In this video Q & A, we talk to George Chrousos about stress and its impact on chronic non-communicable disorders (NCDs) and early life development. Professor Chrousos also discusses the effects of psychological and economical stressors on health, and suggests ways in which we can learn to cope with stress.
Modern imaging modalities lead to frequent detection of adrenal masses, most of them incidental findings. Although the majority of adrenocortical and adrenomedullary tumors are benign, there are no reliable clinical and laboratory markers to distinguish most of them from malignant neoplasms. The molecular mechanisms underlying the pathogenesis of these tumors have recently begun to be unraveled. A fruitful avenue for the elucidation of tumorigenesis has been the study of adrenal tumors that are manifestations of hereditary or postzygotic genetic syndromes, because one knows the "first hit", i.e. the primary gene defect. In contrast, in sporadic adrenal tumors the first hit, possibly a somatic mutation of a tumor-related gene, is unknown, and therefore the sequence of genetic alterations is difficult to establish. In this article we review in addition to our own work the literature on molecular aspects of adrenocortical and adrenomedullary tumorigenesis.
A bstract : The term intrauterine growth retardation (IUGR) is assigned to newborns born with a birth weight and/or birth length below the tenth percentile for their gestational age. Intrauterine growth retardation is usually due to maternal, fetal factors, or placental insufficiency, while endocrine factors represent just a small minority in its etiology. Main endocrine‐related causes of IUGR are disorders in insulin or insulin‐like growth factor‐I (IGF‐I) secretion or action. Newborns with IUGR are at increased risk to develop a metabolic syndrome later in life, namely obesity, arterial hypertension, hypercholesterolemia, cardiovascular disease, impaired glucose tolerance, or diabetes mellitus type 2. This association is the result of the adaptational changes of the fetal endocrine‐metabolic mechanisms to the impaired intrauterine milieu to assure survival in the short term. The persistence of these changes after birth can be detrimental in adult life. Furthermore, premature adrenarche, as well as ovarian hyperandrogenism, seem to be associated with IUGR in girls, demonstrating that IUGR may have long‐lasting effects on both somatic health and reproductive function. Finally, the intrauterine exposure of the fetus to stressors may affect the individual's ability to face stress in postnatal life. Therefore, if optimization of somatic and psychosocial well‐being of the individual is the golden goal of medicine, special attention should be paid to maintain an optimal intrauterine milieu devoid of any stressors with adequate nutrient supply and to reserve ideal psychosocial support to the pregnant woman.
A novel scaling algorithm for ground motion accelerograms (GMs) is proposed in support of incremental dynamic analysis used to establish dependable statistical relationships between scalable intensity measures (IMs) and engineering demand parameters (EDPs) within a performance-based earthquake engineering framework. Specifically, an iterative harmonic wavelet-based scheme is employed to accomplish "surgical" changes to the spectral shape of suites of GMs to span various pre-defined levels of the spectral acceleration at the structural fundamental natural period, the most widely adopted IM. Since the target IM values may not be accomplished precisely by the local spectral modifications, a second step involving global uniform GM scaling is further considered. The proposed algorithm requires significantly smaller global (amplitude) scaling factors compared to the currently used scaling approach in which no initial local GM modification is undertaken. A numerical application of the proposed algorithm to elastoplastic structural systems shows the extent to which spectral shape may influence the displacement response of yielding structures and explains the conservative bias introduced by uniform global scaling.
Design for ductile response is a well-used strategy for reducing design forces in earthquake-resisting structures, and typically requires the use of special details to enhance ductility capacity at locations expected to undergo inelastic response. This chapter describes the use of a kinematically admissible mechanism for determining the locations of the plastic hinges, and a virtual work method of analysis for determining the strengths required at these locations. It describes the method of analysis and addresses a design context. For the case with high gravity loads, superposition of gravity and seismic moments causes a negative moment hinge to develop at one end of the beam and a positive moment hinge along the beam span. By proportioning the structure to develop an intended plastic mechanism, it is ensured that the intended mechanism is the one that develops.
