212 results on '"Vitellius, G."'
Search Results
2. Unilateral or bilateral adrenalectomy in PPNAD: six cases from a single family followed up over 40 years
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Vitellius, G., Donadille, B., Decoudier, B., Leroux, A., Deguelte, S., Barraud, S., Bertherat, J., and Delemer, B.
- Published
- 2022
- Full Text
- View/download PDF
3. Evaluation of the transition program at the University Hospital of Reims from 2015 to 2020.
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Chibane S, Berot A, Lukas-Croisier C, Dollez L, Barraud S, Delemer B, and Vitellius G
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- Humans, Female, Male, Young Adult, Adult, Adolescent, Program Evaluation, Follow-Up Studies, Child, France, Diabetes Mellitus, Type 1 therapy, Hospitals, University, Transition to Adult Care, Glycated Hemoglobin analysis
- Abstract
The transition of young type 1 diabetic (T1D) patients from pediatric to adult healthcare is a high-risk period of loss to follow-up. Since 2015, we have implemented a transition program, involving both pediatric and adult clinicians. The main objective was to evaluate the number of patients who had succeeded this transition program at 1 year. We found that 86% of patients underwent the complete transition program. However, adverse outcomes occurred in 19.1% of patients at 1 year but decreased to 2.9% after 3 years. In 63% of patients their HbA1c level had deteriorated 1 year after the transition day and this level stabilized at around 8% in the following 2 and 3 years. In patients who had improved HbA1c levels the body mass index was lower (P = 0.03) and they lived alone (P = 0.04). Although our program seemed to allow a better follow-up than previously described, this study highlights the importance of further supporting this transition period., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)
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- 2024
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4. Correction: Artifactual hypoglycemia revealing an acrosyndrome: better believe in the glucose sensor.
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Taieb L, Ly TS, Francois M, Toquet S, Vitellius G, and Delemer B
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- 2024
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5. Artifactual hypoglycemia revealing an acrosyndrome: better believe in the glucose sensor.
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Taieb L, Ly TS, Francois M, Toquet S, Vitellius G, and Delemer B
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- 2024
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6. Medullary Thyroid Cancer: Epidemiology and Characteristics According to Data From the Marne-Ardennes Register 1975-2018.
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Caillé S, Debreuve-Theresette A, Vitellius G, Deguelte S, La Manna L, and Zalzali M
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Context: Medullary thyroid cancer (MTC) is a rare disease., Objective: The main objective of our study was to analyze the incidence evolution of MTC with a follow-up of more than 40 years. Further, a descriptive and survival analysis was performed according to the Kaplan-Meier analysis., Design Setting and Patients: This is a retrospective epidemiological study using data from the Marne-Ardennes registry from 1975 to 2018. Two hundred sixty patients with MTC were included., Main Outcome Measures: The incidence was calculated in the territory of the register (Marne and Ardennes departments of France) and standardized on the demographic structure of France. Patient and tumor characteristics were described. An analysis in a subgroup comparing hereditary and sporadic forms was performed. An analysis of survival was performed., Results: The standardized incidence shows an increasing trend over time. The incidence increased significantly from 0.41 to 0.57/100 000 person-years between 1986 and 1996 and 2008 and 2018. The MTC was hereditary in 21.2% of cases. The sex ratio (males:females) was 0.73. The average age at diagnosis was 53 years. Ninety-seven patients (37.3%) were N1, 26 (10%) were M1, and 56 (21.5%) developed metastases during the follow-up. Complete remission was obtained in 58.5% of patients. The disease was refractory for 18.1% of patients. The 5-year survival rate was 88.4%. Sporadic cases had a poorer prognosis than hereditary MTC., Conclusion: Our study demonstrates a moderate increase in the incidence of MTC between 1975 and 2018. The prognosis remains worse for sporadic MTC than for hereditary MTC., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2024
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7. Déficit hypophysaire combiné dans le cadre des mutations homozygotes du gène POMC
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Vitellius, G., primary, Berot, A., additional, Petit, J.M., additional, Gatta Cherifi, B., additional, Delemer, B., additional, and Le Collen, L., additional
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- 2023
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8. Apport de l’imagerie fonctionnelle dans la prise en charge d’un patient porteur d’un macroadénome hypophysaire, d’un paragangliome, d’une tumeur rénale et d’un variant du gène SDHC
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Le Collen, L., primary, Lussey-Lepoutre, C., additional, Vitellius, G., additional, Barraud, S., additional, Lalire, P., additional, Gimenez Roqueplo, A.P., additional, and Delemer, B., additional
- Published
- 2023
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9. Facteurs prédictifs des complications de la chirurgie des séquelles abdominales d’amaigrissement, après chirurgie bariatrique chez les non-fumeurs
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Delecroix, Q., primary, Jayyosi, L., additional, Loron, G., additional, Vitellius, G., additional, Raimond, E., additional, and François, C., additional
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- 2022
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10. [Predictive factors of complications in abdominal sequelae surgery of weight loss, after bariatric surgery in non-smokers].
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Delecroix Q, Jayyosi L, Loron G, Vitellius G, Raimond E, and François C
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- Humans, Retrospective Studies, Non-Smokers, Postoperative Complications surgery, Weight Loss, Bariatric Surgery adverse effects, Plastic Surgery Procedures, Abdominoplasty adverse effects, Obesity, Morbid surgery
- Abstract
The goal of this work was to find the main predictive factors of postoperative complications, other than smoking, after abdominoplasty or bodylift concerning sequelae of post-bariatric weight loss., Patients and Method: A retrospective monocentric study, including abdominoplasties or bodylift, after bariatric surgery was carried out between 01/01/2016 and 12/31/2019. The following were excluded: active smokers, non-bariatric patients and/or patients who had already had an abdominoplasty or body lift and/or who had undergone combined surgery., Results: 105 patients were included (73 bodylifts, 32 abdominoplasties). 68% presented at least one complication. The majority of them only resulted in an extension of local care. The serious complication rate was 2.9%. The risk factors for complications were: a young subject (P=0.014), greater weight loss (P=0.03), longer delay between bariatric surgery and plastic surgery (P=0.0002), performing a bodylift versus an abdominoplasty (P<0.01), gastric banding (P=0.029). Conversely, the bypass appeared to be a factor limiting post-sequelae complications of weight loss (P=0.041). The predictive complication model from the multivariate study concludes that the type of plastic surgery and preoperative BMI play a major role in the risk of complications., Conclusion: Surgery for abdominal weight loss sequelae presents frequent but generally benign complications. Preoperative patient information must therefore be adapted according to initial obesity and the extent of weight loss., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
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- 2023
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11. Efficacy and Safety of Osilodrostat in Paraneoplastic Cushing Syndrome: A Real-World Multicenter Study in France.
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Dormoy A, Haissaguerre M, Vitellius G, Do Cao C, Geslot A, Drui D, Lasolle H, Vieira-Pinto O, Salenave S, François M, Puerto M, Boullay HD, Mayer A, Rod A, Laurent C, Chanson P, Reznik Y, Castinetti F, Chabre O, Baudin E, Raverot G, Tabarin A, and Young J
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- Humans, Prospective Studies, Retrospective Studies, Adrenocorticotropic Hormone, Hydrocortisone therapeutic use, Cushing Syndrome drug therapy, Adrenal Insufficiency
- Abstract
Context: Prospective studies have demonstrated the efficacy of osilodrostat in Cushing disease. No study has evaluated osilodrostat in a series of patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS)., Objective: This work aimed to evaluate in France the real-world efficacy and safety of osilodrostat in patients with PNCS/EAS., Methods: A total of 33 patients with PNCS/EAS with intense/severe hypercortisolism were involved in this retrospective, multicenter, real-world study. Patients received osilodrostat between May 2019 and March 2022 at a median initial dose (range) of 4 mg/day (1-60) and maximum dose, 20 mg/day (4-100), first under patient then cohort temporary authorizations and after marketing authorization. Regimens used titration (n = 6), block and replace (n = 16), or titration followed by block and replace (n = 11)., Results: In 11 patients receiving osilodrostat as first-line monotherapy, median 24-hour urinary free cortisol (24h-UFC) decreased dramatically (from 26 × upper limit of normal [ULN; 2.9-659] to 0.11 × ULN [0.08-14.9]; P < .001). In 9 of them, 24h-UFC normalization was achieved in 2 weeks (median). Thirteen additional patients were previously treated with classic steroidogenesis inhibitors but 10 of these 13 were not controlled. In these patients, osilodrostat monotherapy, used as second line, induced a significantly decreased of 24h-UFC (from 2.6 × ULN [1.1-144] to 0.22 × ULN [0.12-0.66]; P < .01). Nine additional patients received osilodrostat in combination with another anticortisolic drug, decreasing 24h-UFC from 11.8 × ULN (0.3-247) to 0.43 × ULN (0.33-2.4) (P < .01). In parallel, major clinical symptoms/comorbidities improved dramatically with improvement in blood pressure, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of patient treatments. Adrenal insufficiency (grade 3-4) was reported in 8 of 33 patients., Conclusion: Osilodrostat is a rapidly efficient therapy for PNCS/EAS with severe/intense hypercortisolism. Osilodrostat was generally well tolerated; adrenal insufficiency was the main side effect., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2023
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12. Porphyries : une nouvelle étiologie d’insuffisance surrénale primaire ?
