| 1. |
- Bastard, P, et al.
(author)
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Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1
- 2021
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In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 218:7
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Journal article (peer-reviewed)abstract
- Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
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| 2. |
- Sverre, E., et al.
(author)
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Preventable clinical and psychosocial factors predicted two out of three recurrent cardiovascular events in a coronary population
- 2020
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In: BMC Cardiovascular Disorders. - : BioMed Central. - 1471-2261 .- 1471-2261. ; 20:1, s. 1-9
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Journal article (peer-reviewed)abstract
- Background The relative importance of lifestyle, medical and psychosocial factors on the risk of recurrent major cardiovascular (CV) events (MACE) in coronary patients' needs to be identified. The main objective of this study is to estimate the association between potentially preventable factors on MACE in an outpatient coronary population from routine clinical practice. Methods This prospective follow-up study of recurrent MACE, determine the predictive impact of risk factors and a wide range of relevant co-factors recorded at baseline. The baseline study included 1127 consecutive patients 2-36 months after myocardial infarction (MI) and/or revascularization procedure. The primary composite endpoint of recurrent MACE defined as CV death, hospitalization due to MI, revascularization, stroke/transitory ischemic attacks or heart failure was obtained from hospital records. Data were analysed using cox proportional hazard regression, stratified by prior coronary events before the index event. Results During a mean follow-up of 4.2 years from study inclusion (mean time from index event to end of study 5.7 years), 364 MACE occurred in 240 patients (21, 95% confidence interval: 19 to 24%), of which 39 were CV deaths. In multi-adjusted analyses, the strongest predictor of MACE was not taking statins (Relative risk [RR] 2.13), succeeded by physical inactivity (RR 1.73), peripheral artery disease (RR 1.73), chronic kidney failure (RR 1.52), former smoking (RR 1.46) and higher Hospital Anxiety and Depression Scale-Depression subscale score (RR 1.04 per unit increase). Preventable and potentially modifiable factors addressed accounted for 66% (95% confidence interval: 49 to 77%) of the risk for recurrent events. The major contributions were smoking, low physical activity, not taking statins, not participating in cardiac rehabilitation and diabetes. Conclusions Coronary patients were at high risk of recurrent MACE. Potentially preventable clinical and psychosocial factors predicted two out of three MACE, which is why these factors should be targeted in coronary populations.
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| 3. |
- Astuti, D, et al.
(author)
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Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.
- 2001
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 69:1, s. 49-54
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Journal article (peer-reviewed)abstract
- The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.
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| 4. |
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| 5. |
- Lobell, Anna, et al.
(author)
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Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts
- 2014
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:3
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Journal article (peer-reviewed)abstract
- Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-kappa B1 and IL23A genes in the UK and Italian cohorts respectively. Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
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| 6. |
- Schmidt, P.T., et al.
(author)
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Circulating ghrelin levels after food intake during different phases of the migrating motor complex in man.
- 2006
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 36:7, s. 503-509
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Journal article (peer-reviewed)abstract
- Background The timing of the migrating motor complexes (MMC) at food intake may influence gastric emptying and release of regulatory hormones. This report studies the relationships between phases I (motor quiescence) and II (intermediate frequency contractions) of MMC and prandial gut hormone response. Materials and methods Seven fasting volunteers ingested a meal during phase I or II of MMC verified by manometry, using paracetamol as a marker for gastric emptying. Blood was sampled before, during and 210 min after food intake for analysis of ghrelin, motilin, insulin and paracetamol. Results The basal level of ghrelin during phase I was 127·5 ± 25·4 pmol L-1 and during phase II was 132·4 ± 24·8 pmol L-1. After food intake during phase I, ghrelin fell to 77·2 ± 10 pmol L-1; in phase II it fell to 82·7 ± 17·8 pmol L-1 within 60 min and returned to baseline levels after 120 min. Baseline levels of motilin were 16 ± 2 pmol L-1 and 18 ± 3 pmol L-1 during phases I and II, respectively. After food, motilin decreased to 8·5 ± 0·7 pmol L-1 and 8·7 ± 1·0 pmol L-1 within 60 min and returned to baseline after 90 min. Insulin levels in phases I and II were 8·1 ± 1·2 mU L-1 and 8·6 ± 0·7 mU L-1, respectively, reaching 138·9 ± 35·6 mU L-1 and 167·4 ± 30·0 mU L-1 at 45 min postprandially. Conclusions The nutritional status of the gastrointestinal tract at food intake had only a limited impact on plasma ghrelin. After food intake, plasma ghrelin drops, similar to motilin, and resumes preprandial levels within 120 min.
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| 7. |
- Sverre, E., et al.
