Jonathan Seckl

Jonathan Seckl
The University of Edinburgh | UoE · Centre for Cardiovascular Science

About

704
Publications
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Publications

Publications (704)
Article
Full-text available
Abstract Hypothalamic–pituitary–adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematica...
Article
Full-text available
STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS pro...
Article
Full-text available
Respiratory droplets are the primary transmission route for SARS-CoV-2, a principle which drives social distancing guidelines. Evidence suggests that virus transmission can be reduced by face coverings, but robust evidence for how mask usage might affect safe distancing parameters is lacking. Accordingly, we set out to quantify the effects of face...
Preprint
Full-text available
Respiratory droplets are the primary transmission route for SARS-CoV-2. Evidence suggests that virus transmission can be reduced by face coverings, but robust evidence for how mask usage might affect safe distancing parameters is lacking. Accordingly, we investigate the effectiveness of surgical masks and single-layer cotton masks on mitigating dis...
Article
Context Across pregnancy, maternal serum cortisol levels increase up to 3-fold. It is not known whether maternal peripheral cortisol metabolism and clearance change across pregnancy or influence fetal cortisol exposure and development. Objectives The primary study objective was to compare maternal urinary glucocorticoid metabolites, as markers of...
Article
Full-text available
Background Obesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing’s Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoi...
Article
Full-text available
STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS pro...
Article
Introduction: Despite the ongoing increase in the prevalence of obesity, there are few licensed anti-obesity medications, and these therapies have limited efficacy and significant side effects. Therefore, new treatments are being developed, including 11-βhydroxysteroid dehydrogenase type1 (11βHSD1) inhibitors. In vivo, the enzyme 11-βhydroxysteroid...
Article
Full-text available
Deficiency in cytochrome P450 (CYP) 7B1, also known as oxysterol 7α-hydroxylase, in humans leads to hereditary spastic paraplegia type 5 (SPG5) and in some cases in infants to liver disease. SPG5 is medically characterized by loss of motor neurons in the corticospinal tract. In an effort to gain a better understanding of the fundamental biochemistr...
Article
Context Primary Hyperparathyroidism (PHPT) has a prevalence of 0.86% and is associated with increased risk of nephrolithiasis and osteoporosis. PHPT may also be associated with an increased risk of cardiovascular disease and mortality. Objective To identify risk factors for nephrolithiasis, osteoporosis and mortality in PHPT. Design Retrospective...
Article
Objective Radioiodine (RAI) is an effective treatment for Graves’ thyrotoxicosis but is associated with a failure rate of 15% and may be a risk factor for thyroid eye disease (TED) and weight gain. We sought to examine predictors of RAI failure, weight gain, TED and patient satisfaction. Design Retrospective cohort study. Patients 655 episodes of...
Article
Full-text available
Objective: Primary hyperparathyroidism (PHPT) is a common reason for referral to endocrinology but the evidence base guiding assessment is limited. We evaluated the clinical presentation, assessment and subsequent management in PHPT. Design: Retrospective cohort study. Patients: PHPT assessed between 2006 - 2014 (n = 611) in a university hospi...
Article
Full-text available
Chronic exposure to stress during midlife associates with subsequent age-related cognitive decline and may increase the vulnerability to develop psychiatric conditions. Increased hypothalamic-pituitary-adrenal (HPA) axis activity has been implicated in pathogenesis though any causative role for glucocorticoids is unestablished. This study investiga...
Article
Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised...
Article
Full-text available
11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) predominantly converts inert glucocorticoids into active forms, thereby contributing to intracellular glucocorticoid levels. 11β-HSD1 is dynamically regulated during inflammation, including in macrophages where it regulates phagocytic capacity. The resolution of inflammation in some disease models inclu...
Article
Full-text available
Evidence from human studies suggests that high expression of brain mineralocorticoid receptors (MR) may promote resilience against negative consequences of stress exposure, including childhood trauma. We examined, in mice, whether brain MR overexpression can alleviate the effects of chronic early life stress (ELS) on contextual memory formation und...
Data
Figure S2 Adrenal steroid levels following multiple dose administration. 8 healthy male subjects per dose level. A. Day 1 cortisol, B. Day 10 cortisol, C. 4‐androstenedione, D. testosterone, E. DHEA‐s.
Data
Figure S1 Adrenal steroid levels following single dose administration. 6 healthy male and 2 healthy female subjects per dose level. A. Cortisol, B. 4‐androstenedione, C. testosterone and D. DHEA‐s.
Data
Figure S3 ACTH levels following multiple dosing. 8 healthy male subjects per dose level. A. Day 1 and B. Day 10.
Article