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Delemer, B., Marot, D., Vitellius, G., and Talbi, N.
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Une patiente née en 1957 est adressée pour élévation majeure de l’ACTH plasmatique (>2000ng/mL N<60ng/mL) demandé devant une pigmentation cutanée acquise. La patiente présente une forme extrêmement rare de porphyrie, une coproporphyrie héréditaire à l’état homozygote diagnostiquée à l’âge de 10 ans devant des douleurs abdominales et une hyponatrémie à 113mmol/L. Elle évolue sans suivi, ni crise aiguë depuis de nombreuses années avec une fatigue chronique.
- Published
- 2024
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13. The mineralocorticoid receptor modulates timing and location of genomic binding by glucocorticoid receptor in response to synthetic glucocorticoids in keratinocytes.
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Carceller-Zazo E, Sevilla LM, Pons-Alonso O, Chiner-Oms Á, Amazit L, An Vu T, Vitellius G, Viengchareun S, Comas I, Jaszczyszyn Y, Abella M, Alegre-Martí A, Estébanez-Perpiñá E, Lombès M, and Pérez P
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- Animals, Mice, Glucocorticoids pharmacology, Glucocorticoids metabolism, Kinetics, Keratinocytes metabolism, Mice, Knockout, Genomics, Receptors, Glucocorticoid metabolism, Receptors, Mineralocorticoid genetics, Receptors, Mineralocorticoid metabolism
- Abstract
Glucocorticoids (GCs) exert potent antiproliferative and anti-inflammatory properties, explaining their therapeutic efficacy for skin diseases. GCs act by binding to the GC receptor (GR) and the mineralocorticoid receptor (MR), co-expressed in classical and non-classical targets including keratinocytes. Using knockout mice, we previously demonstrated that GR and MR exert essential nonoverlapping functions in skin homeostasis. These closely related receptors may homo- or heterodimerize to regulate transcription, and theoretically bind identical GC-response elements (GRE). We assessed the contribution of MR to GR genomic binding and the transcriptional response to the synthetic GC dexamethasone (Dex) using control (CO) and MR knockout (MR
EKO ) keratinocytes. GR chromatin immunoprecipitation (ChIP)-seq identified peaks common and unique to both genotypes upon Dex treatment (1 h). GREs, AP-1, TEAD, and p53 motifs were enriched in CO and MREKO peaks. However, GR genomic binding was 35% reduced in MREKO , with significantly decreased GRE enrichment, and reduced nuclear GR. Surface plasmon resonance determined steady state affinity constants, suggesting preferred dimer formation as MR-MR > GR-MR ~ GR-GR; however, kinetic studies demonstrated that GR-containing dimers had the longest lifetimes. Despite GR-binding differences, RNA-seq identified largely similar subsets of differentially expressed genes in both genotypes upon Dex treatment (3 h). However, time-course experiments showed gene-dependent differences in the magnitude of expression, which correlated with earlier and more pronounced GR binding to GRE sites unique to CO including near Nr3c1. Our data show that endogenous MR has an impact on the kinetics and differential genomic binding of GR, affecting the time-course, specificity, and magnitude of GC transcriptional responses in keratinocytes., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)- Published
- 2023
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14. Traitement chirurgical du complexe de Carney : surrénalectomie uni ou bilatérale ?
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Vitellius, G., primary and Delemer, B., additional
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- 2020
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15. Characteristics of newly diagnosed type 1 diabetes in paediatric and adult population from Reims University Hospital, France from 1997 to 2019.
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Berot A, Gitton A, Diallo AM, Rahim A, Lukas C, Souchon PF, Salmon AS, François M, Ly S, Vitellius G, Decoudier B, Sulmont V, Delemer B, and Barraud S
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- Adult, Child, Child, Preschool, Hospitals, Humans, Incidence, Retrospective Studies, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 1 epidemiology, Diabetic Ketoacidosis diagnosis, Diabetic Ketoacidosis epidemiology, Diabetic Ketoacidosis etiology, Ketosis
- Abstract
French health insurance data showed that the incidence of type 1 diabetes mellitus (T1DM) in children increased over the years to 2015. The objective of our study was to assess the evolution of the number of incident cases of paediatric and adult type 1 diabetes in our institution, and to describe their clinical presentation and its evolution. All patients with T1DM managed at diagnosis at Reims University Hospital between 1997 and 2019 were included. The clinical and biological data were extracted from the Champagne-Ardenne Diabetes Network database. Included were 847 patients with a median age of 10.3 years. Diagnosis was established in 71% of cases before 15 years, 7.4% after 35 years. The number of newly diagnosed cases was 3.6-times higher in 2019 compared to 1997. Ketoacidosis, the frequency of which decreased with age (P < 0.0001), revealed diabetes in a total of 32% of cases and in 46% of children under 5 years. It was more severe in children than in adults (P = 0.03), and its frequency increased over the study period. Hypotrophy was found in 23% of children under 15 years of age, and was more pronounced before 5 years of age, with no improvement over time. We saw an increase in the frequency of obesity or overweight among adults. Our study showed an increase in incident cases of diabetes in our hospital that continued over time for both children and adults. Clinical features at diagnosis deteriorated during this period for those under 15 years of age with an increase in ketoacidosis frequency., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
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- 2022
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16. Three cases of thyroiditis after COVID-19 RNA-vaccine.
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Brès F, Joyeux MA, Delemer B, Vitellius G, and Barraud S
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- COVID-19 Vaccines adverse effects, Humans, RNA, 2019-nCoV Vaccine mRNA-1273 adverse effects, COVID-19 prevention & control, Graves Disease, Thyroiditis etiology
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- 2022
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17. Contraception use and knowledge related to pregnancy in diabetic women.