(author)
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Challenges in coronary heart disease prevention - experiences from a long-term follow-up study in Norway
- 2021
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In: Scandinavian Cardiovascular Journal. - : Taylor & Francis Group. - 1401-7431 .- 1651-2006. ; 55:2, s. 73-81
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Journal article (peer-reviewed)abstract
- Objective. To determine longitudinal changes in lifestyle behaviour and lipid management in a chronic coronary heart disease (CHD) population. Design. A multi-centre cohort study consecutively included 1127 patients at baseline in 2014-2015, on average 16 months after a CHD event. Data were collected from hospital records, a questionnaire and clinical examination. Seven hundred and seven of 1021 eligible patients participated in a questionnaire-based follow-up in 2019. Data were analysed with univariate statistics. Results. After a mean follow-up of 4.7 years (SD 0.4) from baseline, the percentage of current smokers (15% versus 16%), obesity (23% versus 25%) and clinically significant symptoms of anxiety (21% versus 17%) and depression (13% versus 14%) remained unchanged, whereas the proportion with low physical activity increased from 53% to 58% (p < .001). The proportions with reduced physical activity level were similar in patients over and under 70 years of age. Most patients were still taking statins (94% versus 92%) and more patients used high-intensity statin (49% versus 54%, p < .001) and ezetimibe (5% versus 15%, p < .001) at follow-up. 73% reported >= 1 primary-care consultation(s) for CHD during the last year while 27% reported no such follow-up. There were more smokers among participants not attending primary-care consultations compared to those attending (19% versus 14%, p = .026). No differences were found for other risk factors. Conclusions. We found persistent suboptimal risk factor control in coronary outpatients during long-term follow-up. Closer follow-up and intensified risk management including lifestyle and psychological health are needed to improved secondary prevention and outcome of CHD.
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| 8. |
- Vogt, E. C., et al.
(author)
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Premature menopause and autoimmune primary ovarian insufficiency in two international multi-center cohorts
- 2022
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In: Endocrine Connections. - : Bioscientifica. - 2049-3614. ; 11:5
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Journal article (peer-reviewed)abstract
- Objective: To investigate markers of premature menopause (<40 years) and specifically the prevalence of autoimmune primary ovarian insufficiency (POI) in European women. Design: Postmenopausal women were categorized according to age at menopause and self-reported reason for menopause in a cross-sectional analysis of 6870 women. Methods: Variables associated with the timing of menopause and hormone measurements of 17 beta-estradiol and follicle-stimulating hormone were explored using multivariable logistic regression analysis. Specific immunoprecipitating assays of steroidogenic autoantibodies against 21-hydroxylase (21-OH), side-chain cleavage enzyme (anti-SCC) and 17alpha-hydroxylase (17 OH), as well as NACHT leucine-rich-repeat protein 5 were used to identify women with likely autoimmune POI. Results: Premature menopause was identified in 2.8% of women, and these women had higher frequencies of nulliparity (37.4% vs 19.7%), obesity (28.7% vs 21.4%), osteoporosis (17.1% vs 11.6%), hormone replacement therapy (59.1% vs 36.9%) and never smokers (60.1% vs 50.9%) (P < 0.05), compared to women with menopause >= 40 years. Iatrogenic causes were found in 91 (47%) and non-ovarian causes in 27 (14%) women, while 77 (39%) women were classified as POI of unknown cause, resulting in a 1.1% prevalence of idiopathic POI. After adjustments nulliparity was the only variable significantly associated with POI (odds ratio 2.46; 95% CI 1.63-3.42). Based on the presence of autoantibodies against 21 OH and SCC, 4.5% of POI cases were of likely autoimmune origin. Conclusion: Idiopathic POI affects 1.1% of all women and almost half of the women with premature menopause. Autoimmunity explains 4.5% of these cases judged by positive steroidogenic autoantibodies.
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| 13. |
- Horn, M. A., et al.
(author)
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Screening for X-linked adrenoleukodystrophy among adult men with Addison's disease
- 2013
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In: Clinical Endocrinology. - : Wiley. - 0300-0664. ; 79:3, s. 316-320
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Journal article (peer-reviewed)abstract
- ObjectivesX-linked adrenoleukodystrophy is an important cause of Addison's disease in boys, but less is known about its contribution to Addison's disease in adult men. After surveying all known cases of X-linked adrenoleukodystrophy in Norway in a separate study, we aimed to look for any missed cases among the population of adult men with nonautoimmune Addison's disease. Study designAmong 153 adult men identified in a National Registry for Addison's Disease (75% of identified male cases of Addison's disease in Norway), those with negative indices for 21-hydroxylase autoantibodies were selected. Additionally, cases with low autoantibody indices (48-200) were selected. Sera from subjects included were analysed for levels of very long-chain fatty acids, which are diagnostic for X-linked adrenoleukodystrophy in men. ResultsEighteen subjects had negative indices and 17 had low indices for 21-hydroxylase autoantibodies. None of those with low indices and only one of those with negative indices were found to have X-linked adrenoleukodystrophy; this subject had already been diagnosed because of the neurological symptoms. Cases of Addison's disease proved to be caused by X-linked adrenoleukodystrophy constitute 15% of all adult male cases in Norway; the proportion among nonautoimmune cases was 15%. ConclusionsWe found X-linked adrenoleukodystrophy to be an uncommon cause of Addison's disease in adult men. However, this aetiological diagnosis has far-reaching consequences both for the patient and for his extended family. We therefore recommend that all adult men with nonautoimmune Addison's disease be analysed for levels of very long-chain fatty acids.
