| 11. |
- Bothou, Christina, et al.
(author)
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Current Management and Outcome of Pregnancies in Women With Adrenal Insufficiency : Experience from a Multicenter Survey
- 2020
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In: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 105:8
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Journal article (peer-reviewed)abstract
- Context: Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment.Objective: Multicenter survey on current clinical approaches in managing AI during pregnancy.Design: Retrospective anonymized data collection from 19 international centers from 2013 to 2019.Setting and patients: 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%).Results: Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes.Conclusions: This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.
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| 12. |
- Bäcklund, Nils, et al.
(author)
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Reference intervals of salivary cortisol and cortisone and their diagnostic accuracy in Cushing's syndrome
- 2020
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In: European Journal of Endocrinology. - : Bioscientifica. - 0804-4643 .- 1479-683X. ; 182:6, s. 569-582
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Journal article (peer-reviewed)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. © 2020 European Society of Endocrinology Printed in Great Britain.
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| 13. |
- Bäcklund, Nils, et al.
(author)
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Reference intervals of salivary cortisol and cortisone and their diagnostic accuracy in Cushing’s syndrome
- 2020
-
In: European Journal of Endocrinology. - : Bioscientifica. - 0804-4643 .- 1479-683X. ; 182:6, s. 569-582
-
Journal article (peer-reviewed)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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| 14. |
- Bäcklund, Nils, et al.
(author)
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Salivary cortisol and cortisone in diagnosis of Cushing's syndrome - a comparison of six different analytical methods
- 2023
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In: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter. - 1434-6621 .- 1437-4331. ; 61:10, s. 1780-1791
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Journal article (peer-reviewed)abstract
- Objectives: Salivary cortisol and cortisone at late night and after dexamethasone suppression test (DST) are increasingly used for screening of Cushing's syndrome (CS). We aimed to establish reference intervals for salivary cortisol and cortisone with three liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques and for salivary cortisol with three immunoassays (IAs), and evaluate their diagnostic accuracy for CS.Methods: Salivary samples at 08:00 h, 23:00 h and 08:00 h after a 1-mg DST were collected from a reference population (n=155) and patients with CS (n=22). Sample aliquots were analyzed by three LC-MS/MS and three IA methods. After establishing reference intervals, the upper reference limit (URL) for each method was used to calculate sensitivity and specificity for CS. Diagnostic accuracy was evaluated by comparing ROC curves.Results: URLs for salivary cortisol at 23:00 h were similar for the LC-MS/MS methods (3.4-3.9 nmol/L), but varied between IAs: Roche (5.8 nmol/L), Salimetrics (4.3 nmol/L), Cisbio (21.6 nmol/L). Corresponding URLs after DST were 0.7-1.0, and 2.4, 4.0 and 5.4 nmol/L, respectively. Salivary cortisone URLs were 13.5-16.6 nmol/L at 23:00 h and 3.0-3.5 nmol/L at 08:00 h after DST. All methods had ROC AUCs =0.96.Conclusions: We present robust reference intervals for salivary cortisol and cortisone at 08:00 h, 23:00 h and 08:00 h after DST for several clinically used methods. The similarities between LC-MS/MS methods allows for direct comparison of absolute values. Diagnostic accuracy for CS was high for all salivary cortisol and cortisone LC-MS/MS methods and salivary cortisol IAs evaluated.
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| 15. |
- Casas, Rosaura, et al.