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Feutry L, Barbe C, Marquet-Dupont A, Fèvre A, Lukas-Croisier C, Vitellius G, Delemer B, and Barraud S
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- Adult, Contraception methods, Contraceptive Agents, Female, Humans, Pregnancy, Young Adult, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2 epidemiology, Pregnancy in Diabetics epidemiology
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Background: Diabetes mellitus prevalence is increasing among women of child-bearing age. Diabetic pregnancy is associated with major maternal and fetal risks, and these can be reduced by preconception care. Pregnancy can be planned using appropriate effective contraception. The objective of this study was to assess diabetic patients' knowledge about pregnancy and to describe their contraceptive use., Study Design: An observational study was conducted from February to July 2020 at Reims University Hospital, France. Inclusion criteria were: women aged 18 to 40years, with type 1 (T1D) or type 2 diabetes (T2D). Patients filled out a survey about contraceptive use and knowledge regarding diabetic pregnancy and data were completed from medical records., Results: Eighty-nine T1D and 33 T2D patients were included, with mean ages of 27.9±6.3 and 32.6±4.6years, respectively. Seventy-five percent reported that they had been informed about pregnancy-related risks and 67% about the need to plan pregnancy. The preconception HbA1c target was known by 33% of patients. Appropriate knowledge about pregnancy was greater in T1D patients (65.9%, versus 36.4% in T2D patients; P=0.003). The rate of patients using an effective contraceptive method was 66.4%. Fifteen percent patients for whom contraception was recommended reported having no contraceptive method; 12.5% of contraception users were using a contraindicated method., Conclusion: A large majority of diabetic women were aware of pregnancy-related risks and the importance of pregnancy planning, but there are still gaps, especially in T2D patients. We need to improve our practices by providing more information and better access to appropriate effective contraception., Gov Number: NCT04350879., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
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- 2022
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18. Résistance généralisée aux glucocorticoïdes : une pathologie pas si rare d’expression variable
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Delemer, B., primary, Vitellius, G., additional, Trabado, S., additional, and Lombes, M., additional
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- 2018
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19. Résultats du PHRC National muta-GR : prévalence des mutations NR3C1 dans l’hyperplasie bilatérale des surrénales
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Vitellius, G., primary, Trabado, S., additional, Bouligand, J., additional, Hoeffel, C., additional, Mantel, A. Guiochon, additional, Delemer, B., additional, and Lombes, M., additional
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- 2017
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20. GENETICS IN ENDOCRINOLOGY: Glucocorticoid resistance syndrome
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Vitellius G and Lombes M
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- Adrenocorticotropic Hormone blood, Adrenocorticotropic Hormone genetics, Glucocorticoids blood, Glucocorticoids genetics, Humans, Hydrocortisone blood, Hydrocortisone genetics, Metabolism, Inborn Errors blood, Receptors, Glucocorticoid blood, Receptors, Glucocorticoid genetics, Metabolism, Inborn Errors diagnosis, Metabolism, Inborn Errors genetics, Receptors, Glucocorticoid deficiency
- Abstract
Glucocorticoids (GC) such as cortisol regulate multiple physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene in humans). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, and recruitment of functional transcriptional machinery. Generalized glucocorticoid resistance syndrome, due to GR loss-of-function mutations, may be related to the impairment of one of the GC signaling steps. To date, 31 NR3C1 loss-of-function mutations have been reported in patients presenting with various clinical signs such as hypertension, adrenal hyperplasia, hirsutism or metabolic disorders associated with biological hypercortisolism but without Cushing syndrome signs and no negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Functional characterization of GR loss-of-function mutations often demonstrates GR haploinsufficiency and a decrease of GR target gene induction in relevant cell types. The main signs at presentation are very variable from resistant hypertension, bilateral adrenal hyperplasia likely related to increased ACTH levels but not exclusively, hirsutism to isolated renin-angiotensin-aldosterone system abnormalities in a context of 11βHSD2 deficiency. Some mutated GR patients are obese or overweight together with a healthier metabolic profile that remains to be further explored in future studies. Deciphering the molecular mechanisms altered by GR mutations should enhance our knowledge on GR signaling and ultimately facilitate management of GC-resistant patients. This review also focuses on the criteria facilitating identification of novel NR3C1 mutations in selected patients., (© 2020 European Society of Endocrinology)
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- 2020
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21. Impaired 11β-Hydroxysteroid Dehydrogenase Type 2 in Glucocorticoid-Resistant Patients.
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Vitellius G, Delemer B, Caron P, Chabre O, Bouligand J, Pussard E, Trabado S, and Lombes M
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- Adult, Aged, Cell Line, Tumor, Dexamethasone administration & dosage, Female, HEK293 Cells, Humans, Loss of Function Mutation, Male, Middle Aged, Mineralocorticoid Excess Syndrome, Apparent genetics, Mineralocorticoid Excess Syndrome, Apparent metabolism, Promoter Regions, Genetic, RNA, Messenger metabolism, Receptors, Glucocorticoid agonists, Receptors, Glucocorticoid genetics, Signal Transduction, Mineralocorticoid Excess Syndrome, Apparent, 11-beta-Hydroxysteroid Dehydrogenase Type 2 metabolism, Gene Expression Regulation, Receptors, Glucocorticoid metabolism
- Abstract
Context: Six patients carrying heterozygous loss-of-function mutations of glucocorticoid (GC) receptor (GR) presented with hypercortisolism, associated with low kalemia, low plasma renin, and aldosterone levels, with or without hypertension, suggesting a pseudohypermineralocorticism whose mechanisms remain unclear. We hypothesize that an impaired activity of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2; encoded by the HSD11B2 gene), catalyzing cortisol (F) inactivation, may account for an inappropriate activation of a renal mineralocorticoid signaling pathway in these GC-resistant patients., Objective: We aim at studying the GR-mediated regulation of HSD11B2., Design: The HSD11B2 promoter was subcloned and luciferase reporter assays evaluated GR-dependent HSD11B2 regulation, and 11β-HSD2 expression/activity was studied in human breast cancer MCF7 cells, endogenously expressing this enzyme., Results: Transfection assays revealed that GR transactivated the long (2.1-kbp) HSD11B2 promoter construct, whereas a defective 501H GR mutant was unable to stimulate luciferase activity. GR-mediated transactivation of the HSD11B2 gene was inhibited by the GR antagonist RU486. A threefold increase in HSD11B2 mRNA levels was observed after dexamethasone (DXM) treatment of MCF7 cells, inhibited by RU486 or by actinomycin, supporting a GR-dependent transcription. Chromatin immunoprecipitation further demonstrated a DXM-dependent GR recruitment onto the HSD11B2 promoter. 11β-HSD2 activity, evaluated by the cortisone/F ratio, quantified by liquid chromatography/tandem mass spectrometry, was 10-fold higher in the supernatant of DXM-treated cells than controls, consistent with a GR-dependent stimulation of 11β-HSD2 catalytic activity., Conclusion: Collectively, we demonstrate that 11β-HSD2 expression and activity are transcriptionally regulated by GR. In the context of GR haploinsufficiency, these findings provide evidence that defective GR signaling may account for apparent mineralocorticoid excess in GC-resistant patients., (Copyright © 2019 Endocrine Society.)
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- 2019
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22. Salt-sensitive hypertension in GR mutant rats is associated with altered plasma polyunsaturated fatty acid levels and aortic vascular reactivity.
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Verouti S, Aeschlimann G, Wang Q, Del Olmo DA, Peyter AC, Menétrey S, Winter DV, Odermatt A, Pearce D, Hummler E, and Vanderriele PE
- Abstract
In humans, glucocorticoid resistance is attributed to mutations in the glucocorticoid receptor (GR). Most of these mutations result in decreased ligand binding, transactivation, and/or translocation, albeit with normal protein abundances. However, there is no clear genotype‒phenotype relationship between the severity or age at disease presentation and the degree of functional loss of the receptor. Previously, we documented that a GR
+/- rat line developed clinical features of glucocorticoid resistance, namely, hypercortisolemia, adrenal hyperplasia, and salt-sensitive hypertension. In this study, we analyzed the GR+/em4 rat model heterozygously mutant for the deletion of exon 3, which encompasses the second zinc finger, including the domains of DNA binding, dimerization, and nuclear localization signals. On a standard diet, mutant rats exhibited a trend toward increased corticosterone levels and a normal systolic blood pressure and heart rate but presented with adrenal hyperplasia. They exhibited increased adrenal soluble epoxide hydroxylase (sEH), favoring an increase in less active polyunsaturated fatty acids. Indeed, a significant increase in nonactive omega-3 and omega-6 polyunsaturated fatty acids, such as 5(6)-DiHETrE or 9(10)-DiHOME, was observed with advanced age (10 versus 5 weeks old) and following a switch to a high-salt diet accompanied by salt-sensitive hypertension. In thoracic aortas, a reduced soluble epoxide hydrolase (sEH) protein abundance resulted in altered vascular reactivity upon a standard diet, which was blunted upon a high-salt diet. In conclusion, mutations in the GR affecting the ligand-binding domain as well as the dimerization domain resulted in deregulated GR signaling, favoring salt-sensitive hypertension in the absence of obvious mineralocorticoid excess., (© 2024. The Author(s).)- Published
- 2024
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23. Trois mutations originales du récepteur des glucocorticoïdes révélées par un incidentalome surrénalien
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Vitellius, G., primary, Bouligand, J., additional, Fagart, J., additional, Castinetti, F., additional, Mantel, A. Guiochon, additional, Delemer, B., additional, Trabado, S., additional, and Lombès, M., additional
- Published
- 2015
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24. Functional Characterization of Glucocorticoid Receptor Variants Is Required to Avoid Misinterpretation of NGS Data.
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Foussier L, Vitellius G, Bouligand J, Amazit L, Bouvattier C, Young J, Trabado S, and Lombès M
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Recent advances in genetic analysis technologies such as next-generation sequencing (NGS) have considerably increased the incidental discovery of genetic abnormalities. Six heterozygous missense mutations of the human glucocorticoid receptor (GR; encoded by the NR3C1 gene) have been identified in the context of genetic screening of endocrine pathologies. GR, a nuclear receptor, hormone-induced transcription factor, is involved in many physiological processes. Nevertheless, the pathogenic significance of incidentally discovered mutations remains obscure. The aim of this work was to characterize these variants by evaluating their functional impact on GR signaling. Six original GR variants, located in exon 2, led to amino acid substitutions of the N -terminal domain of GR (F65V, M86V, A229T, A304E, N374S, and R386Q), excluding mainly the activation function tau core 1 domain, the potential site of functional interaction with transcriptional coregulators. Transient cotransfection in HEK293T cells of mutated GR-expressing vectors and a luciferase reporter established dose-response curves for dexamethasone. This excluded any major transactivation abnormality of the mutated GRs (ligand concentration leading to 50% maximal transactivation capacity ≈ 0.2 nM), with maximal transactivation capacity identical to that of the wild-type (WT) GR and without modification of the potentiation of transcriptional coactivator steroid receptor coactivator 2 except in N374S. Moreover, protein expression of mutated GRs and their cytonuclear translocation studied by immunocytochemistry were almost unchanged compared with WT GR. These results underline the silent nature of these missense GR variants and call for cautious interpretation of the discovery of genetic incidentalomas by NGS in the absence of detailed characterization in order to appropriately assess their functional impact on a particular signaling pathway.
