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ACS Omega Apr 2024In the development of proteins, aptamers, and molecular imprints for diagnostic purposes, a major goal is to obtain a molecule with both a high binding affinity and...
In the development of proteins, aptamers, and molecular imprints for diagnostic purposes, a major goal is to obtain a molecule with both a high binding affinity and specificity for the target ligand. Cushing syndrome or Addison's disease can be diagnosed by cortisol level tests. We have previously characterized and solved the crystal structure of an anti-cortisol (17) Fab fragment having a high affinity to cortisol but also significant cross-reactivity to other glucocorticoids, especially the glucocorticoid drug prednisolone. We used native mass spectrometry (MS) to determine the binding affinities of nine steroid hormones to anti-cortisol (17) Fab, including steroidogenic precursors of cortisol. Based on the results, the number of hydroxyl groups in the structure of a steroid ligand plays a key role in the antigen recognition by the Fab fragment as the ligands with three hydroxyl groups, cortisol and prednisolone, had the highest affinities. The antibody affinity toward steroid hormones often decreases with a decrease in the number of hydroxyl groups in the structure. The presence of the hydroxyl group at position C11 increased the affinity more than did the other hydroxyl groups at positions C17 or C21. The binding affinities obtained by native MS were compared to the values determined by surface plasmon resonance (SPR), and the affinities were found to correlate well between these two techniques. Our study demonstrates that native MS with a large dynamic range and high sensitivity is a versatile tool for ligand binding studies of proteins.
PubMed: 38645339
DOI: 10.1021/acsomega.3c09027 -
Archives de Pediatrie : Organe Officiel... May 2024Adrenal insufficiency (AI) is one of the most life-threatening disorders resulting from adrenal cortex dysfunction. Symptoms and signs of AI are often nonspecific, and...
Adrenal insufficiency (AI) is one of the most life-threatening disorders resulting from adrenal cortex dysfunction. Symptoms and signs of AI are often nonspecific, and the diagnosis can be missed and lead to the development of AI with severe hypotension and hypovolemic shock. We report the case of a 13-year-old child admitted for cardiac arrest following severe hypovolemic shock. The patient initially presented with isolated mild abdominal pain and vomiting together with unexplained hyponatremia. He was discharged after an initial short hospitalization with rehydration but with persistent hyponatremia. After discharge, he had persistent refractory vomiting, finally leading to severe dehydration and extreme asthenia. He was admitted to pediatric intensive care after prolonged hypovolemic cardiac arrest with severe anoxic encephalopathy leading to brain death. After re-interviewing, the child's parents reported that he had experienced polydipsia, a pronounced taste for salt with excessive consumption of pickles lasting for months, and a darkened skin since their last vacation 6 months earlier. A diagnosis of autoimmune Addison's disease was made. Primary AI is a rare life-threatening disease that can lead to hypovolemic shock. The clinical symptoms and laboratory findings are nonspecific, and the diagnosis should be suspected in the presence of unexplained collapse, hypotension, vomiting, or diarrhea, especially in the case of hyponatremia.
Topics: Humans; Adolescent; Male; Addison Disease; Shock; Hyponatremia; Adrenal Insufficiency; Heart Arrest
PubMed: 38644058
DOI: 10.1016/j.arcped.2024.02.005 -
Cryobiology Jun 2024The study is devoted to the effect of lowered resuscitation temperature (26 °C) on cryopreserved porcine adrenal glands functional activity in vitro and in vivo under...
The study is devoted to the effect of lowered resuscitation temperature (26 °C) on cryopreserved porcine adrenal glands functional activity in vitro and in vivo under xenotransplantation. The adrenals were collected from newborn pigs, cryopreserved with 5 % DMSO at a rate of 1 °C/min, resuscitated at 26 or 37 °C for 48 h (5 % CO, DMEM), embedded into small intestinal submucosa, and transplanted to bilaterally adrenalectomized rats. It has been shown that the glands resuscitated at 26 °C have suppressed free-radical processes and can produce cortisol and aldosterone in vitro, and may lead to elevated blood levels of these hormones. Moreover, the adrenal grafts maintain blood glucose levels and promote the formation of glycogen stores. Thus, the resuscitation at 26 °C can improve the quality of grafts and favor the introduction and application of the cryopreserved organs and tissues for transplantation in clinical and experimental practice.