(author)
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Glutamic Acid Decarboxylase Injection Into Lymph Nodes: Beta Cell Function and Immune Responses in Recent Onset Type 1 Diabetes Patients
- 2020
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In: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 11
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Journal article (peer-reviewed)abstract
- In spite of intensive treatment Type 1 diabetes leads to serious complications. Preservation of residual beta cell function makes the disease milder, facilitates treatment, prevents complications and increase survival. So far immune interventions have had limited effect, and some serious adverse events and risks. In an open pilot trial we aimed to improve efficacy of GAD-alum treatment using lymph-node administration in combination with oral vitamin D. Here we report the clinical effect and focus on biomarkers for response to treatment. Patients (n = 12) aged 12 to 24 years with recent onset of Type 1 diabetes received 4 μg GAD-alum into lymph-node at day 30, 60, and 90, and oral Vitamin D 2000 U/d, days 1 to 120. Beta cell function was estimated by Mixed Meal Tolerance Tests. GADA, GADA subclasses, GAD65-induced cytokines and proliferation, and T cells markers were analyzed. The treatment was tolerable with no adverse events. Fasting C-peptide and insulin requirement remained stable at 15 months, while HbA1c was lower than baseline. Stimulated C-peptide showed no change at 6 months but declined after 15 months (81% of baseline). Eleven patients remained in partial remission (IDAAC < 9). Patients (n = 9) with better clinical outcome had reduced proportion of IgG1 and increased IgG2, IgG3, and IgG4, increased IL-10 secretion, and reduction of proliferation and CD8+ T cells activation. Patients with poorer clinical response had higher baseline levels of GAD65-induced cytokines and T-cell activation, and an increased ratio of effector/central memory T cells. Intra-lymphatic GAD treatment combined with Vitamin D might preserve beta cell function and improve clinical course in T1D. Patients with less benefit have a different quality of immune response both before and after treatment.
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| 16. |
- Casas, Rosaura, 1954-, et al.
(author)
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Intra-lymphatic administration of GAD-alum in type 1 diabetes : long-term follow-up and effect of a late booster dose (the DIAGNODE Extension trial)
- 2022
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In: Acta Diabetologica. - : Springer. - 0940-5429 .- 1432-5233. ; 59:5, s. 687-696
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Journal article (peer-reviewed)abstract
- Aim: To evaluate the long-term effect of intra-lymphatic administration of GAD-alum and a booster dose 2.5 years after the first intervention (DIAGNODE Extension study) in patients with recent-onset type 1 diabetes.Methods: DIAGNODE-1: Samples were collected from 12 patients after 30 months who had received 3 injections of 4 μg GAD-alum into a lymph node with one-month interval. DIAGNODE Extension study: First in human, a fourth booster dose of autoantigen (GAD-alum) was given to 3 patients at 31.5 months, who were followed for another 12 months. C-peptide was measured during mixed meal tolerance tests (MMTTs). GADA, IA-2A, GADA subclasses, GAD65-induced cytokines, PBMCs proliferation and T cells markers were analyzed.Results: After 30-month treatment, efficacy was still seen in 8/12 patients (good responders, GR). Partial remission (IDAA1c < 9) had decreased compared to 15 months, but did not differ from baseline, and HbA1c remained stable. GAD65-specific immune responses induced by the treatment started to wane after 30 months, and most changes observed at 15 months were undetectable. GADA subclasses IgG2, IgG3 and IgG4 were predominant in the GR along with IgG1. A fourth intra-lymphatic GAD-alum dose to three patients after 31.5 months gave no adverse events. In all three patients, C-peptide seemed to increase the first 6 months, and thereafter, C-peptide, HbA1c, insulin requirement and IDAA1c remained stable.Conclusion: The effect of intra-lymphatic injections of GAD-alum had decreased after 30 months. Good responders showed a specific immune response. Administration of a fourth booster dose after 31.5 months was safe, and there was no decline in C-peptide observed during the 12-month follow-up.
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| 17. |
- Consiglio, Camila, et al.
(author)
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Immune system adaptation during gender-affirming testosterone treatment
- 2023
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In: Journal of Reproductive Immunology. - : Elsevier. - 0165-0378 .- 1872-7603. ; 159, s. 29-30
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Journal article (other academic/artistic)abstract
- Biological sex impacts human immune responses, modulating susceptibility and severity to immune-related diseases. Female generally mount more robust immune responses than males, resulting in lower infection severity and greater autoimmunity incidence. Here, we addressed the contribution of testosterone to human immune function by analyzing a cohort of subjects undergoing gender-affirming testosterone treatment. We performed systems-level immunomonitoring through mass cytometry, scRNA and scA-TAC-Sequencing, and proteome profiling of blood samples at baseline and following 3 and 12 months of treatment. Testosterone treatment was associated with a low-grade inflammatory profile, evidenced by upregulation of proinflammatory plasma proteome (e.g., EN-RAGE, OSM, TNF), and induction of an inflammatory transcriptional program associated with NFkB signaling, and TNF signaling. Following testosterone treatment, higher NFkB activity was revealed in CD4 T, CD8 T, and NK cells in scATACseq analyses. Further, testosterone increased monocytic inflammatory responses upon bacterial stimulation in vitro. Although testosterone was associated with this inflammatory profile, it also exerted negative effects on antiviral immunity. Firstly, the percentage of plasmacytoid dendritic cells (pDC) decreased over transition, with pDC also displaying phenotypic changes associated with lower IFN responses. Secondly, bulk transcriptomics analyses show an overall reduction of IFNa responses. Thirdly, testosterone treatment led to reduced IFNa production upon PBMCs stimulation with a viral agonist. Our results show that testosterone has broad effects on the human immune system, and significantly modulates important players in antiviral immunity and inflammatory response. Identifying pathways involved in immune sexual dimorphism will help define novel targets for effective prevention and treatment of immune-mediated diseases.