- Published
- 2019
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25. Pathophysiology of Glucocorticoid Signaling.
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Vitellius G, Trabado S, Bouligand J, Delemer B, and Lombès M
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- Cushing Syndrome genetics, Genetic Predisposition to Disease, Humans, Hypothalamo-Hypophyseal System physiology, Mutation, Pituitary-Adrenal System physiology, Polymorphism, Genetic, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Signal Transduction genetics, Glucocorticoids metabolism, Metabolism, Inborn Errors genetics, Metabolism, Inborn Errors metabolism, Receptors, Glucocorticoid deficiency
- Abstract
Glucocorticoids (GC), such as cortisol or dexamethasone, control various physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert most of their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, coactivator interaction and recruitment of functional transcriptional machinery. Any step may be impaired and may account for altered GC signaling. Partial or generalized glucocorticoid resistance syndrome may result in a reduced level of functional GR, a decreased hormone affinity and binding, a defect in nuclear GR translocation, a decrease or lack of DNA binding and/or post-transcriptional GR modifications. To date, 26 loss-of-function NR3C1 mutations have been reported in the context of hypertension, hirsutism, adrenal hyperplasia or metabolic disorders. These clinical signs are generally associated with biological features including hypercortisolism without negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Patients had often low plasma aldosterone and renin levels despite hypertension. Only one GR gain-of-function mutation has been described associating Cushing's syndrome phenotype with normal urinary-free cortisol. Some GR polymorphisms (ER22/23EK, GR-9β) have been linked to glucocorticoid resistance and a healthier metabolic profile whereas some others seemed to be associated with GC hypersensitivity (N363S, BclI), increasing cardiovascular risk (diabetes type 2, visceral obesity). This review focuses on the earlier findings on the pathophysiology of GR signaling and presents criteria facilitating identification of novel NR3C1 mutations in selected patients., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
- Full Text
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26. Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study.
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Vitellius G, Trabado S, Hoeffel C, Bouligand J, Bennet A, Castinetti F, Decoudier B, Guiochon-Mantel A, Lombes M, and Delemer B
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- Adrenal Gland Neoplasms epidemiology, Aged, Cells, Cultured, Female, Follow-Up Studies, France epidemiology, Humans, Male, Middle Aged, Prevalence, Adrenal Gland Neoplasms diagnostic imaging, Adrenal Gland Neoplasms genetics, Incidental Findings, Mutation genetics, Receptors, Glucocorticoid genetics
- Abstract
Background: Recently discovered mutations of NR3C1 gene, encoding for the GR, in patients with glucocorticoid resistance and bilateral adrenal incidentalomas prompted us to investigate whether GR mutations might be associated with adrenal hyperplasia., Objective: The multicenter French Clinical Research Program (Muta-GR) was set up to determine the prevalence of GR mutations and polymorphisms in patients harboring bilateral adrenal incidentalomas associated with hypertension and/or biological hypercortisolism without clinical Cushing's signs., Results: One hundred patients were included in whom NR3C1 sequencing revealed five original heterozygous GR mutations that impaired GR signaling in vitro . Mutated patients presented with mild glucocorticoid resistance defined as elevated urinary free cortisol (1.7 ± 0.7 vs 0.9 ± 0.8 upper limit of normal range, P = 0.006), incomplete 1 mg dexamethasone suppression test without suppressed 8-AM adrenocorticotrophin levels (30.9 ± 31.2 vs 16.2 ± 17.5 pg/mL) compared to the non-mutated patients. Potassium and aldosterone levels were lower in mutated patients (3.6 ± 0.2 vs 4.1 ± 0.5 mmol/L, P = 0.01, and 17.3 ± 9.9 vs 98.6 ± 115.4 pg/mL, P = 0.0011, respectively) without elevated renin levels, consistent with pseudohypermineralocorticism. Ex vivo characterization of mutated patients' fibroblasts demonstrated GR haploinsufficiency as revealed by below-normal glucocorticoid induction of FKBP5 gene expression. There was no association between GR polymorphisms and adrenal hyperplasia in this cohort, except an over-representation of BclI polymorphism., Conclusion: The 5% prevalence of heterozygous NR3C1 mutations discovered in our series is higher than initially thought and encourages GR mutation screening in patients with adrenal incidentalomas to unambiguously differentiate from Cushing's states and to optimize personalized follow-up., (© 2018 European Society of Endocrinology.)
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- 2018
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27. Mutations of Glucocorticoid Receptor in Bilateral Adrenal Hyperplasia (MUTA-GR)
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- 2024
28. Three Novel Heterozygous Point Mutations of NR3C1 Causing Glucocorticoid Resistance.
- Author
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Vitellius G, Fagart J, Delemer B, Amazit L, Ramos N, Bouligand J, Le Billan F, Castinetti F, Guiochon-Mantel A, Trabado S, and Lombès M
- Subjects
- Adrenal Gland Neoplasms drug therapy, Adult, Animals, Binding Sites, COS Cells, Cell Nucleus metabolism, Chlorocebus aethiops, Cushing Syndrome genetics, Cytoplasm metabolism, DNA, Neoplasm metabolism, Dexamethasone pharmacology, Female, HEK293 Cells, Humans, Male, Middle Aged, Models, Molecular, Mutation, Missense, Protein Structure, Secondary, Protein Transport, Receptors, Glucocorticoid metabolism, Adrenal Gland Neoplasms genetics, Drug Resistance, Neoplasm, Glucocorticoids pharmacology, Point Mutation, Receptors, Glucocorticoid chemistry, Receptors, Glucocorticoid genetics
- Abstract
Generalized glucocorticoid resistance is associated with glucocorticoid receptor (GR; NR3C1) mutations. Three novel heterozygous missense NR3C1 mutations (R477S, Y478C, and L672P) were identified in patients presenting with adrenal incidentalomas, glucocorticoid excess without Cushing syndrome. Dexamethasone (DXM) binding studies demonstrated that the affinity of GRR477S and GRY478C mutants, located in the DNA-binding domain (DBD) of GR, was similar to wild-type GR (Kd = 2-3 nM). In contrast, GRL672P mutant, located in the ligand-binding domain (LBD) of GR, was unable to bind glucocorticoids and was more sensitive to protein degradation. GR subcellular distribution revealed a marked decrease in DXM-induced nuclear translocation of GRR477S and GRY478C mutants, whereas GRL672P remained exclusively cytoplasmic. Chromatin immunoprecipitation demonstrated impaired recruitment of DBD mutants onto the regulatory sequence of FKBP5. Transactivation assays disclosed the lack of transcriptional activity of GRR477S and GRL672P , whereas GRY478C had a reduced transactivation capacity. Three-dimensional modeling indicated that R477S lost two essential hydrogen bonds with DNA, Y478C resulted in altered interaction with surrounding amino-acids, destabilizing DBD, whereas L672P altered the H8 helix folding, leading to unstructured LBD. This study identifies novel NR3C1 mutations with their molecular consequences on altered GR signaling and suggests that genetic screening of NR3C1 should be conducted in patients with subclinical hypercorticism., (© 2016 WILEY PERIODICALS, INC.)
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- 2016
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29. Impaired 11β-HSD1 Activity in a Male Patient With Cushing Disease Resulting in Lack of the Full Cushingoid Phenotype.
