The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

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How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

Secret History: Return of the Black Death Channel 4, 7-8pm In 1348 the Black Death swept through London, killing people within days of the appearance of their first symptoms. Exactly how many died, and why, has long been a mystery. This Secret History documentary follows experts as they pick through the evidence and reveal why the plague killed on such a scale. And they ask, what might be coming next?

Medscape

These guidelines have been replaced by British Guideline on the Management of Asthma. A national clinical guideline. Superseded By 2012 Revision Of 2008 Guideline: British Guideline on the Management of Asthma. Thorax 2008 May; 63(Suppl 4): 1–121.

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British guideline on the management of asthma: A national clinical guideline

Although the rate of acute severe adverse cutaneous reactions to medications is low, these reactions can affect anyone who takes medications and can result in death or disability1. Even a small number of cases associated with a particular drug may alter the recommendations for its use2–4. Prompt differentiation of severe adverse cutaneous reactions from less serious skin disorders may be difficult. Rapid recognition of severe reactions is essential. Prompt withdrawal of the offending drug is often the most important action to minimize morbidity. Adverse cutaneous reactions to drugs are frequent, affecting 2 to 3 percent of hospitalized . . .

Severe Adverse Cutaneous Reactions to Drugs

Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sen...

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Genetic Sensitivity to the Environment: The Case of the Serotonin Transporter Gene and Its Implications for Studying Complex Diseases and Traits

Drug-induced gingival enlargement (DIGE) is a fibrotic condition that can be caused by the antihypertensive drug nifedipine and the anti-seizure drug phenytoin, but the molecular etiology of this type of fibrosis is not well understood and the role of confounding factors such as inflammation remains to be fully investigated. The aim of this study was to develop an ex vivo gingival explant system to allow investigation of the effects of nifedipine and phenytoin alone on human gingival tissue. Comparisons were made to the histology of human DIGE tissue retrieved from individuals with DIGE. Increased collagen, fibronectin, and proliferating fibroblasts were evident, but myofibroblasts were not detected in DIGE samples caused by nifedipine and phenytoin. In healthy gingiva cultured in nifedipine or phenytoin-containing media, the number of cells positive for p-SMAD2/3 increased, concomitant with increased CCN2 and periostin immunoreactivity compared to untreated explants. Collagen content assessed through hydroxyproline assays was significantly higher in tissues cultured with either drug compared to control tissues, which was confirmed histologically. Matrix fibronectin levels were also qualitatively greater in tissues treated with either drug. No significant differences in proliferating cells were observed between any of the conditions. Our study demonstrates that nifedipine and phenytoin activate canonical transforming growth factor-beta signaling, CCN2 and periostin expression, as well as increase collagen density, but do not influence cell proliferation or induce myofibroblast differentiation. We conclude that in the absence of confounding variables, nifedipine and phenytoin alter matrix homeostasis in gingival tissue explants ex vivo, and drug administration is a significant factor influencing ECM accumulation in gingival enlargement.

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Nifedipine and phenytoin induce matrix synthesis, but not proliferation, in intact human gingival connective tissue ex vivo.

Historically genetics has not been considered when prescribing drugs for children. However, it is clear that genetics are not only an important determinant of disease in children but also of drug response for many important drugs that are core agents used in the therapy of common problems in children. Advances in therapy and in the ethical construct of children's research have made pharmacogenomic assessment for children much easier to pursue. It is likely that pharmacogenomics will become part of the therapeutic decision making process for children, notably in areas such as childhood cancer where the benefits and risks of therapy are considerable.

Pharmacogenomics in children.

Objective Exploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates. Design Prospective, single-centre, open-label, pharmacokinetics study in preterm neonates. Setting Neonatal intensive care unit at McMaster Children’s Hospital. Patients Neonates with a gestational age ≤28+6 weeks treated with oral ibuprofen for closure of a PDA. Methods Population pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation. Main outcome measure Association between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC0–72h >900 mg·hour/L). Results Twenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours’ postdose on the first day, a strong correlation between ibuprofen concentrations and AUC0–72h was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure. Conclusion We designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC0–72h >900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA.

https://adc.bmj.com/content/archdischild/early/2021/05/10/archdischild-2020-321381.full.pdf

Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, drug‐induced severe adverse reaction that usually occurs 3–6 weeks after initial exposure to certain drugs. It affects mainly adults and children to a lesser extent. Clinical features include fever, facial oedema, generalized skin rash, lymphadenopathy, haematological abnormalities and internal organ involvement. The objective was to investigate the clinical and laboratory features of patients with DRESS in our centre.

Michael J. Rieder

Papers

Nifedipine and phenytoin induce matrix synthesis, but not proliferation, in intact human gingival connective tissue ex vivo.

Pharmacogenomics in children.

Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates.

Drug reaction with eosinophilia and systemic symptoms (DRESS): A tertiary care centre retrospective study

Hair cortisol as a novel biomarker of HPA suppression by inhaled corticosteroids in children