Topics: Animals; Adrenal Glands; Transplantation, Heterologous; Cryopreservation; Swine; Hydrocortisone; Rats; Blood Glucose; Aldosterone; Male; Glycogen; Resuscitation; Organ Preservation; Cryoprotective Agents; Dimethyl Sulfoxide
PubMed: 38616031
DOI: 10.1016/j.cryobiol.2024.104895 -
European Journal of Endocrinology Mar 2024Various glucocorticoid replacement therapies (GRTs) are available for adrenal insufficiency (AI). However, their effectiveness in restoring glucocorticoid rhythm and...
BACKGROUND
Various glucocorticoid replacement therapies (GRTs) are available for adrenal insufficiency (AI). However, their effectiveness in restoring glucocorticoid rhythm and exposure lacks adequate biochemical markers. We described the diurnal salivary cortisol (SalF) and cortisone (SalE) rhythm among different GRTs and analysed the associations between saliva-derived parameters and life quality questionnaires.
METHODS
Control subjects (CSs, n = 28) and AI patients receiving hydrocortisone (HC, n = 9), cortisone acetate (CA, n = 23), and dual-release hydrocortisone once (DRHC-od, n = 10) and twice a day (DRHC-td, n = 6) collected 9 saliva samples from 07:00 to 23:00. Patients compiled Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, and Addison disease-specific quality-of-life questionnaires. SalE and SalF were measured by liquid chromatography-mass spectrometry. Exposure was monitored using SalE for HC and DRHC and SalF for CA. Area under the curve (AUC) was computed. Different GRTs were compared by Z-scores calculated from saliva-derived parameters. Questionnaire results predictors were evaluated with multiple regression analysis.
RESULTS
Compared with controls, all GRTs resulted in glucocorticoid overexposure in the morning. Hydrocortisone, CA, and DRHC-td caused overexposure also in afternoon and evening. Compared with other treatments, CA determined increased Z-score-07:00 (P < .001), DRHC-td determined increased Z-score-AUC07:00→14:00 (P = .007), and DRHC-od induced lower Z-score-AUC14:00→23:00 (P = .015). Z-scores-AUC14:00→16:00 ≥ .619 best predicted questionnaire scores.
CONCLUSIONS
None of the GRTs mimics normal glucocorticoid rhythmicity and exposure. SalE, SalF, and Z-score may be useful markers for monitoring and comparing different GRTs. Excess glucocorticoid in early afternoon best associated with depressive symptoms and worse life and sleep quality.
Topics: Humans; Glucocorticoids; Hydrocortisone; Pilot Projects; Adrenal Insufficiency; Cortisone; Saliva
PubMed: 38571387
DOI: 10.1093/ejendo/lvae037 -
Revue Medicale Suisse Apr 2024Since its first description in 1855, our understanding of primary adrenal insufficiency has greatly evolved. However, diagnosis is often delayed, as symptoms are... (Review)
Review
Since its first description in 1855, our understanding of primary adrenal insufficiency has greatly evolved. However, diagnosis is often delayed, as symptoms are frequently nonspecific in the early stages of the disease. In this article, we review the classical manifestations, associated diseases, as well as the diagnostic algorithm for primary adrenal insufficiency, aiming to enable earlier diagnosis.
Topics: Humans; Addison Disease
PubMed: 38568062
DOI: 10.53738/REVMED.2024.20.868.694 -
Critical Care (London, England) Apr 2024Vitamin D deficiency in critically ill patients is associated with poor outcomes, and vitamin D supplementation is recommended for patients with chronic kidney disease.... (Observational Study)
Observational Study
BACKGROUND
Vitamin D deficiency in critically ill patients is associated with poor outcomes, and vitamin D supplementation is recommended for patients with chronic kidney disease. Whether acute kidney injury (AKI) is associated with altered Vitamin D metabolism is unknown. We aimed to compare the longitudinal profiles of serum 25(OH)D and 1,25(OH)D concentrations in critically ill patients with and without moderate to severe AKI and explore the impact of renal recovery and parathyroid hormone (PTH).