- Author
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Weber, Robert J, Kawaja, Christopher, Wallerstein, Robert, Kunwar, Sandeep M, and Liu, Chienying
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CUSHING'S syndrome ,GLUCOCORTICOID receptors ,CORTISONE ,HYDROCORTISONE ,ADRENOCORTICOTROPIC hormone - Abstract
We present a patient who had surgically confirmed CD but without the full cushingoid phenotype despite markedly elevated cortisol. Nonpathologic causes of elevated ACTH and cortisol were eliminated as were pathogenic variants in the glucocorticoid receptor gene. Further studies of urine metabolites, cortisol half-life, and the ratios of cortisone to cortisol conversion revealed impaired 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. There have only been 2 prior reports of impaired 11β-HSD1 resulting in lack of classic cushingoid features in the past 2 decades. Our patient's presentation and previous reports demonstrate the key role of 11β-HSD1 in modulating intracellular cortisol concentration, therefore shielding the peripheral tissues from the effects of excess cortisol. When patients present with markedly elevated cortisol but without classic cushingoid features, impaired 11β-HSD1 should be considered in the differential diagnosis. [ABSTRACT FROM AUTHOR]
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- 2024
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30. Diabetes Mellitus in Non-Functioning Adrenal Incidentalomas: Analysis of the Mild Autonomous Cortisol Secretion (MACS) Impact on Glucose Profile.
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Trandafir, Alexandra-Ioana, Ghemigian, Adina, Ciobica, Mihai-Lucian, Nistor, Claudiu, Gurzun, Maria-Magdalena, Nistor, Tiberiu Vasile Ioan, Petrova, Eugenia, and Carsote, Mara
- Subjects
TYPE 2 diabetes ,CUSHING'S syndrome ,GLUCOSE analysis ,LITERATURE reviews ,BLOOD sugar - Abstract
Non-functioning adrenal incidentalomas (NFAIs) have been placed in relationship with a higher risk of glucose profile anomalies, while the full-blown typical picture of Cushing's syndrome (CS) and associated secondary (glucocorticoid-induced) diabetes mellitus is not explicitly confirmed in this instance. Our objective was to highlight the most recent data concerning the glucose profile, particularly, type 2 diabetes mellitus (T2DM) in NFAIs with/without mild autonomous cortisol secretion (MACS). This was a comprehensive review of the literature; the search was conducted according to various combinations of key terms. We included English-published, original studies across a 5-year window of publication time (from January 2020 until 1 April 2024) on PubMed. We excluded case reports, reviews, studies on T1DM or secondary diabetes, and experimental data. We identified 37 studies of various designs (14 retrospective studies as well 13 cross-sectional, 4 cohorts, 3 prospective, and 2 case–control studies) that analysed 17,391 individuals, with a female-to-male ratio of 1.47 (aged between 14 and 96 years). T2DM prevalence in MACS (affecting 10 to 30% of NFAIs) ranged from 12% to 44%. The highest T2DM prevalence in NFAI was 45.2% in one study. MACS versus (non-MACS) NFAIs (n = 16) showed an increased risk of T2DM and even of prediabetes or higher fasting plasma glucose or HbA1c (no unanimous results). T2DM prevalence was analysed in NFAI (N = 1243, female-to-male ratio of 1.11, mean age of 60.42) versus (non-tumour) controls (N = 1548, female-to-male ratio of 0.91, average age of 60.22) amid four studies, and two of them were confirmatory with respect to a higher rate in NFAIs. Four studies included a sub-group of CS compared to NFAI/MACS, and two of them did not confirm an increased rate of glucose profile anomalies in CS versus NFAIs/ACS. The longest period of follow-up with concern to the glycaemic profile was 10.5 years, and one cohort showed a significant increase in the T2DM rate at 17.9% compared to the baseline value of 0.03%. Additionally, inconsistent data from six studies enrolling 1039 individuals that underwent adrenalectomy (N = 674) and conservative management (N = 365) pinpointed the impact of the surgery in NFAIs. The regulation of the glucose metabolism after adrenalectomy versus baseline versus conservative management (n = 3) was improved. To our knowledge, this comprehensive review included one of the largest recent analyses in the field of glucose profile amid the confirmation of MACS/NFAI. In light of the rising incidence of NFAI/AIs due to easier access to imagery scans and endocrine evaluation across the spectrum of modern medicine, it is critical to assess if these patients have an increased frequency of cardio-metabolic disorders that worsen their overall comorbidity and mortality profile, including via the confirmation of T2DM. [ABSTRACT FROM AUTHOR]
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- 2024
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31. Aldosteron und Niere – eine komplexe Interaktion.
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Schwarz, Christoph and Lindner, Gregor
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- 2024
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32. Impaired Cognitive Functions in Prolonged Social Isolation: Results of Human Studies and Animal Experiments.
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Krupina, N. A. and Shirenova, S. D.
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SCIENTIFIC literature ,SOCIAL isolation ,HYPOTHALAMIC-pituitary-adrenal axis ,GLUCOCORTICOID receptors ,ANIMAL experimentation - Abstract
Close social connections are essential for mental and physical health and well-being at any age. A significant proportion of the world's population has experienced lockdown conditions due to the COVID-19 pandemic. There is a growing body of scientific literature on the adverse effects of social isolation on attention, memory, perception, executive function, and other aspects of cognitive processes. This can make people's daily lives more difficult, reducing their quality of life. This review seeks to systematize accumulated scientific data acquired in longitudinal population studies on the relationship between social isolation and the development of cognitive impairment in humans, and also analyzes data on the effects of social isolation of different durations on learning and memory processes obtained in experimental studies in animals. Questions are raised regarding the possible connection of these social isolation-induced disorders with changes in the functioning of one of the stress reactivity systems, i.e., the hypothalamic-pituitary-adrenal axis, and the immunoinflammatory response. [ABSTRACT FROM AUTHOR]
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- 2024
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33. Diagnosis and management of non-CAH 46,XX disorders/ differences in sex development.
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Abalı, Zehra Yavas and Guran, Tulay
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GONADS ,ADRENOGENITAL syndrome ,DNA copy number variations ,GENETIC techniques ,AROMATASE ,DIAGNOSIS - Abstract
Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11b-hydroxylase, 3b-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD. [ABSTRACT FROM AUTHOR]
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- 2024
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34. Molecular mechanisms of glucocorticoid resistance.
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Huang H and Wang W
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- Humans, Receptors, Glucocorticoid genetics, Mutation, Signal Transduction, Drug Resistance genetics, Glucocorticoids therapeutic use, Metabolism, Inborn Errors drug therapy, Metabolism, Inborn Errors genetics
- Abstract
Background: As a powerful anti-inflammatory, immunosuppressive, and antiproliferative drug, glucocorticoid (GC) plays an important role in the treatment of various diseases. However, some patients may experience glucocorticoid resistance (GCR) in clinical, and its molecular mechanism have not been determined., Methods: The authors performed a review of the literature on GCR focusing on mutations in the NR3C1 gene and impaired glucocorticoid receptor (GR) signalling, using METSTR (2000 through May 2022) to identify original articles and reviews on this topic. The search terms included 'glucocorticoid resistance/insensitive', 'steroid resistance/insensitive', 'NR3C1', and 'glucocorticoid receptor'., Results: Primary GCR is mainly caused by NR3C1 gene mutation, and 31 NR3C1 gene mutations have been reported so far. Secondary GCR is caused by impaired GC signalling pathways, including decreased expression of GR, impaired nuclear translocation of GR, and impaired binding of GR to GC and GR to target genes. However, the current research is more on the expression level of GR, and there are relatively few studies on other mechanisms. In addition, methods for improving GC sensitivity are rarely reported., Conclusion: The molecular mechanisms of GCR are complex and may differ in different diseases or different patients. In future studies, when exploring the mechanism of GCR, methods to improve GC sensitivity should also be investigated., (© 2022 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)
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- 2023
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35. Spontaneous Adrenal Hemorrhage in a Pregnant Woman With Glucocorticoid Resistance Syndrome.
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Jagtap, Varsha, Lila, Anurag, Karlekar, Manjiri, Sarathi, Vijaya, and Bandgar, Tushar
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GLUCOCORTICOIDS ,REPRODUCTIVE technology ,ADRENAL insufficiency ,SYNDROMES ,MISSENSE mutation ,HEMORRHAGE ,ACUTE abdomen - Abstract
Glucocorticoid resistance syndrome is a rare disorder with no genetically proven cases reported from India; in addition, there are no descriptions available regarding its management during pregnancy. A 27-year-old woman, hypertensive since the age of 17 years, presented with hypokalemic paresis. She reported regular menses and acne. On investigation, she had elevated serum cortisol that remained unsuppressed after a low-dose dexamethasone suppression test. Genetic analysis revealed a novel, homozygous missense variant in exon 5 of the NR3C1 gene confirming glucocorticoid resistance syndrome. She was managed with oral dexamethasone followed by tapering of antihypertensive drugs. A year later, she conceived with assisted reproductive techniques when dexamethasone was replaced with prednisolone, necessitating the reintroduction of antihypertensive drugs to maintain normotension and potassium supplements to manage hypokalemia. She presented with acute abdomen at 36 weeks of gestation; evaluation revealed right adrenal hemorrhage, which was managed conservatively. Postpartum, the right adrenal lesion reduced in size and an underlying right adrenal myelolipoma was unveiled. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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36. Two cases of pancreatic neuroendocrine tumors with ectopic ACTH syndrome during their disease course.
