| 1. |
- Saevik, Ase Bjorvatn, et al.
(författare)
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Altered biomarkers for cardiovascular disease and inflammation in autoimmune Addison's disease - a cross-sectional study
- 2023
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Ingår i: European Journal of Endocrinology. - : Bioscientifica. - 0804-4643 .- 1479-683X. ; 189:4, s. 438-447
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Increased prevalence of cardiovascular disease has been reported in autoimmune Addisons disease (AAD), but pathomechanisms are poorly understood.Design: Cross-sectional study.Methods: We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 mu g tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH.Results: Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = -0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (-0.15 normalized protein expression [NPX], P = .0001, and -0.25 NPX, P = .0003, respectively).Conclusions: We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small.
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| 2. |
- Wahlberg, Jeanette, 1969-, et al.
(författare)
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Altered Chemokine Th1/Th2 Balance in Addison's Disease: Relationship with Hydrocortisone Dosing and Quality of Life
- 2014
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 46:1, s. 48-53
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Tidskriftsartikel (refereegranskat)abstract
- The adrenalitis found in autoimmune Addison’s disease (AAD) is considered having a Th1-driven pathogenesis. Circulating Th1- and Th2-associated chemokines responsible for the trafficking of leukocytes to inflammatory sites are markers for the Th1/Th2 balance. The aim of the study was to assess if the same daily hydrocortisone dose of 30 mg given in either 2 or 4 doses to patients with AAD could affect the Th1/Th2 balance of circulating chemokines.Fifteen patients (6 women) with AAD were included in this randomised, placebo controlled, double blind cross-over study. Samples for chemokines, Th1-associated (CXCL10, CXCL11) and Th2-associated (CCL17, CCL22), were drawn 5 times during a 24-h period at the end of each treatment period and analysed with Luminex. Seven control subjects did the same diurnal blood sampling once. Subjects with AAD had higher median diurnal levels of the Th1-associated chemokines than controls, CXCL10 [43 (33–56) pg/ml vs. 22 (19–34) pg/ml, p<0.01] and CXCL11 [37 (29–48) pg/ml vs. 16 (9–24) pg/ml, p<0.001], whereas no significant difference was found regarding the Th2-related chemokines. Similar chemokine levels were found when the same hydrocortisone dose of 30 mg was divided in 2 or 4 doses. Levels of CXCL11 correlated negatively with scores of SF-36 domains (high score indicate better health) of General Health (GH) and total score for Physical Component Summary (PCS), and these negative correlations were most pronounced at 04:00 h on the 2-dose regimen. Patients with AAD have a dominant Th1 chemokine profile that partially correlates to reduced quality of life.
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| 3. |
- Axfors, Cathrine, et al.
(författare)
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Preferences for Gender Affirming Treatment and Associated Factors Among Transgender People in Sweden
- 2023
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Ingår i: Sexuality Research & Social Policy. - : Springer Nature. - 1868-9884 .- 1553-6610. ; 20:2, s. 479-490
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionGender affirming surgery of primary and/or secondary sex characteristics has been shown to alleviate gender dysphoria. A descriptive snapshot of current treatment preferences is useful to understand the needs of the transgender population seeking health care. This study aimed to describe preferences for gender affirming treatment, and their correlates, among individuals seeking health care for gender dysphoria in Sweden after major national legislative reforms.MethodsCross-sectional study where transgender patients (n = 232) recruited from all six Gender Dysphoria centers in Sweden 2016–2019, answered a survey on treatment preferences and sociodemographic, health, and gender identity-related information during the same time-period. Factors associated with preferring top surgery (breast augmentation or mastectomy), genital surgery, and other surgery (e.g., facial surgery) were examined in univariable and multivariable regression analyses in the 197 people without prior such treatment. Main study outcomes were preferences for feminizing or masculinizing hormonal and surgical gender affirming treatment.ResultsThe proportion among birth assigned male and assigned female patients preferring top surgery was 55.6% and 88.7%, genital surgery 88.9% and 65.7%, and other surgery (e.g., facial surgery) 85.6% and 22.5%, respectively. Almost all participants (99.1%) wanted or had already received hormonal treatment and most (96.7%) wished for some kind of surgical treatment; 55.0% wanted both top and genital surgery. Preferring a binary pronoun (he/she) and factors indicating more severe gender incongruence were associated with a greater wish for surgical treatment. Participants with somatic comorbidities were less likely to want genital surgery, while aF with lacking social support were less likely to want internal genital surgery, in the multivariable analyses.ConclusionsIn this sample of Swedish young adults seeking health care for gender dysphoria, preferences for treatment options varied according to perceived gender identity.Policy ImplicationsThe study fndings underline the need for individualized care and fexible gender afrming treatmentoptions. The role of somatic comorbidities should be further explored, and support should be ofered to transgender peoplein need. There is an unmet need for facial surgery among aM
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| 4. |
- Baldimtsi, Evangelia, 1981-, et al.
