To assess the effects of age on both the pituitary ACTH response to corticotropin-releasing hormone (CRH) and the secretory responses of cortisol (F) and dehydroepiandrosterone (DHEA) to endogenous rises in ACTH, we measured evening basal and ovine CRH (oCRH; 1 mu/kg)-stimulated plasma concentrations of ACTH,F, and DHEA in 49 healthy men, aged 21-86 yr. By analysis of variance, we found no change with age in either the basal concentration of ACTH or the magnitude of the peak ACTH response to oCRH. Older men had higher basal F levels (P less than 0.05), while basal plasma levels of CBG and ratios of F to CBG did not vary significantly with age (P greater than 0.1). We also found no significant increase with age in the magnitude of the peak F response to oCRH (P greater than 0.2), although peak F responses occurred significantly earlier (P less than 0.03) in the older men. Basal plasma levels of DHEA decreased significantly with age (P less than 0.001), as did the magnitude of peak DHEA responses to endogenous ACTH rises (P less than 0.01). There was no alteration in the timing of the peak DHEA response with age (P greater than 0.7). We conclude that while ACTH and F responses to evening injections of oCRH are well maintained in healthy aging men, that of DHEA is discordantly decreased. The present findings are compatible with the hypotheses that there is a diminished sensitivity of ACTH secretion to negative feedback regulation by glucocorticoids in older men, and there is an ACTH-independent age-related diminution in adrenal androgen secretion.
Ovine and human corticotropin-releasing factors (CRF) have similar potencies in causing adrenocorticotropic hormone (ACTH) and cortisol secretion in normal humans. Using long-acting ovine CRF (1 µg/kg body weight as an intravenous bolus), we tested patients with Cushing's syndrome, adrenal insufficiency, and psychiatric conditions with mild hypercortisolism. Over 95% of hypercortisolemic patients with a pituitary adenoma responded with increases in plasma ACTH and cortisol concentrations; patients with the ectopic ACTH syndrome had no ACTH or cortisol responses; patients with ACTH-independent hypercortisolism of adrenal origin had low or undetectable plasma ACTH concentrations before and after CRF without any cortisol response. The differences in responses of patients with adrenal insufficiency of primary, pituitary, or suprapituitary type likewise suggest value of the CFR test in their differential diagnosis. The responses in the psychiatric patients should permit differentiation between Cushing's syndrome and hypercortisolism of psychiatric origin.
Summary The selection of a scalar Intensity Measure (IM) for performing analytical vulnerability (loss) assessment across a building class is addressed. We investigate the ability of several IM choices to downgrade the effect of seismological parameters (sufficiency) as well as reduce the record‐to‐record variability (efficiency) for both highrise and lowrise sets of ‘index’ buildings. These characteristics are explored in unprecedented detail, employing comparisons and statistical significance testing at given levels of local engineering demand parameters (story drift ratios and peak floor accelerations) that relate to losses, instead of global variables such as the maximum interstory drift. Thus, a detailed limit‐state‐specific view is offered for the suitability of different scalar IMs for loss assessment. As expected, typical single‐period spectral values are found to introduce unwanted bias at high levels of scaling, both for a single as well as a class of buildings. On the other hand, the geometric mean of the spectral acceleration values estimated at several periods between the class‐average second‐mode and an elongated class‐average first‐mode period offers a practical choice that significantly reduces the spectral‐shape bias without requiring the development of new ground motion prediction equations. Given that record selection remains a site‐ and building‐specific process, such an improved IM can help achieve reliable estimates for building portfolios, as well as single structures, at no additional cost. Copyright © 2015 John Wiley & Sons, Ltd.
Cushing’s syndrome (CS) results from prolonged exposure of tissues to excess of glucocorticoids. After Harvey Cushing’ s initial report in the early 20th century (1), CS has been etiologically subdivided into adenocorticotropin hormone (ACTH)-independent (nonpituitary) or ACTH-dependent (2–4). Endogenous CS is rare, with an overall incidence of approx two to four new cases per million of population per year. ACTH-dependent CS accounts for approx 85% of endogenous cases. In the majority of these cases (80%), the cause is autonomous pituitary ACTH secretion and is referred to as Cushing’s disease (CD). In the remaining 20%, the ACTH secretion source is ectopic. CD has a female to male preponderance (8/1), whereas the ectopic ACTH syndrome is more common in men (3/1). Ectopic corticotropin-releasing hormone (CRH) production causing CS has also been described in approx 11 cases (5–7). In this chapter, we focus on the diagnosis and treatment of CD which generally presents between the second and sixth decades of life, with a peak incidence at age 35 yr (2).