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Murakami, Masatoshi, Hirahata, Keisuke, Fujimori, Nao, Yamamoto, Takeo, Oda, Yoshinao, Kozono, Shingo, Ueda, Keijiro, Ito, Testuhide, Nakamura, Masafumi, and Ogawa, Yoshihiro
- Abstract
Pancreatic neuroendocrine tumors (PanNETs) are rare malignant tumors that occur in the pancreas. They are divided into functioning and non-functioning tumors based on the presence or absence of their specific hormonal hyper-expression symptoms. Adrenocorticotropic hormone (ACTH)-producing PanNETs are rare, functional tumors, and their clinical characteristics and outcomes have not been well reported. Here, we report the cases of two patients with PanNETs who presented with ectopic ACTH syndrome (EAS) during the course of their disease. Case 1 involved a non-functioning PanNET at the time of surgery. During treatment for recurrent liver metastases, the patient presented with EAS and tumor-associated hypercalcemia, probably due to ACTH and parathyroid hormone-related peptide (PTHrP) production from the liver tumor. Case 2 was a gastrinoma, and similar to Case 1, this patient presented with EAS during the treatment of recurrent liver metastases. It is not uncommon for patients with PanNETs to have multiple hormones and develop secondary hormone secretion during their disease course, although tumor phenotypes differ between primary and metastatic sites. In patients with functioning PanNETs, symptom control with anti-hormonal therapy is essential, in addition to anti-tumor therapy, especially for EAS, which is an endocrine emergency disease that requires prompt diagnosis and treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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37. Paraneoplastic neurological syndromes of small cell lung cancer.
- Author
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Barahman, Maedeh, Shamsaei, Gholamreza, Kashipazha, Davood, Bahadoram, Mohammad, and Akade, Esma’il
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SMALL cell lung cancer ,THERAPEUTIC use of antineoplastic agents ,LUNG cancer treatment ,AUTOANTIBODY analysis ,PATHOLOGICAL physiology - Abstract
Purpose:This article reviews the relevant literature on paraneoplastic neurological syndromes of small cell lung cancer and discusses the clinical presentation, pathophysiology, and diagnosis of these syndromes. It also includes a summary of the current treatment options for the management of them. Views: Paraneoplastic syndromes are a group of signs and symptoms that develop due to cancer in a remote site, mainly triggered by an autoantibody produced by the tissues involved or lymphocytes during anti-cancer defense. Among the cancers associated with paraneoplastic syndromes, lung cancers are the most common type, with small cell lung cancer being the most common subtype. The most common antibody associated with paraneoplastic syndromes is anti-Hu. Neurological and neuroendocrine syndromes comprise the majority of small cell lung cancer-related paraneoplastic syndromes. Classical paraneoplastic neurological syndromes include inappropriate antidiuretic hormone secretion, Cushing’s syndrome, myasthenia gravis, Lambert-Eaton myasthenic syndrome, limbic encephalitis, paraneoplastic cerebellar degeneration, opsoclonus myoclonus ataxia, sensory neuropathy, and chorea. Conclusions: Antibodies mediate paraneoplastic syndromes, and antibody detection is a crucial part of diagnosing these entities. Managing the underlying tumor is the best treatment approach for most paraneoplastic syndromes. Therefore, early diagnosis of small cell lung cancer may significantly improve the prognosis of paraneoplastic syndromes associated with it. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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38. Role of glucocorticoid receptor mutations in hypertension and adrenal gland hyperplasia.
- Author
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Verouti S, Hummler E, and Vanderriele PE
- Subjects
- Adrenal Glands, Animals, Glucocorticoids, Humans, Hyperplasia genetics, Metabolism, Inborn Errors, Mice, Mutation, Rats, Receptors, Mineralocorticoid genetics, Hypertension etiology, Receptors, Glucocorticoid deficiency, Receptors, Glucocorticoid genetics
- Abstract
Hypertension is one of the leading causes of premature death in humans and exhibits a complex aetiology including environmental and genetic factors. Mutations within the glucocorticoid receptor (GR) can cause glucocorticoid resistance, which is characterized by several clinical features like hypercortisolism, hypokalaemia, adrenal hyperplasia and hypertension. Altered glucocorticoid receptor signalling further affects sodium and potassium homeostasis as well as blood pressure regulation and cell proliferation and differentiation that influence organ development and function. In salt-sensitive hypertension, excessive renal salt transport and sympathetic nervous system stimulation may occur simultaneously, and, thus, both the mineralocorticoid receptor (MR) and the GR-signalling may be implicated or even act interdependently. This review focuses on identified GR mutations in human primary generalized glucocorticoid resistance (PGGR) patients and their related clinical phenotype with specific emphasis on adrenal gland hyperplasia and hypertension. We compare these findings to mouse and rat mutants harbouring genetically engineered mutations to further dissect the cause and/or the consequence of clinical features which are common or different., (© 2022. The Author(s).)
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- 2022
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39. Glucocorticoid resistance syndrome.
- Author
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Vitellius, Géraldine and Lombes, Marc
- Subjects
GLUCOCORTICOIDS ,RENIN-angiotensin system ,CUSHING'S syndrome ,GLUCOCORTICOID receptors ,ADRENAL insufficiency ,LIGAND binding (Biochemistry) - Abstract
Glucocorticoids (GC) such as cortisol regulate multiple physiol ogical functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert their e ffects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene in humans). GC signaling follows several consecutive step s leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, and recruitment of functional transcriptional machinery. Generalized glucocorticoid resistance syndrome, due to GR loss-of-function mutations, may be related to the impairment of one of the GC signaling steps. To date, 31 NR3C1 loss-of-function mutations have been reported in patients prese nting with various clinical signs such as hypertension, adrenal hyperplasia, hirsutism or metabolic disorders associated with biological hypercortisolism but without Cushing syndrome signs and no negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Functional characterization of GR loss-of-function mutations often demonstrates GR haploinsufficiency and a decrease of GR target gene induction in relevant cell types. The main signs at presentation are very variable from resistant hypertension, bilateral adrenal hyperplasia likely related to i ncreased ACTH levels but not exclusively, hirsutism to isolated renin-angiotensin-aldosterone system abnormalities in a context of 11ßHSD2 deficiency. Some mutated GR patients are obese or overweight together with a healthier meta bolic profile that remains to be further explored in future studies. Deciphering the molecular mechanisms altered by GR mutations should enhance our knowledge on GR signaling and ultimately facilitate management of GC-resista nt patients. This review also focuses on the criteria facilitating identification of novel NR3C1 mutations in selected patients. Correspondence. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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40. Access to nutrition advice and knowledge, attitudes and practices of pregnant women in Ireland: A cross-sectional study.
- Author
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McCarthy EK, Ní Riada C, O'Brien R, Minogue H, McCarthy FP, and Kiely ME
- Subjects
- Humans, Female, Ireland, Pregnancy, Cross-Sectional Studies, Adult, Young Adult, Surveys and Questionnaires, Prenatal Care methods, Prenatal Care statistics & numerical data, Health Services Accessibility statistics & numerical data, Diet, Healthy statistics & numerical data, Diet, Healthy psychology, Nutritional Status, Dietary Supplements statistics & numerical data, Counseling methods, Health Knowledge, Attitudes, Practice, Pregnant Women psychology
- Abstract
Background: Healthy nutritional status, appropriate gestational weight gain and a balanced diet are important predictors of perinatal health outcomes. However, gaps exist in the translation of nutrition recommendations into dietary practices of women before and during pregnancy. The present study explored the relationship between access to nutrition advice, nutrition knowledge, attitudes and practices among pregnant women., Methods: Pregnant women aged > 18 years in Ireland were eligible to complete a self-administered survey consisting of four subsections (demographics, nutrition knowledge, attitudes and practices) delivered online through Qualtrics., Results: In this convenience sample (n = 334, median [interquartile range] gestation, 25.0 [16.0, 34.0] weeks), 85% had at least an honours bachelor degree and 88.9% planned their pregnancy. Two out of five women received nutrition advice during their pregnancy, mostly from a midwife. Based on the percentage of correct answers (of 15 questions), women with previous nutrition education (e.g., school home economics) had better median [interquartile range] nutrition knowledge than those with none (80.0% [66.7, 86.7%] vs. 73.3% [60.0, 80.0%], p < 0.001). Those who received nutrition advice during pregnancy did not score higher than those who did not (73.3% [66.7, 80.0%] vs. 73.3% [66.7, 80.0%], p = 0.6). Over three-quarters of participants considered nutritional supplement use to be very or extremely important. Although 73.6% and 92.4% took supplements prior to and during pregnancy, only 25.7% reported compliance with periconceptional folic acid supplementation guidelines. Half of respondents considered healthy eating during pregnancy as very or extremely important., Conclusions: Access to nutrition advice during pregnancy was inadequate with poor nutrition knowledge, attitudes and practices observed. Accessible, evidence-based nutrition education for women prior to and during pregnancy is required., (© 2024 The Author(s). Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)
- Published
- 2024
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41. Integrating network pharmacology and animal experimental validation to investigate the action mechanism of oleanolic acid in obesity.