Earlier puberty, especially in girls, is associated with physical and mental disorders. Prenatal glucocorticoid exposure influences the timing of puberty in animal models, but the human relevance of those findings is unknown. We studied whether voluntary consumption of licorice, which contains glycyrrhizin (a potent inhibitor of placental 11β- hydr...
Chapter
The early life environment is crucial for later life health including mental health and cognitive function. Exposure to glucocorticoids in utero is thought to be a key underlying mechanism. Here we review the evidence from both animal and human studies that alterations in fetal exposure to glucocorticoids impact on fetal brain development with impl...
Data
Table S1. Oligonucleotide sequences for polymerase chain reaction amplification of ‘floppy’ cDNA template for brain‐derived neurotrophic factor (BDNF) probe synthesis. Table S2. Adrenal weight, body weight and basal AM plasma corticosterone (CORT) levels in aged behaviourally tested aged mice. Fig. S1. 11β‐Hydroxysteroid dehydrogenase type 1 (11β...
Article
Full-text available
Background and purpose: Reducing glucocorticoid exposure in the brain via intracellular inhibition of the cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD1) has emerged as a therapeutic strategy to treat cognitive impairment in early Alzheimer's disease (AD). We sought to discover novel, brain-penetrant 11β-HSD1 inhibitors as...
Article
Full-text available
Background: Preterm birth associates with a substantially increased risk of later cardiovascular disease and neurodevelopmental disorders. Understanding underlying mechanisms will facilitate the development of screening and intervention strategies to reduce disease risk. Changes in DNA methylation have been proposed as one mechanism linking the ea...
Article
The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) interconverts active glucocorticoids and their intrinsically inert 11-keto forms. The type 1 isozyme, 11β-HSD1, predominantly reactivates glucocorticoids in vivo and can also metabolise bile acids. 11β-HSD1-deficient mice show altered inflammatory responses and are protected against the adverse...
Article
Full-text available
Mice lacking the intracellular glucocorticoid-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) are protected from age-related spatial memory deficits. 11β-HSD1 is expressed predominantly in brain, liver and adipose tissue. Reduced glucocorticoid levels in brain in the absence of 11β-HSD1 may underlie the improved memory in age...
Article
Background Thionamides are associated with a high risk of recurrence following cessation. Thyrotropin receptor-stimulating antibody (TRAb) levels at diagnosis and/or after thionamides may be biomarkers of this risk. This study assesses the natural history of Graves’ thyrotoxicosis following thionamide withdrawal and factors that predict recurrence;...
Article
The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic 'lean' mouse model, which has been selected for low adiposity over 60 generations, to identify mitochondrial thiosulfate sulfurtransferase (Tst; also known as r...
Article
Fetoplacental glucocorticoid overexposure is a significant mechanism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) plays a key role. We previously discovered that Hsd11b2(-/-) mice, lacking 11β-HSD2, show ma...
Article
Endogenous glucocorticoid action within cells is enhanced by pre-receptor metabolism by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts intrinsically inert cortisone and 11-dehydrocorticosterone into active cortisol and corticosterone, respectively. 11β-HSD1 is highly expressed in immune cells elicited to the mouse peritoneum dur...
Article
Full-text available
Background: -The hypertensive syndrome of Apparent Mineralocorticoid Excess is caused by loss of function mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), allowing inappropriate activation of the mineralocorticoid receptor (MR) by endogenous glucocorticoid. Hypertension is attributed to sodium retention in the dist...
Article
Full-text available
Early-life stress is a risk factor for the development of psychopathology, particularly in women. Human studies have shown that certain haplotypes of NR3C2, encoding the mineralocorticoid receptor (MR), that result in gain of function, may protect against the consequences of stress exposure, including childhood trauma. Here, we tested the hypothesi...
Data
Figure S1. Initial assessment of young and aged wild‐type and 11β‐HSD1‐deficient mice in the Y‐maze following a 1‐min inter‐trial interval (ITI). Figure S2. Comparison of scatter plots of log intensity values (four replicates combined) for young and aged wild‐type mice main comparisons. Figure S3. Comparison of scatter plots of log intensity valu...
Article
Full-text available
Exposure to chronic stress is a risk factor for cognitive decline and psychopathology in genetically predisposed individuals. Preliminary evidence in humans suggests that mineralocorticoid receptors (MRs) may confer resilience to these stress-related changes. We specifically tested this idea using a well-controlled mouse model for chronic stress in...
Article
Full-text available
Mice deficient in the glucocorticoid-regenerating enzyme 11β-HSD1 resist age-related spatial memory impairment. To investigate the mechanisms/pathways involved, we used microarrays to identify differentially expressed hippocampal genes that associate with cognitive ageing and 11β-HSD1. Aged wild-type mice were separated into memory-impaired and uni...