METHODS
In this prospective, observational study in two centres in the UK, critically ill patients with and without AKI underwent serial measurement of serum 25(OH)D and 1,25(OH)D and plasma PTH concentrations for 5 days. Linear mixed model analysis and sensitivity analyses were performed.
RESULTS
Serial data of 137 patients were analysed. Seventy-one patients had AKI stage II/III of whom 23 recovered kidney function during the 5-day study period; 66 patients did not have AKI at enrolment of whom 14 developed new AKI. On day of enrolment, patients' serum 25(OH)D concentrations were low (median 18 nmol/L) but there was no significant difference between patients with and without AKI. Median serum 1,25(OH)D levels were significantly lower in patients with AKI II/III (41 pmol/L [IQR 26, 58]) compared to similarly unwell patients without AKI (54 pmol/L [IQR 33, 69]) during the 5-day period. Recovery of kidney function in patients with AKI was associated with a rise in 1,25(OH)D concentrations. Plasma PTH results were impacted by serum calcium and magnesium levels but not associated with 1,25(OH)D levels.
CONCLUSIONS
Critically ill patients with moderate-to-severe AKI have significantly lower serum 1,25(OH)D concentrations than similarly sick patients without AKI but there was no difference in serum 25(OH)D concentrations. Recovery of AKI was associated with a rise in serum 1,25(OH)D concentrations. More research is needed to investigate the health benefits and safety of supplementation with active vitamin D in critically ill patients with moderate-to-severe AKI. Trial registration Clinicaltrials.gov (NCT02869919), registered on 16 May 2016.
Topics: Humans; Prospective Studies; Critical Illness; Vitamin D; Vitamin D Deficiency; Parathyroid Hormone; Acute Kidney Injury
PubMed: 38566240
DOI: 10.1186/s13054-024-04869-4 -
Frontiers in Immunology 2024Autoimmune Addison's disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide...
Autoimmune Addison's disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes and , which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.
Topics: Humans; Addison Disease; DNA Copy Number Variations; Genome-Wide Association Study; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Adaptor Proteins, Signal Transducing
PubMed: 38562931
DOI: 10.3389/fimmu.2024.1374499 -
Archives of Gynecology and Obstetrics Jun 2024The simultaneous occurrence of primary ovarian insufficiency (POI) and autoimmune diseases has been noted and debated in some epidemiological research. This...
Assessment of bidirectional relationships between autoimmune diseases and primary ovarian insufficiency: insights from a bidirectional two-sample Mendelian randomization analysis.
PURPOSE
The simultaneous occurrence of primary ovarian insufficiency (POI) and autoimmune diseases has been noted and debated in some epidemiological research. This bidirectional two-sample Mendelian randomization (MR) study aimed to investigate the causal relationships between autoimmune diseases and POI.
METHODS
We obtained summary-level data for ten autoimmune diseases and POI from published large-scale genome-wide association studies and the FinnGen consortium of European ancestry. A series of filtering steps was performed to discern independent genetic variants. Causal estimates were mainly calculated by the inverse variance weighting method and verified through multiple sensitivity analyses.
RESULTS
Of the ten autoimmune diseases, genetically predicted Addison's disease (odds ratio [OR] = 1.26, 95% confidence interval [CI]: 1.09-1.47, P = 0.003) and systemic lupus erythematosus (OR = 1.12, 95% CI 1.02-1.24, P = 0.021) were associated with an increased risk of POI, and sensitivity analyses confirmed the robustness of the results. In addition, there were weak associations between liability to POI and elevated risks of type 1 diabetes (OR = 1.05, 95% CI 1.00-1.10, P = 0.046) and autoimmune thyroid disease (OR = 1.03, 95% CI 1.01-1.05, P = 0.015).
CONCLUSION
This study revealed that Addison's disease and systemic lupus erythematosus are potential risk factors for POI, underscoring the necessity to consider the impact of autoimmune factors in the diagnosis and treatment of POI.
Topics: Humans; Primary Ovarian Insufficiency; Mendelian Randomization Analysis; Female; Autoimmune Diseases; Lupus Erythematosus, Systemic; Genome-Wide Association Study; Addison Disease; Diabetes Mellitus, Type 1
PubMed: 38551704
DOI: 10.1007/s00404-024-07482-6 -
Andrology Mar 2024Data on sexual function in patients with adrenal insufficiency are scarce and largely controversial.