- Author
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Liu, Tianfeng, Wang, Jiliang, Tong, Ying, Wu, Lele, Xie, Ying, He, Ping, Lin, Shujue, and Hu, Xuguang
- Subjects
STEROID receptors ,LABORATORY animals ,RNA polymerase II ,MOLECULAR dynamics ,OBESITY ,GENE ontology - Abstract
Background: Obesity, a condition associated with the development of widespread cardiovascular disease, metabolic disorders, and other health complications, has emerged as a significant global health issue. Oleanolic acid (OA), a pentacyclic triterpenoid compound that is widely distributed in various natural plants, has demonstrated potential anti-inflammatory and anti-atherosclerotic properties. However, the mechanism by which OA fights obesity has not been well studied. Method: Network pharmacology was utilized to search for potential targets and pathways of OA against obesity. Molecular docking and molecular dynamics simulations were utilized to validate the interaction of OA with core targets, and an animal model of obesity induced by high-fat eating was then employed to confirm the most central of these targets. Results: The network pharmacology study thoroughly examined 42 important OA targets for the treatment of obesity. The key biological processes (BP), cellular components (CC), and molecular functions (MF) of OA for anti-obesity were identified using GO enrichment analysis, including intracellular receptor signaling, intracellular steroid hormone receptor signaling, chromatin, nucleoplasm, receptor complex, endoplasmic reticulum membrane, and RNA polymerase II transcription Factor Activity. The KEGG/DAVID database enrichment study found that metabolic pathways, PPAR signaling pathways, cancer pathways/PPAR signaling pathways, insulin resistance, and ovarian steroidogenesis all play essential roles in the treatment of obesity and OA. The protein-protein interaction (PPI) network was used to screen nine main targets: PPARG, PPARA, MAPK3, NR3C1, PTGS2, CYP19A1, CNR1, HSD11B1, and AGTR1. Using molecular docking technology, the possible binding mechanism and degree of binding between OA and each important target were validated, demonstrating that OA has a good binding potential with each target. The molecular dynamics simulation's Root Mean Square Deviation (RMSD), and Radius of Gyration (Rg) further demonstrated that OA has strong binding stability with each target. Additional animal studies confirmed the significance of the core target PPARG and the core pathway PPAR signaling pathway in OA anti-obesity. Conclusion: Overall, our study utilized a multifaceted approach to investigate the value and mechanisms of OA in treating obesity, thereby providing a novel foundation for the identification and development of natural drug treatments. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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42. Family planning behaviours among women with diabetes mellitus: a scoping review.
- Author
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Awang Dahlan, Sarah, Idris, Idayu Badilla, Mohammed Nawi, Azmawati, and Abd Rahman, Rahana
- Subjects
FAMILY planning ,DIABETES ,UNPLANNED pregnancy ,GESTATIONAL diabetes ,FAMILY planning services - Abstract
Introduction: Diabetes mellitus in pregnancies is associated with adverse outcomes both for the mothers and babies. Postponing pregnancy in unoptimized conditions and stabilisation of glucose should be prioritized. This scoping review is aimed to determine the scope and at the same time map the types of evidence available that is related to family planning behaviours among women with diabetes mellitus, with a particular focus on their factors which influence family planning usage and subsequently enable the identification of knowledge gaps in preventing unintended pregnancies among this high-risk population. Methods: This scoping review is guided by the methodological framework by Arksey and O'Malley's and Prisma-ScR checklist. PubMed, EBSCO and OVID were searched for empirical studies between 2000 and February 2022 using the search terms "family planning", "contraceptive" and "diabetes mellitus". Data were summarized according to the study characteristics and levels of factors influencing family planning behaviours. Results: Thirty-five articles that met the eligibility criteria included 33 quantitative studies, one qualitative study and one mixed-methods study. The prevalence of family planning methods used by women with diabetes mellitus varied ranging from 4.8 to 89.8% among the studied population. Women with diabetes mellitus were reported to be less likely to utilise any family planning methods compared to women without diabetes mellitus. Conclusions: Most of the evidence to date on family planning behaviours among women with diabetes mellitus focuses on the role of individual level sociodemographic factors. Few studies focused on exploring determinants at multiple levels. In this review we found that there is limited evidence on disease control and pregnancy intention in relation to their family planning practices. Future studies with more clinical and contextual factors are needed to guide the strengthening of family planning services for high-risk group women specifically for women with diabetes mellitus. Plain English summary: As the prevalence of diabetes mellitus is increasing globally, more women in reproductive age group are living with diabetes mellitus. Pregnant women with uncontrolled diabetes mellitus have higher risk for complications, both to the mothers and the baby. Therefore, it is very important that family planning needs of women with diabetes mellitus are met. This review is aimed to identify what is known and not known about the factors influencing family planning behaviours among women with diabetes mellitus. We searched three databases for studies published from 2000 to February 2022. Our review included 35 articles and nearly all of the studies were quantitative, with one qualitative and one mixed-methods study. Among the studies that compared between women with diabetes mellitus and without diabetes mellitus, less women with diabetes mellitus were using family planning. Some papers also include the reasons or barriers for using family planning among the studied population. Majority of the articles described sociodemographic were factors related to family planning usage, while only few studies explored beyond individual factors. Little information on the clinical profile of the women with diabetes mellitus were known. Future research should examine clinical and other non-individual factors influencing family planning among this particular group of women as sexual and reproductive health in general is very much influenced by cultural or healthcare system factors. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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43. Glucocorticoid Receptor Antagonism Improves Glucose Metabolism in a Mouse Model of Polycystic Ovary Syndrome.
- Author
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Li, Sheng, Ying, Zhixiong, Gentenaar, Max, Rensen, Patrick C N, Kooijman, Sander, Visser, Jenny A, Meijer, Onno C, and Kroon, Jan
- Subjects
POLYCYSTIC ovary syndrome ,GLUCOCORTICOID receptors ,GLUCOSE metabolism ,METABOLIC models ,ANDROGEN receptors ,HYPERGLYCEMIA - Abstract
Context Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with obesity, insulin resistance, and dyslipidemia. Hyperandrogenism is a major characteristic of PCOS. Increased androgen exposure is believed to deregulate metabolic processes in various tissues as part of the PCOS pathogenesis, predominantly through the androgen receptor (AR). Notably, various metabolic features in PCOS are similar to those observed after excess glucocorticoid exposure. Objective We hypothesized that glucocorticoid receptor (GR) signaling is involved in the metabolic symptoms of PCOS. Methods In a PCOS model of chronic dihydrotestosterone (DHT) exposure in female mice, we investigated whether GR signaling machinery was (de)regulated, and if treatment with a selective GR antagonist alleviated the metabolic symptoms. Results We observed an upregulation of GR messenger RNA expression in the liver after DHT exposure. In white adipose tissues and liver we found that DHT upregulated Hsd11b1 , which encodes for the enzyme that converts inactive into active glucocorticoids. We found that preventive but not therapeutic administration of a GR antagonist alleviated DHT-induced hyperglycemia and restored glucose tolerance. We did not observe strong effects of GR antagonism in DHT-exposed mice on other features like total fat mass and lipid accumulation in various tissues. Conclusion We conclude that GR activation may play a role in glucose metabolism in DHT-exposed mice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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44. Cortisol controls endoplasmic reticulum stress and hypoxia dependent regulation of insulin receptor and related genes expression in HEK293 cells.
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Minchenko, Dmytro O., Khita, Olena O., Viletska, Yuliia M., Sliusar, Myroslava Y., Rudnytska, Olha V., Kozynkevych, Halyna E., Bezrodnyi, Borys H., Khikhlo, Yevgen P., and Minchenko, Oleksandr H.