(författare)
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Systemic biomarkers of microvascular alterations in type 1 diabetes associated neuropathy and nephropathy : A prospective long-term follow-up study
- 2023
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Ingår i: Journal of diabetes and its complications. - : Elsevier. - 1056-8727 .- 1873-460X. ; 37:12
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: This study aimed to investigate circulating biomarkers associated with the risk of developing diabetic peripheral neuropathy (DPN) and nephropathy in type 1 diabetes (T1D).MATERIALS AND METHODS: Patients with childhood-onset T1D (n = 49, age 38.3 ± 3.8 yrs.) followed prospectively were evaluated after 30 years of diabetes duration. DPN was defined as an abnormality in nerve conduction tests. Matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor TIMP-1, neutrophil gelatinase-associated lipocalin-2 (NGAL), soluble P-selectin (sP-selectin), estimated GFR (eGFR), micro/macroalbuminuria and routine biochemistry were assessed. For comparison, control subjects were included (n = 30, age 37.9 ± 5.5 yrs.).RESULTS: In all, twenty-five patients (51 %) were diagnosed with DPN, and nine patients (18 %) had nephropathy (five microalbuminuria and four macroalbuminuria). Patients with DPN had higher levels of TIMP-1 (p = 0.036) and sP-selectin (p = 0.005) than controls. Patients with DPN also displayed higher levels of TIMP-1 compared to patients without DPN (p = 0.035). Patients with macroalbuminuria had kidney disease stage 3 with lower eGFR, higher levels of TIMP-1 (p = 0.038), and NGAL (p = 0.002). In all patients, we found only weak negative correlations between eGFR and TIMP-1 (rho = -0.304, p = 0.040) and NGAL (rho = -0.277, p = 0.062, ns), respectively. MMP-9 was higher in patients with microalbuminuria (p = 0.021) compared with normoalbuminuric patients.CONCLUSIONS: Our findings indicate that TIMP-1 and MMP-9, as well as sP-selectin and NGAL, are involved in microvascular complications in T1D. Monitoring and targeting these biomarkers may be a potential strategy for treating diabetic nephropathy and neuropathy.
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| 5. |
- Baldimtsi, Evangelia, et al.
(författare)
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The role of chemokines in type 1 diabetes-associated neuropathy
- 2023
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Ingår i: Endocrinology, diabetes & metabolism. - : John Wiley & Sons. - 2398-9238. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: To investigate whether circulating chemokines contribute to the development of diabetic peripheral neuropathy (DPN) in patients with type 1 diabetes (T1D).METHODS: Fifty-two patients with childhood-onset T1D (mean age 28 ± 4 yrs.; diabetes duration 19.5 ± 5.5 yrs.) and 19 control subjects (mean age 26.5 ± 4.5 yrs.) were included in a cross-sectional analysis of this long-term longitudinal cohort study. A subgroup of 24 patients was followed prospectively for a further 10 yrs. Plasma levels of Th1- (CXCL9, CXCL10 and CXCL11), Th2- (CCL17 and CCL22) and Th17-associated (CXCL8 and CCL20) chemokines were assessed in all subjects. Additionally, the TID patients underwent clinical examination and electroneurography.RESULTS: The frequency of neuropathy was 21% (11/52). Higher levels of CXCL9 levels were found in patients with DPN compared with control subjects (p = .019); by contrast, no difference between patients without DPN and control subjects was seen after adjustment for multiple comparisons. In patients with DPN, CXCL10 correlated negatively with suralis MCV and suralis SNAP (rho -0.966, p < .001 and rho -0.738, p < .001, respectively) and was positively correlated with the vibration perception threshold (rho 0.639, p = .034), while CXCL8 correlated negatively with the cold perception threshold (rho -0.645, p = .032). The frequency of neuropathy increased to 54% (13/24) in the subgroup of 23 TID patients, followed by an additional 10 yrs.CONCLUSIONS: Changes in Th1- and Th17-associated chemokines were associated with impaired peripheral sensory nerve function and nerve conduction after long disease duration in childhood-onset T1D.