Incremental dynamic analysis (IDA) is a parametric analysis method that has recently emerged in several different forms to estimate more thoroughly structural performance under seismic loads. It involves subjecting a structural model to one (or more) ground motion record(s), each scaled to multiple levels of intensity, thus producing one (or more) curve(s) of response parameterized versus intensity level. To establish a common frame of reference, the fundamental concepts are analysed, a unified terminology is proposed, suitable algorithms are presented, and properties of the IDA curve are looked into for both single‐degree‐of‐freedom and multi‐degree‐of‐freedom structures. In addition, summarization techniques for multi‐record IDA studies and the association of the IDA study with the conventional static pushover analysis and the yield reduction R‐factor are discussed. Finally, in the framework of performance‐based earthquake engineering, the assessment of demand and capacity is viewed through the lens of an IDA study. Copyright © 2001 John Wiley & Sons, Ltd.
Type 2 diabetes mellitus (T2DM) is a multifactorial disorder defined by insulin resistance, β-cell dysfunction, and chronic hyperglycemia. Although peripheral mechanisms have been extensively studied, increasing evidence implicates the gastrointestinal tract in disease onset. Insights from bariatric surgery, gut hormone signaling, and incretin-based therapies suggest that the gut contributes actively beyond nutrient absorption. Yet, a cohesive framework integrating these observations remains absent, leaving a critical gap in our understanding of T2DM's upstream pathophysiology. This work builds upon the anti-incretin theory, which posits that nutrient-stimulated neurohormonal signals-termed "anti-incretins"-arise from the proximal intestine to counteract incretin effects and regulate glycemic homeostasis. The excess of anti-incretin signals, perhaps stimulated by macronutrient composition or chemical additives of modern diets, disrupts this balance and may cause insulin resistance and β-cell depletion, leading to T2D. We hypothesize that the neuroendocrine signals produced by cholecystokinin (CCK)-I and secretin-S cells, both located in the proximal intestine, function as endogenous anti-incretins. In this context, we hypothesize a novel model centered on the chronic overstimulation of I and S cells by high-fat, high glycemic index modern diets. This drives what we term "amplified digestion"-a state marked by heightened vagal and hormonal stimulation of biliary and pancreatic secretions, increased enzymatic and bile acid activity, and alterations in bile acid composition. This condition leads to an extended breakdown of carbohydrates, lipids, and proteins into absorbable units, thereby promoting excessive nutrient absorption and ultimately contributing to insulin resistance and progressive β-cell failure. Multiple lines of clinical, surgical, and experimental evidence converge to support our model, rooted in the physiology of digestion and absorption. Western dietary patterns appear to induce an over-digestive adaptation-marked by excessive vagal and hormonal stimulation of biliary and pancreatic secretion-which amplifies digestive signaling. This heightened state correlates with increased nutrient absorption, insulin resistance, and β-cell dysfunction. Interventions that disrupt this maladaptive signaling-such as truncal vagotomy combined with duodenal bypass-may offer novel, physiology-based strategies for T2DM treatment. This hypothesis outlines a potential upstream contributor to insulin resistance and T2DM, grounded in digestive tract-derived neurohormonal dysregulation. This gut-centered model may provide insight into early, potentially reversible stages of the disease and identify a conceptual therapeutic target. Nonetheless, both the hypothesis and the accompanying surgical strategy-truncal vagotomy combined with proximal intestinal bypass-remain highly exploratory and require systematic validation through mechanistic and clinical studies. Further investigation is warranted to clarify the molecular regulation of I and S enteroendocrine cells, including the genetic and epigenetic factors that may drive hypersecretion. While speculative, interventions-surgical or pharmacologic-designed to modulate these digestive signals could represent a future avenue for research into T2DM prevention or remission, pending rigorous evidence.
Primary Generalized Glucocorticoid Resistance or Chrousos Syndrome is a rare endocrinologic condition, which affects almost all tissues, and is characterized by resistance of tissues to glucocorticoids. The clinical spectrum of Chrousos syndrome is broad, ranging from asymptomatic cases to severe cases of mineralocorticoid and/or androgen excess. At the molecular level, Chrousos syndrome has been associated with defects in the NR3C1 gene that encodes the human glucocorticoid receptor (hGR). We and others have applied molecular and structural biology methods to investigate the molecular mechanisms of action of the mutant hGRs. We demonstrated that the defective hGRs impair several steps of glucocorticoid signaling cascade depending on the position of the NR3C1 gene defect. In clinical practice, when Chrousos syndrome is suspected, a detailed personal and family history should be obtained, while physical examination should include an assessment for signs of mineralocorticoid and/or androgen excess. Suspected patients should then undergo a detailed endocrinologic evaluation with particular emphasis on the measurement of serum cortisol concentrations and determination of the 24-hour urinary free cortisol (UFC) excretion on 2 or 3 consecutive days. Affected subjects demonstrate resistance of the HPA axis to dexamethasone suppression, which may vary depending on the severity of the condition. The diagnosis of Chrousos syndrome is confirmed by sequencing of the coding region of the NR3C1 gene, including the intron/exon junctions. Treatment of Chrousos syndrome involves administration of high doses of mineralocorticoid-sparing synthetic glucocorticoids, which activate the mutant and/or wild-type hGRα, and suppress the endogenous secretion of ACTH in affected subjects. For complete coverage of this and related areas in Endocrinology, visit our free web-books, www.endotext.org and www.thyroidmanager.org .
