Aspects of adrenal function in children

The research work comprising this thesis is partly clinical and partly biochemical. The clinical aspects concern the diagnosis and treatment of congenital adrenal hyperplasia and an assessment of some children of small stature. Most of these patients have been in Professor J.H. Hutchison's Wards at the Royal Hospital for Sick Children, Glasgow, and I am indebted to him for allowing access to this clinical material. Indebtedness is also due to Ur. James R. Davidson, General Director of Quarrier's Homes, Bridge of Weir, in Whose care were some of the children of small stature. The biochemical aspect of the thesis is a study of urinary steroids in cases of congenital adrenal hyperplasia. While principally to assist in their management, the investigation was extended to urinary aldosterone and 17-oxosteroid studies. In the children of small stature, the metabolism of hydrocortisone has been assessed by the estimation of the urinary metabolites of this compound. From the findings, hepatic reductase activity and 11-oxidation of hydro cortisone have been deduced. In Chapter 4 there is a critical analysis of the value of urinary aldosterone estimation in infancy and childhood

Ailing, Aging, Addicted: Studies of Compromised Leadership

What role did drug abuse play in John F. Kennedy\u27s White House, and how was it kept from the public? How did general anesthetics and aging affect the presidency of Ronald Reagan? Why did Winston Churchill become more egocentric, Woodrow Wilson more self- righteous, and Josef Stalin more paranoid as they aged—and how did those qualities alter the course of history? Was Napoleon poisoned with arsenic or did underlying disease account for his decline at the peak of his power? Does syphilis really explain Henry VIII\u27s midlife transformation? Was there more than messianism brewing in the brains of some zealots of the past, among them Adolf Hitler, Joan of Arc, and John Brown? Most important of all, when does one man\u27s illness cause millions to suffer, and when is it merely a footnote to history? To answer such questions requires the clinical intuition of a practicing physician and the scholarly perspective of a trained historian. Bert Park, who qualifies on both counts, offers here fascinating second opinions, basing his retrospective diagnoses on a wide range of sources from medicine and history. Few books so graphically portray the impact on history of physiologically compromised leadership, misdiagnosis, and inappropriate medical treatment. Park not only untangles medical mysteries from the past but also offers timely suggestions for dealing with such problems in the future. As a welcome sequel to his first work, The Impact of Illness on World Leaders, this book offers scholars, physicians, and general readers an entertaining, albeit sobering, analysis. Bert E. Park, M.D., is a practicing neurological surgeon, an adjunct professor of history, and a member of the Editorial Advisory Committee of the Papers of Woodrow Wilson. Historians will be grateful for Park\u27s meticulous and wide-ranging citations and well-crafted index. This book will entertain, provoke, and stimulate historians, physicians, and general readers alike, and should stimulate further scholarship concerning the pathography of world leaders. —Bulletin of the History of Medicinehttps://uknowledge.uky.edu/upk_history_in_general/1003/thumbnail.jp

Medical treatment and monitoring for disorders of cortisol and adrenocorticotrophin excess and deficiency

Background: Disorders of cortisol secretion have high mortality and morbidity if inadequately treated. Medical treatment is an essential part of patient management and has improved prognosis and morbidity, however, there are unanswered questions about effectiveness, safety, accuracy and monitoring. The hypothesis in this thesis was that medical treatments can restore physiological cortisol and adrenocorticotrophin hormone (ACTH) levels in patients with disorders of cortisol excess and deficiency. Methods: Five studies examined the treatment and monitoring of cortisol secretion disorders. Two studies examined medical treatment of cortisol and ACTH excess, Cushings syndrome (CS) and Nelson’s syndrome (NS), two studies examined new methods for replacing cortisol in children with adrenal insufficiency and one study examined potential for a novel biomarker of cortisol replacement in congenital adrenal hyperplasia (CAH). Results: Study 1, demonstrated that medical therapy with the steroidogenesis enzyme inhibitor metyrapone was effective in restoring eucortisolaemia and reducing hypercortisolaemia in 50-80% of patients with CS. Study 2, demonstrated that medical therapy with pasireotide, a multi-receptor somatostatin analogue, reduced plasma ACTH levels in patients with Nelson’s syndrome. Study 3, showed that it is possible to replace cortisol with hydrocortisone through nasogastric tubes, however, there are variable drug loses due to interaction with the administering equipment and the study provided practical solutions. Study 5, showed that a novel formulation of hydrocortisone granules administered sprinkled on soft food (applesauce or yoghurt) are bioequivalent to granules delivered directly to the back of the tongue. Study 4, showed that haemoglobin and haematocrit are positively correlated with androgen and steroid precursor levels in women with CAH and provide a novel biomarker. Conclusions. Medical therapy for cortisol excess and deficiency can be improved. Metyrapone and pasireotide are effective in improving cortisol and ACTH levels in patients with CS and Nelson’s syndrome, respectively. The replacement of cortisol in paediatric adrenal insufficiency can be done through nasogastric tubes if required and with food to improve accurate dosing in neonates, infants and children. Markers of erythropoiesis may be used as a biomarker to monitor disease control in women with CAH

The effects of xenobiotics on steroidogenesis in human: "in vitro" and "in vivo" investigations