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| 6. |
- Barcenilla, Hugo, et al.
(författare)
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Intralymphatic GAD-alum Injection Modulates B Cell Response and Induces Follicular Helper T Cells and PD-1+ CD8+ T Cells in Patients With Recent-Onset Type 1 Diabetes
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naïve and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD65 only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes.
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| 7. |
- Bélteky, Malin, et al.
(författare)
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Maternal respiratory infections in early pregnancy increases the risk of type 1 diabetes
- 2020
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Ingår i: Pediatric Diabetes. - : Hindawi Publishing Corporation. - 1399-543X .- 1399-5448. ; 21:7, s. 1193-1201
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Tidskriftsartikel (refereegranskat)abstract
- Background/objective: Is exposure to maternal infections and use of antibiotics in the prenatal period associated with increased risk of T1D, regardless of genetic risk?Methods: Data on infections and use of antibiotics during pregnancy were collected from questionnaires at birth from parents to 16 292 children in the All Babies in Southeast Sweden (ABIS) cohort and validated against national diagnosis registers. As of November 2017, 137 ABIS children had developed T1D, 72 boys and 65 girls (0.8% of the original cohort).Results: More cases were born in spring and summer than fall and winter. However, onset of T1D appeared to be more common in either summer or winter. In univariate analyses, respiratory tract infection in the first trimester (P = .002) and gastroenteritis during pregnancy (P = .04) were associated with later risk of T1D in the offspring. Other types of infection or antibiotic treatment were not associated with an increased risk. In a multiple logistic regression model, a mother with an autoimmune disease (P < .001), father with T1D (P < .001) and respiratory tract infection during the first trimester (P = .005) remained as risk factors for T1D in the offspring. In children with neutral HLA alleles antibiotic treatment may increase the risk of T1D (P = .01, OR 3.46, 95% CI 1.25-9.55).Conclusions: In the general population there seems to be an association between seasonal maternal respiratory tract infection in the first trimester of pregnancy and later risk of T1D in the offspring. HLA may play a role for the effect of exposure to infections and antibiotics.
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| 8. |
- Bengtsson, Daniel, 1975-
(författare)
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Cushing’s disease and aggressive pituitary tumours : Aspects on epidemiology, treatment, and long-term follow-up
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on clinical and epidemiological aspects of aggressive pituitary tumours/carcinomas and Cushing’s disease. Pituitary carcinomas account for only 0.1-0.2% of the tumours originating from the anterior pituitary gland and are defined solely by the event of distant metastases, whereas aggressive pituitary tumours are defined by their clinical behaviour of rapid/progressive growth despite optimal treatment with surgery, radiotherapy and medical agents. The prognosis for individuals with aggressive tumours/carcinomas has been poor with few treatment options. However, case reports indicated better outcomes after treatment with the alkylating agent temozolomide. In study I and III, we investigated 24 patients (16 aggressive tumours and 8 carcinomas) given treatment with temozolomide. We found an initial response rate (tumour regression ≥30%) in 10/21 evaluable patients, with complete regression in two carcinomas. Favourable response was associated with low tumour expression of the DNA repair protein MGMT; in responders median 9% (range 5-20%) vs non-responders median 93% (50-100%). Our results also indicated a longer survival in patients with low MGMT. Out of 11 patients with MGMT >10%, nine died with an estimated median survival of 26 months (95% CI 14-38), whereas only 1/6 patients with lower MGMT died from tumour progression during a follow-up of median 83 months (range 12-161).One of the patients in study I and III had a corticotroph pituitary carcinoma and in addition, Lynch syndrome (LS), a hereditary cancer-predisposing syndrome caused by germline mutations in DNA mismatch repair (MMR) genes and primarily associated with colon and endometrial carcinomas. In study II, we investigated the characteristics of the pituitary carcinoma and found loss of MSH2 and MSH6 protein expression, consistent with the patient’s germline mutation in MSH2. This was the first published case of a pituitary tumour associated with LS. In addition, we identified all known Swedish patients with LS (n=910) and searched for diagnostic codes consistent with a pituitary tumour in the Swedish national patient register. We found in total three patients with clinically relevant pituitary tumours, the reported prevalence in the background population is around 1:1000.The last two studies in the thesis focused on Cushing’s disease (CD), i.e. an ACTH-secreting pituitary tumour resulting in excess levels of cortisol. CD is associated with multiple comorbidities and increased mortality. The reversibility of comorbidities and mortality risk after remission of cortisol levels have been under debate. Study IV examined psychiatric consequences of CD, measured by the use of psychotropic drugs. 