2,243 publications from this institution
We examined the responsiveness of the pituitary- adrenal axis to ovine corticotropin-releasing hormone (oCRH) in 14 women with systemic lupus erythematosus receiving chronic, alternate day glucocorticoid therapy with prednisone. Testing was done twice and in a random order (at 2000 h) on the day when the steroid was taken (12 h after the last dose) and on the day when no glucocorticoid was administered (36 h after the last dose). Plasma ACTH and cortisol responses were markedly blunted on the day of treatment and mildly blunted on the day off treatment compared to those in normal subjects. Altered metabolic clearance of exogenous oCRF was not responsible for this difference, since the plasma disappearance curves of immunoreactive oCRH were similar on both days. The degree of suppression was dependent on the dose of prednisone, and the amount of cortisol secreted during the oCRH test was directly proportional to the logarithm of the concurrent plasma ACTH level. Thus, the cortisol response to ACTH was normal in all patients. These data suggest that the blunting of responsiveness to oCRH on both days of testing represents prednisolone suppression of the corticotroph cell. Despite this, the adrenal glands retain normal responsiveness to ACTH, suggesting that moderate decreases in daily ACTH secretion are compatible with sustaining normal adrenal function. Hence, the site of the mild suppression of the hypothalamic-pituitary-adrenal axis during chronic, alternate day treatment with glucocorticoids is central, whereas the adrenal glands appear to remain functionally unaffected.
We have determined the nucleotide sequence of the proximal 3625 nucleotides 5′ flanking the major mRNA start site of the human corticotropin releasing hormone gene (hCRH) and identified several putative regulatory elements. Interestingly, we did not detect any glucocorticoid responsive elements; we did however find five interspersed perfect half palindromic estrogen responsive elements, which might confer estrogen regulatability to the hCRH gene. We have identified a segment spanning from-2835 to-2972, which has about 72% homology to the 3′ terminal half of the human Alu I family of highly repetitive elements, and another one, which spans from-2213 to-2580 and has greater than 80% homology to members of human type O family of repetitive elements. These elements may confer DNA fragility, since the foci for hCRH and the human fragile site FRA8F colocalize in human chromosome 8. The structural information reported represents a first step in the study of regulation of the hCRH gene at the molecular level.
The dramatic fluctuations in the energy demands of living organisms by the rhythmic succession of night and day on our planet has prompted a geophysical evolutionary need for a biological temporal organization necessary for maintenance of homeostasis and adaptation to environmental changes across phylogeny. The intrinsic circadian system (CS) represents a highly conserved and complex internal biological “clock”, adjusted to the 24-hour rotation of the earth about itself. This system creates and maintains cellular and organismal rhythmicity and enables a nyctohemeral coordination of multi-level physiologic processes, ranging from gene expression to behaviour. The suprachiasmatic nucleus (SCN) of the hypothalamus is the primary pacemaker of the circadian system of the organism, while a ubiquitous peripheral oscillating network of cellular molecular clocks participates in a complex circadian hierarchy. A critical loss of this harmoniously timed circadian order at different organizational levels is defined as “chronodisruption”, a condition that may alter the fundamental properties of basic homeostatic systems at molecular, cellular and organismal levels, and lead to a breakdown of biobehavioral adaptive mechanisms, resulting in maladaptive stress regulation and increased sensitivity and vulnerability to stress. Chronodisruption has been linked to neuroendocrine, immune, cardiometabolic and autonomic dysregulation, with blunted diurnal rhythms, specific sleep pattern pathologies and cognitive deficits, as well as with altered circadian gene expression. This condition may, thus, play a central role in the development of mental and somatic disease. Nevertheless, circadian and sleep disturbances are often clinically considered as “secondary” manifestations in most disorders, neglecting the potentially important pathophysiological role of CS. Understanding the pathophysiologic mechanisms of circadian dysregulation and their role in stress-related, systemic disease could provide new insights into disease mechanisms and could help advance chronobiological treatment possibilities and preventive strategies in populations at risk.
The influence of the vertical component of ground motion is investigated for assessing the distribution of the seismic response of unanchored rigid blocks. Multiple stripes of site‐hazard‐consistent ground motions are employed for calculating the seismic response of rigid rocking blocks with and without the inclusion of the vertical component. The comparison of the resulting response is being made both for single records and full suites, employing a paired record versus an ensemble‐statistics comparison, respectively. It is shown that on a single record basis, the vertical component may have a non‐negligible but highly variable influence on the rocking response, sometimes detrimental, sometimes beneficial. Still, when considering any large ensemble of records, the effect becomes statistically insignificant, except for the very specific case of rocking uplift for stocky blocks. To this end, for cases where the appearance of uplift is associated with damage, closed‐form expressions are proposed to modify the lognormal fragility function of rocking initiation given the block slenderness and the ratio of the peak vertical over the peak horizontal ground acceleration.