Exploring sexual function in adrenal insufficiency: findings from the Dual RElease hydrocortisone versus conventionAl glucocorticoid replaceMent therapy in hypocortisolism (DREAM) trial.
BACKGROUND
Data on sexual function in patients with adrenal insufficiency are scarce and largely controversial.
OBJECTIVES
To investigate sexual dysfunction in patients with primary and secondary adrenal insufficiency and the effects of switching to once-daily dual-release hydrocortisone on sexual function in outcome assessors blinded, randomized, multicenter, active comparator clinical trial.
MATERIALS AND METHODS
Eighty-nine adrenal insufficiency patients on conventional, multiple daily doses of glucocorticoid replacement, enrolled in the Dual RElease hydrocortisone versus conventionAl glucocorticoid replaceMent in hypocortisolism (DREAM) trial, were randomly assigned to continue their therapy or to switch to an equivalent dose of dual-release hydrocortisone. Sixty-three patients (34 women) consented to sex steroid measurements and questionnaires completion for quality of life (Addison's disease-specific quality-of-life questionnaire) and sexual function evaluation (female sexual function index for women, International Index of Erectile Function-Erectile Function for men) at baseline and 24 weeks after randomization.
RESULTS
At baseline, sexual dysfunction was observed in 41% of women and 59% of men with adrenal insufficiency. In both sexes, no associations were found between sexual function and hormone levels, whereas Addison's disease-specific quality-of-life questionnaire total and fatigue domain scores positively correlated with total female sexual function index and International Index of Erectile Function-Erectile Function scores. At 24 weeks, there was no significant difference either in sexual function or sex steroid levels between study groups. In the dual-release hydrocortisone group, the variation in the female sexual function index desire domain score was positively associated with the change in Addison's disease-specific quality-of-life questionnaire's symptom domain score (ρ = 0.478, p = 0.045).
DISCUSSION
Sexual dysfunction is common in adrenal insufficiency patients and is likely explained by multiple factors. dual-release hydrocortisone treatment is not directly associated with sexual function improvement, but an indirect effect mediated by quality-of-life amelioration cannot be excluded.
PubMed: 38545799
DOI: 10.1111/andr.13635 -
The Journal of Nutrition May 2024There is an increasing body of evidence supporting a link between low intakes of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) and numerous diseases and health... (Review)
Review
There is an increasing body of evidence supporting a link between low intakes of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) and numerous diseases and health conditions. However, few people are achieving the levels of fish/seafood or eicosapentaenoic acid and docosahexaenoic acid intake recommended in national and international guidelines. Knowledge of a person's ω-3 LCPUFA status will benefit the interpretation of research results and could be expected to lead to an increased effort to increase intake. Dietary intake survey methods are often used as a surrogate for measuring ω-3 PUFA tissue status and its impact on health and functional outcomes. However, because individuals vary widely in their ability to digest and absorb ω-3 PUFA, analytical testing of biological samples is desirable to accurately evaluate ω-3 PUFA status. Adipose tissue is the reference biospecimen for measuring tissue fatty acids, but less-invasive methods, such as measurements in whole blood or its components (e.g., plasma, serum, red blood cell membranes) or breast milk are often used. Numerous commercial laboratories provide fatty acid testing of blood and breast milk samples by different methods and present their results in a variety of reports such as a full fatty acid profile, ω-3 and ω-6 fatty acid profiles, fatty acid ratios, as well as the Omega-3 Index, the Holman Omega-3 Test, OmegaScore, and OmegaCheck, among others. This narrative review provides information about the different ways to measure ω-3 LCPUFA status (including both dietary assessments and selected commercially available analytical tests of blood and breast milk samples) and discusses evidence linking increased ω-3 LCPUFA intake or status to improved health, focusing on cardiovascular, neurological, pregnancy, and eye health, in support of recommendations to increase ω-3 LCPUFA intake and testing.
Topics: Humans; Diet; Fatty Acids, Omega-3; Nutritional Status; Recommended Dietary Allowances
PubMed: 38522783
DOI: 10.1016/j.tjnut.2024.03.015