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- 2024
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45. Ectoin attenuates cortisone-induced skin issues by suppression GR signaling and the UVB-induced overexpression of 11β-HSD1.
- Author
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Xu D and Wu Y
- Abstract
Background: Accelerated pace of modern work and lifestyles subject individuals to various external and psychological stressors, which, in turn, can trigger additional stress through visible signs of fatigue, hair loss, and obesity. As the primary stress hormone affecting skin health, cortisol connects to the glucocorticoid receptor (GR) to aggravate skin issues induced by stress. This activation depends on the expression of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in skin cells, which locally converts cortisone-produced by the central and peripheral hypothalamic-pituitary-adrenal axis-into its active form., Methods: Our study delves deeper into stress's adverse effects on the skin, including the disruption of keratinocyte structural proteins, the loss of basement membrane proteins, and the degradation of collagen., Results: Remarkably, we discovered that Ectoin, an amino acid derivative obtained from halophilic bacteria, is capable of mitigating the inhibitory impacts of cortisone on the expression of cutaneous functional proteins, including involucrin, loricrin, laminin-5, and claudin-1. Moreover, Ectoin reduces the suppressive effect of stress on collagen and hyaluronic acid synthesis by impeding GR signal transduction. Additionally, Ectoin counterbalances the UVB-induced overexpression of 11β-HSD1, thereby diminishing the concentration of endogenous glucocorticoids., Conclusion: Our findings illuminate the significant potential of Ectoin as a preventative agent against stress-induced skin maladies., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)
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- 2024
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46. Contraceptive Methods in Diabetic Women Referring to Government Diabetes Clinics in Northern Iran.
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Mansour-Ghanaei, Roya, Donyaei-Mobarrez, Yalda, and Abouzari-Gazafroodi, Kobra
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TREATMENT of diabetes ,PUBLIC hospitals ,CROSS-sectional method ,WOMEN ,DESCRIPTIVE statistics ,RESEARCH methodology ,CONTRACEPTION ,DATA analysis software - Abstract
Background: Unwanted pregnancies in diabetic women can endanger the mother and the fetus. The present study was conducted to determine contraceptive methods for diabetic women referred to government diabetes clinics in the north of Iran. Methods: A total of 153 diabetic women referred to government clinics in Guilan were included in this cross-sectional study. A questionnaire made by the researcher regarding personal and social information and information related to contraceptive methods was administered. Data were analyzed analytically using SPSS version 19. Results: The findings of the present study revealed that 87.6% of diabetic women used contraceptive methods, of which 44.4% utilized low-effective contraceptive methods (withdrawal method and condoms), and 43.2% opted for highly effective contraceptive methods (tubal ligation, oral contraceptive pill, intrauterine device, and vasectomy). Decision regarding the choice of contraceptive methods was mainly made by couples, followed by consultation with a doctor. Conclusions: A relatively high percentage of diabetic women use less effective contraceptive methods, and the decision to use contraceptive methods is made mainly by couples. Therefore, targeted reproductive health interventions and providing counseling services as part of medical care for diabetic women seem necessary. [ABSTRACT FROM AUTHOR]
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- 2023
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47. Diabetes Mellitus and Pregnancy : Knowledge Assessment (DMPKA)
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- 2022
48. Hunger & satiety signals: another key mechanism involved in the NAFLD pathway.
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López-Méndez, Iván, Maldonado-Rojas, Andrea Del Carmen, Uribe, Misael, and Juárez-Hernández., Eva
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HUNGER ,NON-alcoholic fatty liver disease ,DISEASE progression - Abstract
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent metabolic disease, although prevalence could change according to region, nowadays is considered a public health problem whose real impact on the health system is unknown. NAFLD has a multifactorial and complex pathophysiology, due to this, developing a unique and effective pharmacological treatment has not been successful in reverting or avoiding the progression of this liver disease. Even though NAFLD pathophysiology is known, all actual treatments are focused on modifying or regulating the metabolic pathways, some of which interplay with obesity. It has been known that impairments in hunger and satiety signals are associated with obesity, however, abnormalities in these signals in patients with NAFLD and obesity are not fully elucidated. To describe these mechanisms opens an additional option as a therapeutic target sharing metabolic pathways with NAFLD, therefore, this review aims to describe the hormones and peptides implicated in both hunger-satiety in NAFLD. It has been established that NAFLD pharmacological treatment cannot be focused on a single purpose; hence, identifying interplays that lead to adding or modifying current treatment options could also have an impact on another related outcome such as hunger or satiety signals. [ABSTRACT FROM AUTHOR]
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- 2023
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49. Clinical, Pathophysiologic, Genetic, and Therapeutic Progress in Primary Bilateral Macronodular Adrenal Hyperplasia.
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Bertherat, Jérôme, Bourdeau, Isabelle, Bouys, Lucas, Chasseloup, Fanny, Kamenický, Peter, and Lacroix, André
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PATHOLOGICAL physiology ,HYPERPLASIA ,HYDROCORTISONE - Abstract
Patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) usually present bilateral benign adrenocortical macronodules at imaging and variable levels of cortisol excess. PBMAH is a rare cause of primary overt Cushing's syndrome but may represent up to one-third of bilateral adrenal incidentalomas with evidence of cortisol excess. The increased steroidogenesis in PBMAH is often regulated by various G protein–coupled receptors (GPCRs) aberrantly expressed in PBMAH tissues; some receptor ligands are ectopically produced in PBMAH tissues, creating aberrant autocrine/paracrine regulation of steroidogenesis. The bilateral nature of PBMAH and familial aggregation led to the identification of germline heterozygous inactivating mutations of the ARMC5 gene, in 20% to 25% of the apparent sporadic cases and more frequently in familial cases; ARMC5 mutations/pathogenic variants can be associated with meningiomas. More recently, combined germline mutations/pathogenic variants and somatic events inactivating the KDM1A gene were specifically identified in patients affected by glucose-dependent insulinotropic peptide (GIP)-dependent PBMAH. Functional studies demonstrated that inactivation of KDM1A leads to GIP-receptor (GIPR) overexpression and over- or downregulation of other GPCRs. Genetic analysis is now available for early detection of family members of index cases with PBMAH carrying identified germline pathogenic variants. Detailed biochemical, imaging, and comorbidity assessment of the nature and severity of PBMAH is essential for its management. Treatment is reserved for patients with overt or mild cortisol/aldosterone or other steroid excesses, taking in account comorbidities. It previously relied on bilateral adrenalectomy; however, recent studies tend to favor unilateral adrenalectomy or, less frequently, medical treatment with cortisol synthesis inhibitors or specific blockers of aberrant GPCR. [ABSTRACT FROM AUTHOR]
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- 2023
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50. The impact of a stress management intervention including cultural components on stress biomarker levels and mental health indicators among indigenous women.
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Aker, Amira, Serghides, Lena, Cotnam, Jasmine, Jackson, Randy, Robinson, Margaret, Gauvin, Holly, Mushquash, Christopher, Gesink, Dionne, Amirault, Marni, and Benoit, Anita C.
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CULTURE -- Psychological aspects ,SALIVA analysis ,STRESS management ,BIOMARKERS ,INDIGENOUS women ,CONFIDENCE intervals ,AGE distribution ,MENTAL health ,POST-traumatic stress disorder ,TREATMENT effectiveness ,DESCRIPTIVE statistics ,RESEARCH funding ,HUMAN beings ,PSYCHOLOGICAL stress ,EDUCATIONAL attainment ,PSYCHOSOCIAL factors - Abstract
We examined the effectiveness of a 26-week culture-inclusive intervention on reducing salivary stress biomarker levels, and perceived stress, depressive, and post-traumatic stress disorder (PTSD) symptoms measured using scales in 53 Indigenous women in Ontario, Canada. Statistical analyses compared the average biomarker levels, and the area under the curve (AUC) of biomarkers. Differences in biomarkers and mental health scale scores pre- and post-intervention were compared using mixed models with a random intercept. Interaction terms were included between the intervention and age, education, disability, and HIV status, individually, to test for sub-group differences. Cortisol AUC post-intervention was decreased compared to pre-intervention (β -1.29 µg/dL; 95%CI -2.35, -0.23). There was a slight decrease in perceived stress levels (aOR: -2.80; 95%CI -5.09, -0.50). The associations were stronger among women of younger age, higher education, and no disabilities. These interventions can be effective, but future interventions should target Indigenous population sub-groups to address individual needs. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
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