.
(författare)
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Clinical and immunological characteristics of Autoimmune Addison's disease : a nationwide Swedish multicenter study
- 2017
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 102:2, s. 379-389
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's 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: 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.MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.RESULTS: 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<0.0001). AAD patients had lower BMI (p<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).CONCLUSIONS: 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.
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| 7. |
- Ley, Charles, et al.
(författare)
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Detection of early osteoarthritis in the centrodistal joints of Icelandic horses: Evaluation of radiography and low-field magnetic resonance imaging
- 2016
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Ingår i: Equine Veterinary Journal. - : Wiley. - 0425-1644 .- 2042-3306. ; 48, s. 57-64
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Tidskriftsartikel (refereegranskat)abstract
- Reasons for performing studyValidated noninvasive detection methods for early osteoarthritis (OA) are required for OA prevention and early intervention treatment strategies.ObjectivesTo evaluate radiography and low-field magnetic resonance imaging (MRI) for the detection of early stage OA osteochondral lesions in equine centrodistal joints using microscopy as the reference standard.Study designProspective imaging of live horses and imaging and microscopy of cadaver tarsal joints.MethodsCentrodistal (distal intertarsal) joints of 38 Icelandic research horses aged 27-29 months were radiographed. Horses were subjected to euthanasia approximately 2 months later and cadaver joints examined with low-field MRI. Osteochondral joint specimens were classified as negative or positive for OA using light microscopy histology or scanning electron microscopy. Radiographs and MRIs were evaluated for osteochondral lesions and results compared with microscopy.ResultsForty-two joints were classified OA positive with microscopy. Associations were detected between microscopic OA and the radiography lesion categories; mineralisation front defect (P<0.0001), joint margin lesion (P<0.0001), central osteophyte (P = 0.03) and the low-field MRI lesion categories; mineralisation front defect (P = 0.01), joint margin lesion (P = 0.02) and articular cartilage lesion (P = 0.0003). The most frequent lesion category detected in microscopic OA positive joints was the mineralisation front defect in radiographs (28/42 OA positive joints, specificity 97%, sensitivity 67%). No significant differences were detected between the sensitivity and specificity of radiography and low-field MRI pooled lesion categories, but radiography was often superior when individual lesion categories were compared.ConclusionsEarly stage centrodistal joint OA changes may be detected with radiography and low-field MRI. Detection of mineralisation front defects in radiographs may be a useful screening method for detection of early OA in centrodistal joints of young Icelandic horses.
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| 8. |
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| 9. |
- Ley, Charles, et al.
(författare)
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Evaluation of osteochondral sample collection guided by computed tomography and magnetic resonance imaging for early detection of osteoarthritis in centrodistal joints of young icelandic horses
- 2013
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Ingår i: Veterinary Radiology and Ultrasound. - 1058-8183 .- 1740-8261. ; 55, s. 1-
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Histologic examination with light microscopy is considered the reference standard to detect osteoarthritis (OA) in its earliest stages1, 2. In early OA, articular cartilage changes develop in focal and specific regions of the affected joint3 but the locations of these regions in specific joints and species are uncertain and are likely to vary among individuals. When osteochondral samples are collected from predetermined anatomic sites for histologic examination of joints early in the disease process, then it is possible that OA will fail to be detected because the associated lesions may not be included in the collection site. This study evaluates a method for computed tomography (CT) and magnetic resonance imaging (MRI) guided osteochondral sample collection for the detection of early stage OA lesions in joints from young Icelandic horses. Materials and Methods: CT and MRI were semiquanitatively graded to evaluate the extent of suspected OA changes in right centrodistal joints from the cadavers of 24 Icelandic horses aged 29 to 31 months. The anatomic regions with the highest grade of change were identified, and osteochondral samples were obtained from these regions. Samples were also obtained from the same centrodistal joints at predetermined sites. Histologic examination of all samples was performed, with samples classified as negative or positive for OA, and results were compared between sample collection method. Results: Histologic examination revealed OA lesions in 29% (7/24) of centrodistal joints with predetermined method and in 62% (15/24) with the image-guided method. Significant associations were detected between histologic OA and the summed image-guided sample collection site image grades, central osteophytes, articular cartilage thickness abnormalities, grade-2 articular mineralisation front defects, and grade-2 marginal osteophytes. Discussion/Conclusion:An image-guided sample collection method is recommended when histologic examination will be used as the reference standard for the detection of early-stage OA in centrodistal joints of horses. CT and MRI aided the detection of focal changes suggestive of early stage OA in the centrodistal joints of equine cadavers and may be useful for detection of similar disease in live horses. The first morphological changes of centrodistal joint OA are suspected to be in the articular cartilage and the articular mineralisation front regions.
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| 10. |
- Ley, Charles, et al.
(författare)
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High-resolution microscopy of osteochondral lesions in the distal tarsal joints of young icelandic horses
- 2013
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Ingår i: Veterinary Radiology and Ultrasound. - 1058-8183 .- 1740-8261. ; 55, s. 1-
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Distal tarsal joint osteoarthritis (OA) is a common cause of lameness in adult Icelandic horses1 and high-detail radiography and microscopic OA changes are reported in young Icelandic horses suggesting the disease starts when the horses are young and develops slowly2. Thus young Icelandic horses are potentially an excellent natural model for the early stages of osteoarthritis. This study describes and characterises novel mineralised and non-mineralised osteochondral lesion types in left distal tarsal region joint samples from twenty-two 29 to 31 month-old Icelandic horses. Materials and Methods: Combinations of confocal scanning light microscopy, backscattered electron scanning electron microscopy (including novel iodine staining methods) and three-dimensional microcomputed tomography were used on samples obtained with guidance from clinical computed tomography and magnetic resonance imaging equipment. Osteochondral lesion types were described and the frequency of lesion types calculated. Associations and correlations between osteochondral lesion types were investigated for centrodistal joints. Results: Lesion types were identified in hyaline articular cartilage (HAC), articular calcified cartilage (ACC), subchondral bone (SCB) and the joint margin tissues. The highest lesion frequency was in the centrodistal joint where several lesion types including HAC chondrocyte necrosis, HAC fibrillation, HAC central chondrocyte clusters, ACC arrest and ACC advancement had moderate to high frequency, significant associations and strong correlations. Joint margin lesions had high frequency in centrodistal and tarsometatarsal joints but no significant associations with other lesion types. The frequency of SCB lesions in all joints was low. Hypermineralised protrusions and cracks of the ACC were detected. Discussion/Conclusions: Our results provide detailed morphological information about how tissues respond during the early stages of OA and that these changes occur in HAC and ACC, rather than in the SCB. We speculate that chondrocyte death and chondrocyte hyperplasia in the HAC result in the ACC arrest and ACC advancement respectively. Thinning or loss of the ACC resulting from ACC arrest may have a key role in the development and perpetuation of OA since this likely results in areas in the ACC that allow increased transfer of substances between the SCB and the intra-articular compartments. Young Icelandic horses offer a promising model for the study of ACC behaviour in early OA, a morphological region that we believe is crucial in the early stages of OA development.
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