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| 14. |
- Husebye, E. S., et al.
(author)
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Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency
- 2014
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 275:2, s. 104-115
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Research review (peer-reviewed)abstract
- Primary adrenal insufficiency (PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow-up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21-hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life-threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow-up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self-adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up.
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| 16. |
- Orrem, Hilde L, et al.
(author)
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Acute heart failure following myocardial infarction : complement activation correlates with the severity of heart failure in patients developing cardiogenic shock.
- 2018
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In: ESC Heart Failure. - : John Wiley & Sons. - 2055-5822. ; 5:3, s. 292-301
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Journal article (peer-reviewed)abstract
- AIMS: Heart failure (HF) is an impending complication to myocardial infarction. We hypothesized that the degree of complement activation reflects severity of HF following acute myocardial infarction.METHODS AND RESULTS: The LEAF trial (LEvosimendan in Acute heart Failure following myocardial infarction) evaluating 61 patients developing HF within 48 h after percutaneous coronary intervention-treated ST-elevation myocardial infarction herein underwent a post hoc analysis. Blood samples were drawn from inclusion to Day 5 and at 42 day follow-up, and biomarkers were measured with enzyme immunoassays. Regional myocardial contractility was measured by echocardiography as wall motion score index (WMSI). The cardiogenic shock group (n = 9) was compared with the non-shock group (n = 52). Controls (n = 44) were age-matched and sex-matched healthy individuals. C4bc, C3bc, C3bBbP, and sC5b-9 were elevated in patients at inclusion compared with controls (P < 0.01). The shock group had higher levels compared with the non-shock group for all activation products except C3bBbP (P < 0.05). At Day 42, all products were higher in the shock group (P < 0.05). In the shock group, sC5b-9 correlated significantly with WMSI at baseline (r = 0.68; P = 0.045) and at Day 42 (r = 0.84; P = 0.036). Peak sC5b-9 level correlated strongly with WMSI at Day 42 (r = 0.98; P = 0.005). Circulating endothelial cell activation markers sICAM-1 and sVCAM-1 were higher in the shock group during the acute phase (P < 0.01), and their peak levels correlated with sC5b-9 peak level in the whole HF population (r = 0.32; P = 0.014 and r = 0.30; P = 0.022, respectively).CONCLUSIONS: Complement activation discriminated cardiogenic shock from non-shock in acute ST-elevation myocardial infarction complicated by HF and correlated with regional contractility and endothelial cell activation, suggesting a pathogenic role of complement in this condition.
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| 17. |
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| 18. |
- Sævik, Åse Bjorvatn, et al.
(author)
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Clues for early detection of autoimmune Addison's disease : myths and realities
- 2018
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In: Journal of Internal Medicine. - : Wiley-Blackwell Publishing Inc.. - 0954-6820 .- 1365-2796. ; 283:2, s. 190-199
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Journal article (peer-reviewed)abstract
- Background: Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce.Objective: Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD.Material and methods: A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values.Results: Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L-1 [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L-1 [2-442]) than in those without (81 nmol L-1 [1-668], P < 0.001).Conclusion: The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis.
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| 19. |
- Skinningsrud, Beate, et al.
(author)
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Multiple Loci in the HLA Complex Are Associated with Addison's Disease.
- 2011
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 96, s. 1703-1708
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Journal article (peer-reviewed)abstract
- Context: A strong association between autoimmune Addison's disease (AAD) and major histocompatibility complex class II-encoded HLA-DRB1-DQA1-DQB1 haplotypes is well known. Recent evidence from other autoimmune diseases has suggested that class I-encoded HLA-A and HLA-B gene variants confer HLA-DRB1-DQA1-DQB1-independent effects on disease. Objective: We aimed to explore AAD predisposing effects of HLA-A and -B and further investigate the role of MICA and HLA-DRB1-DQA1-DQB1 in a much larger material than has previously been studied. Design: HLA-A, -B, -DRB1, and -DQB1 and a microsatellite in MICA were genotyped in 414 AAD patients and 684 controls of Norwegian origin. Results: The strongest association was observed for the DRB1 locus, in which the DRB1*03:01 and DRB1*04:04 conferred increased risk of AAD, particularly in a heterozygous combination [odds ratio 22.13; 95% confidence interval (11.39-43.98); P = 6 × 10(-20)]. After conditioning on DRB1, association with AAD was still present for HLA-B and MICA, suggesting the presence of additional risk factors. Conclusions: The major histocompatibility complex harbors multiple risk loci for AAD, in which DRB1 appears to represent the main risk factor.
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