Steroid hormones have a pivotal role in many physiological processes. For example, the glucocorticoids are crucial in the regulation and maintenance of sugar balance, immunity, stress response, and mood, whereas the mineralocorticoids are involved in electrolyte- and water balance thus regulating blood pressure. Androgens are crucial for muscle function, cardiovascular system and the development and maintenance of male characteristics. Therefore, the disruption of the steroidogenesis is associated with severe diseases such as cancer, metabolic syndrome, cardiovascular diseases, immune disorders, impaired brain function, and developmental dysfunctions. In the first part of this thesis, we were interested in the in vitro investigation of xenobiotics affecting the human steroidogenesis. We focused on the adrenal steroidogenesis, which is rather neglected by many regulatory agencies, despite its pivotal role in humans. We provided a critical overview of the current available cell lines used to screen for potential endocrine disruptors and to study their effects on adrenal steroidogenesis. Moreover, we discussed their advantages/disadvantages, and the need for improvements of the well-established human carcinoma cell line H295R and the associated validated OECD test guideline 456, namely the “H295R steroidogenesis assay”. This resulted in a refined version of the H295R steroidogenesis assay, which is distinguished from the currently used OECD protocols by analyzing multiple adrenal steroids simultaneously with exclusive separation techniques combined with mass spectrometry, as well as including additional controls, such as medium composition at the starting time and reference compounds with known mechanism. The obtained results of the steroid changes can then be further combined with the observed effects on gene expression, providing first mechanistic hints on steroidogenesis disruption. By using the newly established refined version of the H295R steroidogenesis assay, we demonstrated that exposure of H295R cells to the UV-filter octyl methoxycinnamate and the plasticizer acetyl tributylcitrate resulted in increased corticosteroid levels, as well as enhanced CYP11B2 expression, similar to the corticosteroid inducer torcetrapib (positive control). To summarize, the refined H295R steroidogenesis assay is a valuable in vitro tool to screen and study chemicals potentially disrupting the production of adrenal steroids and provides initial mechanistic evidence in combination with gene expression data. Many psychoactive drugs can lead to immense increases in cortisol by stimulating the hypothalamic-pituitary-adrenal (HPA) axis. However, a comprehensive analysis of drug induced changes of several steroids, such as glucocorticoids, mineralocorticoids and adrenal androgens along with their full time courses is missing. In the second part of this thesis, we studied the effects of lysergic acid diethylamide (LSD), which has sparked a renewed interest in psychiatric research, lisdexamfetamine, a new drug for the treatment of attention deficit hyperactivity disorder (ADHD), and D-amphetamine on the circulating steroids in vivo. Plasma samples were obtained from two individual clinical trials, where healthy volunteers were administered a single dose of either LSD (200 µg), lisdexamfetamine dimesylate (100 mg) or immediate-release D-amphetamine sulfate (40.3 mg) at equimolar doses. Both studies were conducted using a randomized, double-blind, placebo-controlled, cross-over design and plasma steroids for the concentration–time profiles were quantified by ultra-high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). We could demonstrate, that LSD produces significant acute effects on circulating steroids compared to placebo in 16 healthy volunteers. The glucocorticoids cortisol, cortisone, corticosterone and 11-dehydrocorticosterone were significantly increased following LSD administration, indicating HPA axis stimulation. Cortisol and corticosterone reached the maximum concentration (cmax) after 2.5 h and 1.9 h of LSD administration, respectively. Evaluation of the relationship between the LSD concentration in plasma and the glucocorticoid response to LSD indicated no acute pharmacological tolerance. Furthermore, the androgens dehydroepiandrosterone (cmax and the area under the concentration-time curve from time 0 to 10 h (AUC10)) and androstenedione (AUC10) were significantly increased by LSD, but not the other androgens, mineralocorticoids or progestogens compared to placebo. We showed, that the administration of equivalent doses of lisdexamfetamine and D-amphetamine exhibit an identical pharmacokinetic profile for plasma D-amphetamine. However, lisdexamfetamine administration showed a significantly longer onset time (1.4 vs. 0.8 h) and tmax (4.4 vs. 3.2 h) for plasma D-amphetamine compared to D-amphetamine administration, due to the rate-limiting hydrolysis of lisdexamfetamine. Furthermore, lisdexamfetamine and D-amphetamine showed a similar enhancement of glucocorticoid production (cortisol, cortisone, corticosterone, 11-dehydrocorticosterone, and 11-deoxycortisol), increases in androgen precursors (dehydroepiandrosterone, its sulphated metabolite, and androstenedione) and adrenocorticotropic hormone (ACTH) in plasma in 24 healthy volunteers. This suggests a HPA axis stimulation. Moreover, an acute pharmacological tolerance of the drug-induced change in active glucocorticoids was demonstrated. The other circulating steroids, such as the mineralocorticoids (aldosterone and 11-deoxycorticosteone), androgens (testosterone and androsterone) and progestins (17α-hydroxyprogesterone and progesterone (but not the male progesterone levels)), were not affected by lisdexamfetamine or D-amphetamine. In conclusion, LSD, lisdexamfetamine and D-amphetamine had an acute and profound effect on the circulating steroids, especially on the glucocorticoids, suggesting HPA stimulation. This emphasizes the need for further research to understand drug induced changes in steroid homeostasis during chronic administration of amphetamine based ADHD treatments, notably in the pediatric population. Obtained results, should then support an appropriate benefit-risk assessment of these drugs

Food science sourcebook

2 v. : ill. ; 26 cm2nd edition.Rev. ed. of: Source book for food scientists. c1978"An AVI book."Pt. 1. Terms and descriptions -- pt. 2. Food composition,properties, and general data

Tagungsband 1: Proceedings zum 11. Leipziger Tierärztekongress, 07. – 09. Juli 2022

Band 1 beinhaltet neben den typischen „Haustieren“ unter anderem die Artikel zur Berufspolitik und -ethik