Previous studies in the rat have demonstrated that 11-deoxycortisol [compound S (pregn-4-ene-17a,21-diol3,20-dione)], a competitive glucocorticoid antagonist in vitro, fails to behave as an antagonist in growth and adrenal suppression bioassays in nonadrenalectomized animals. This is probably explained by conversion of 11-deoxycortisol to cortisol by the adrenal glands. A'-ll-Deoxycortisol (pregn-l,4,9(l>l)-triene17a,21-diol-3,20 dione) has been shown to resist 11-hydroxylation because of the double bond at the 9-11 position and, hence, should be a more effective antiglucocorticoid in vivo. This hypothesis was tested by comparing the in vivo antiglucocorticoid activity of A'-ll-deoxycortisol with that of 11-deoxycortisol. The affinity of both compounds for the rat thymus glucocorticoid receptor was similar (equilibrium dissociation constant, 3 X 10' M). Both compounds antagonized dexamethasone-induced liver glycogen accumulation in nonadrenalectomized rats, A ' -11deoxycortisol being 3-fold more potent than 11-deoxycortisol. Neither compound showed agonist activity in this bioassay. A-ll-Deoxycortisol showed partial agonist-antagonist activity in 1-week growth suppression and thymus suppression assays, while 11-deoxycortisol behaved as a glucocorticoid agonist. Both compounds failed to antagonize dexamethasone and acted as agonists of equal potency in a 1-week adrenal suppression assay. A-ll-Deoxycortisol, administered to adrenalectomized rats, lost all its agonist activity in the growth suppression assay and exhibited only antagonist activity. These observations suggest that adrenal 11-hydroxylation of both 11-deoxycortisol and A''-ll-deoxycortisol produces metabolites with agonist activity. A-ll-Deoxycortisol retains antagonist activity, probably because conversion to the agonist metabolite is less complete and its intrinsic antagonist activity is greater. These observations support the hypothesis that analogs of 11-deoxycortisol with increased resistance to 11-hydroxylation will have increased antiglucocorticoid activity in intact (nonadrenalectomized) animals. (Endocrinology 107: 472,1980) C useful antagonists for mineralocorticoids, estrogens, and androgens have been in use for many years (1-3). An effective glucorticoid antagonist, however, has not as yet been developed. Since the discovery of the antiglucocorticoid properties of progesterone in the 1960s (4, 5), many steroidal compounds have been reported to antagonize glucocorticoid activity in in vitro test systems (6-10), and their mechanism of action has been extensively studied in vitro (6, 11-13). The in vitro antiglucocorticoids lack the 11-/?hydroxyl group (4-9), except for the 17/8-carboxamide derivatives (10). Attempts to show in vivo antiglucocorticoid activity with 11-deoxycortisol, an effective antiglucocorticoid in Received October 22,1979. Address requests for reprints to: Dr. George P. Chrousos, National Institutes of Health, Building 10, Room 10B09, Bethesda, Maryland 20205. * Ph.D. candidate at George Washington University Department of Pharmacology at the time this work was completed. 1 The following abbreviations are used: 11-deoxycortisol (compound S), pregn-4-ene-17a,21-diol; A-'11-deoxycortisol, pregn-l,4,9(ll)triene-17a,21-diol-3,20-dione; dexamethasone, 9a-fluoro-16a-methylpregna-l,4-diene-ll/U7a,21-triol-3,20-dione. vitro (6,-9, 11-13), initially yielded conflicting results (14-17). We postulated that in vivo 11-hydroxylation of 11-deoxycortisol might explain its failure under certain conditions (14, 15) to behave as a glucocorticoid antagonist (18). Since the ll-/?-hydroxylase system, except in rare cases of gonadal tumors (19, 20), has been found to occur only in the adrenal glands (21), 11-deoxycortisol was tested in adrenalectomized rats and was shown to be a pure antagonist of dexamethasone (18). However, 11deoxycortisol failed to antagonize dexamethasone in intact rats and, in fact, it exhibited glucocorticoid agonist activity. This was attributed to its conversion to cortisol by adrenal 11-hydroxylation (18). These observations suggested that analogs of 11-deoxycortisol resistant to 11-hydroxylation might have increased antiglucocorticoid activity in vivo. The current study tests this hypothesis by comparing the in vivo antiglucocorticoid activity of 11-deoxycortisol and A-ll-deoxycortisol, an analog which has been shown to be metabolized in vitro by 11-hydroxylase approximately 5-10% as rapidly as 11-deoxycortisol (22-24).
