Glucocorticoid receptor effects on the immune system and infl ammation

Thomas Addison’s discovery in the mid-1800s that the adrenal cortex was essential for survival preceded by nearly a century the demonstration that this gland produced at least two distinct hormones, each essential for normal life. How glucocorticoids sustained life remained a mystery for decades. In 1949 glucocorticoids were found to have powerful anti-infl ammatory activity, a discovery which led to their use as “miracle drugs” in many diseases 1. Since their introduction in 1948, they have become so important that some authors divide the history into BC and AC (before cortisol and after cortisol) 2. Today, glucocorticoids are among the most important drugs used in routine clinical practice because of their clinically important anti-infl ammatory and immunosuppressive effects. The list of indications for glucocorticoid treatment is long. Diseases in which glucocorticoid treatment plays a major role include common disorders such as asthma, nephrotic syndrome, rheumatoid arthritis, dermatological diseases, Crohn’s disease, systemic diseases, organ transplantation, and malignancies. However, serious adverse effects often accompany treatment. Many adverse effects are partly or mainly caused by glucocorticoid receptor transactivating effects. By contrast, anti-infl ammatory effects are mostly mediated by glucocorticoid receptor transrepression. The challenge is balancing desired therapeutic effects and adverse reactions. Recently, population based individual variability in cortisol sensitivity and its implications for health profi les and risk for disease is coming into focus

Ultralow-dose dexamethasone to preserve endogenous cortisol stress response in nonclassical congenital adrenal hyperplasia: A new promising treatment

Introduction: Nonclassical congenital adrenal hyperplasia (CAH) is characterized by sufficient cortisol and aldosterone production at the cost of androgen overproduction. Hydrocortisone or dexamethasone in supraphysiological doses are current treatment; however, their downside is suppression of endogenous cortisol production resulting in corticosteroid dependency. We aimed to treat children with nonclassical CAH with a ultralow-dose dexamethasone to normalize androgen levels, without a detrimental effect on endogenous cortisol production. Case Presentation: We recruited five patients diagnosed with nonclassical CAH on the basis of clinical presentatio

How Do Pathogens Evolve Novel Virulence Activities?

This article is part of the Top 10 Unanswered Questions in MPMI invited review series.We consider the state of knowledge on pathogen evolution of novel virulence activities, broadly defined as anything that increases pathogen fitness with the consequence of causing disease in either the qualitative or quantitative senses, including adaptation of pathogens to host immunity and physiology, host species, genotypes, or tissues, or the environment. The evolution of novel virulence activities as an adaptive trait is based on the selection exerted by hosts on variants that have been generated de novo or arrived from elsewhere. In addition, the biotic and abiotic environment a pathogen experiences beyond the host may influence pathogen virulence activities. We consider host-pathogen evolution, host range expansion, and external factors that can mediate pathogen evolution. We then discuss the mechanisms by which pathogens generate and recombine the genetic variation that leads to novel virulence activities, including DNA point mutation, transposable element activity, gene duplication and neofunctionalization, and genetic exchange. In summary, if there is an (epi)genetic mechanism that can create variation in the genome, it will be used by pathogens to evolve virulence factors. Our knowledge of virulence evolution has been biased by pathogen evolution in response to major gene resistance, leaving other virulence activities underexplored. Understanding the key driving forces that give rise to novel virulence activities and the integration of evolutionary concepts and methods with mechanistic research on plant-microbe interactions can help inform crop protection.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license

Novel Insights into Obesity in Preschool Children with Autism Spectrum Disorder

Obesity is present in 8–32% of the children with Autism Spectrum Disorder (ASD). However, most studies are performed in school-aged children from the USA. The current study compares obesity rates of Dutch preschoolers with ASD with children from the Dutch general population and explores which child- and parental factors are related to obesity in children with ASD. This cross-sectional study is part of the ongoing Tandem Study (Dutch Trial register: NL7534). Seventy-eight children with ASD aged 3–7 years and their parents (77 mothers, 67 fathers) participated. Child factors are: Body Mass Index (by physical measurement), child eating behavior (Child Eating Behavior Questionnaire), child problem behavior (Child Behavior Checklist), and ASD severity (Autism Diagnostic Observation Scale 2). Parental factors are: BMI (by physical measurement), parental eating behavior (Dutch Eating Behavior Inventory), parenting stress (The Parenting Stress Questionnaire) and highest completed educational level (SES). Children with ASD were 8 times more often obese (16.8%) than children from the general population (2.0%). Child BMI correlated positively with child food approach behavior and maternal BMI, and correlated negatively with child ‘Slowness in eating’. There was no correlation between child BMI and ASD severity, problem behavior, parental eating behavior, parental stress and SES. Thus, Dutch, preschool children with ASD have 8 times higher obesity rates than children from the general population. More attention to obesity risk in research and clinical care could contribute to the quality of life of individuals with ASD and their families. Clinical Trial Registration: Dutch Trial register, NL7534, https://trialsearch.who.int/Trial2.aspx?TrialID=NL7534 .</p