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| 18. |
- Dietrich, Fabricia, et al.
(author)
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Immune response differs between intralymphatic or subcutaneous administration of GAD-alum in individuals with recent onset Type 1 diabetes
- 2022
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In: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 38:3
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Journal article (peer-reviewed)abstract
- Aims: Immunomodulation with autoantigens potentially constitutes a specific and safe treatment for Type 1 diabetes (T1D). Studies with GAD-alum administrated subcutaneously have shown to be safe, but its efficacy has been inconclusive. Administration of GAD-alum into the lymph nodes, aimed to optimize antigen presentation, has shown promising results in an open-label clinical trial. Here we compared the immune response of the individuals included in the trial with a group who received GAD-alum subcutaneously in a previous study.Materials and methods: Samples from T1D individuals collected 15 months after administration of either three doses 1 month apart of 4 μg GAD-alum into lymph nodes (LN, n=12) or two doses one month apart of 20 μg subcutaneously (SC, n=12) were studied. GADA, GADA subclasses, GAD65 -induced cytokines, PBMCs proliferation and T cells markers were analyzed.Results: Low doses of GAD-alum into the lymph nodes induced higher GADA levels than higher doses administrated subcutaneously. Immune response in the LN group was characterized by changes in GADA subclasses, with a relative reduction of IgG1 and enhanced IgG2, IgG3 and IgG4 proportion, higher GAD65 -induced secretion of IL-5, IL-10 and TNF-α and reduction of cell proliferation and CD8+ T cells. These changes were not observed after subcutaneous injections of GAD-alum.Conclusions: GAD-specific immune responses 15 months after lymph node injections of GAD-alum differed from the ones induced by subcutaneous administration of the same autoantigen.
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| 19. |
- Eriksson, Daniel, et al.
(author)
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GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility
- 2021
-
In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10-8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2).
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| 20. |
- Ernersson, Åsa, et al.
(author)
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Reduced Health Related Quality of Life, Increased Fatigue and Daytime Sleepiness in Women with Hyperprolactinemia
- 2023
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In: Hormone and Metabolic Research. - : Thieme Medical Publishers. - 0018-5043 .- 1439-4286. ; 55:4, s. 266-272
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Journal article (peer-reviewed)abstract
- Prolactin has many physiological effects and seems to be involved in the human quality of life and well-being. The aim of this study was to describe health related quality of life, fatigue and daytime sleepiness in women with untreated hyperprolactinemia. In total 32 women (mean age 37.0 ± 10.9) with verified hyperprolactinemia completed a questionnaire including questions on fatigue, measured with the Swedish version of the Fatigue Impact Scale (FIS), propensity to fall in sleep, measured with the Swedish version of the Epworth Sleepiness Scale (ESS), and Health related quality of life (HRQoL), measured by the Short-Form-36 scale (SF-36). For comparison Swedish normative data were used. The women were also interviewed regarding different symptoms related to hyperprolactinemia and the answers were analyzed using qualitative content analysis. HRQoL, as measured with SF-36, was significantly lower in all dimensions, except in physical function, compared to the Swedish reference population. Total FIS was 54.3 (41.1) and mean score on the ESS was 8.7 (4.2) indicating increased fatigue and deterioration in night sleep. The women felt very tired, and several of them rarely felt rested in the morning. The restless night sleep and the fatigue during the daytime got them to feel feeble and sometimes to find it difficult to concentrate, which affected both their mood and life in general. Women diagnosed with hyperprolactinemia reported deterioration in night sleep, increased rate of fatigue, and a reduced health related quality of life in comparison with the reference population.
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