179 patients with CD and a quadrupled matched control group were followed from diagnosis and at 5- and 10-year follow-up. We found that use of antidepressants remained at around 25% of patients with CD, regardless of remission status, at diagnosis and follow-up, whereas drugs for somatic comorbidities decreased. Use of antidepressants, sleeping pills and anxiolytics was higher in patients with CD compared to controls at diagnosis and 5-year follow-up. A cross-sectional analysis of 76 patients in sustained biochemical remission for median 9.3 years showed that 25% were taking antidepressants, a significantly higher use than controls, OR 2.0 (95% CI 1.1-3.8). In addition, patients with CD had a higher use of psychotropic drugs, already in the 5-year period before diagnosis.Study V investigated mortality and causes of death in 371 patients with CD, compared to a quadrupled matched control group. Follow-up was median 10.6 years (IQR 5.7-18.2) after time of diagnosis. Overall mortality was increased in patients with CD, HR 2.1 (95% CI 1.5-2.8) and remained elevated for patients in remission at last follow-up (n=303), HR 1.5 (1.02-2.2). For patients not in remission (n=31), HR was 5.6 (2.7-11.6). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death in patients with CD. Main conclusions of the thesis:Temozolomide improves outcome in patients with aggressive pituitary tumours/carcinomas and a low MGMT expression in the tumour predicts a favourable outcome. As additional therapies evolve, MGMT may help to tailor the treatment.Germline mutations in MMR genes may contribute to the development and clinical course of pituitary tumours and may be a novel cause of hereditary pituitary tumours.Patients with Cushing’s disease have a high use of psychotropic drugs that remains elevated despite achievement of biochemical remission, suggesting persisting negative effects on mental health and highlighting the need for long-term monitoring of psychiatric symptoms. In addition, psychiatric symptoms may be early and important signs of CD.Efforts to achieve biochemical remission are crucial to reduce mortality in CD. However, patients in remission still have an increased mortality compared to controls. This underscores the need for life-long monitoring and treatment of associated comorbidities in patients with CD.
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| 9. |
- Bengtsson, Daniel, 1975-, et al.
(författare)
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Increased Mortality Persists after Treatment of Cushing's Disease: A Matched Nationwide Cohort Study
- 2022
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Context: Whether biochemical remission normalizes life expectancy in Cushing's disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls. Objective and setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort. Design and participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (n = 1484) matched at the diagnosis date by age, sex, and residential area were included. Main outcome measures: Mortality and causes of death. Results: The median diagnosis age was 44 years (interquartile range 32-56), and the median follow-up was 10.6 years (5.7-18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5-2.8)1. The HRs were 1.5 (1.02-2.2) for patients in remission at the last follow-up In = 303), 1.7 (1.03-2.8) for those in remission after a single pituitary surgery In = 177), and 5.6 (2.7-11.6) for those not in remission (n = 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death. Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status.
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| 10. |
- Bengtsson, Daniel, et al.
(författare)
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Psychotropic Drugs in Patients with Cushing's Disease Before Diagnosis and at Long-Term Follow-Up: A Nationwide Study
- 2021
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 106:6, s. 1750-1760
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Tidskriftsartikel (refereegranskat)abstract
- Context: Psychiatric symptoms are common in Cushing's disease (CD) and seem only partly reversible following treatment. Objective: To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up. Design: Nationwide longitudinal register-based study. Setting: University Hospitals in Sweden. Subjects: CD patients diagnosed between 1990 and 2018 (N = 372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis, and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed. Main outcome measures: Data from the Swedish Prescribed Drug Register and the Patient Register. Results: In the 5-year period before and at diagnosis, use of antidepressants (odds ratio [OR] 2.2 [95% confidence interval (CI) 1.3-3.7]) and 2.3 [1.6-3.5]), anxiolytics [2.9 (1.6-5.3) and 3.9 (2.3-6.6)], and sleeping pills [2.1 (1.2-3.7) and 3.8 (2.4-5.9)] was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants [2.4 (1.53.9)] and sleeping pills [3.1 (1.9-5.3)]. Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (interquartile range 8.1-10.4) had higher use of antidepressants [OR 2.0 (1.1-3.8)] and sleeping pills [2.4 (1.3-4.7)], but not of drugs for hypertension. Conclusions: Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.
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