Novel Insights into Obesity in Preschool Children with Autism Spectrum Disorder

Obesity is present in 8–32% of the children with Autism Spectrum Disorder (ASD). However, most studies are performed in school-aged children from the USA. The current study compares obesity rates of Dutch preschoolers with ASD with children from the Dutch general population and explores which child- and parental factors are related to obesity in children with ASD. This cross-sectional study is part of the ongoing Tandem Study (Dutch Trial register: NL7534). Seventy-eight children with ASD aged 3–7 years and their parents (77 mothers, 67 fathers) participated. Child factors are: Body Mass Index (by physical measurement), child eating behavior (Child Eating Behavior Questionnaire), child problem behavior (Child Behavior Checklist), and ASD severity (Autism Diagnostic Observation Scale 2). Parental factors are: BMI (by physical measurement), parental eating behavior (Dutch Eating Behavior Inventory), parenting stress (The Parenting Stress Questionnaire) and highest completed educational level (SES). Children with ASD were 8 times more often obese (16.8%) than children from the general population (2.0%). Child BMI correlated positively with child food approach behavior and maternal BMI, and correlated negatively with child ‘Slowness in eating’. There was no correlation between child BMI and ASD severity, problem behavior, parental eating behavior, parental stress and SES. Thus, Dutch, preschool children with ASD have 8 times higher obesity rates than children from the general population. More attention to obesity risk in research and clinical care could contribute to the quality of life of individuals with ASD and their families. Clinical Trial Registration: Dutch Trial register, NL7534, https://trialsearch.who.int/Trial2.aspx?TrialID=NL7534 .</p

Long-Term Efficacy of T3 Analogue Triac in Children and Adults With MCT8 Deficiency: A Real-Life Retrospective Cohort Study

Context Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. Objective Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. Methods In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. Results From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. Conclusions Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency

Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry

Biomarkers; Congenital adrenal hyperplasia; HydrocortisoneBiomarcadores; Hiperplasia suprarrenal congénita; HidrocortisonaBiomarcadors; Hiperplàsia suprarenal congènita; HidrocortisonaObjective Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4). Design Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries. Patients Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry. Measurements Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM). Results Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1–9.2) were taking a median 11.3 mg/m2/day (8.6–14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0–104.0). Median D4 under 12 years was 0 nmol/L (0–2.0) and above 12 years was 10.5 nmol/L (3.9–21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R2 = 0.29). In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p  0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m2/day for every 1 point increase in weight standard deviation score. Discussion Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain.This project has received support from the I-CAH Registry project that receives unrestricted education grants from Diurnal Ltd and Neurocrine Biosciences. The initial development of the Registry was supported by the Medical Research Council (G1100236), the Seventh European Union Framework Program (201444) and the European Society for Paediatric Endocrinology Research Unit. NRL is funded by an NIHR Academic Clinical Fellowship. SRA is supported by the Gardiner Lectureship at the University of Glasgow. This study was funded by an award to NPK from the DFG, German Research Foundation (KR3363/3-1)

Reproducibility and utility of an overnight 0.25 mg dexamethasone suppression test as a marker for glucocorticoid sensitivity in children with asthma

Purpose: Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment in children. However, there is considerable inter-individual variation in glucocorticoid sensitivity, leading to over- as well as undertreatment. A simple and fast test to predict glucocorticoid sensitivity would enable more tailored therapy in children with asthma. Aim: To study reproducibility and utility of an overnight 0.25 mg dexamethasone suppression test (DST) with salivary cortisol levels as marker for glucocorticoid sensitivity in asthmatic children. Methods: 23 children with atopic asthma were recruited for two overnight 0.25 mg DST's, 1 month apart. Results: Baseline cortisol levels correlated well between both tests. However, cortisol levels, change in cortisol levels or fractional suppression of cortisol levels after dexamethasone did not correlate between the two tests. Bland-Altman plots showed that the difference in salivary cortisol levels between test 1 and 2 of an individual patient could go up to 12 nmol/l, which is a clinically relevant difference. ICS dose did not correlate with baseline cortisol levels, height and BMI SDS. Conclusion: The low-dose salivary DST test in its current form is not suitable for use in clinical practice in children with asthma, due to low reproducibility. Therefore, studies using the 0.25 mg salivary DST should be interpreted cautiously