Publications

The placenta is the source of many hypothalamic peptides. We now report that GH-releasing hormone (GHRH) mRNA was detectable in rat placenta. On Northern blot hybridization analysis, the size of the placental GHRH transcript was the same with the putative GHRH precursor mRNA. On in situ hybridization, the cells expressing the GHRH mRNA had the morphological characteristics of cytotrophoblasts. In addition, immunoreactive (IR) postranslational products of GHRH were present in rat placental extracts and in the effluent of in vitro perifused placentae. On gel filtration chromatography, the bulk of IR-GHRH present in placental extracts and perifusion effluent had the same size as the authentic hypothalamic GHRH (5.2K). A higher mol wt form of IR-GHRH of about 10K was also present and may represent the pro-GHRH predicted from the sequence of the GHRH cDNA. The mean basal release of IR-GHRH in the perifusion effluent from full thickness rat placental fragments was 337.3 ± 38.5 (±SE; n = 48) pg/10 min fraction · g tissue. Depolarization by 56 mM KC1 increased the concentration of the secreted immunoreactive peptide to 632.2 ± 50.5. A 10-min exposure to 8-bromo-cAMP caused an immediate, monophasic, and dose-dependent increase in IR-GHRH secretion, which lasted between 20-30 min. The ensuing response to a KC1 pulse was similar in size and pattern to that in the control channels. In contrast, a 10-min pulse of phorbol 12-myristate 13-acetate (a protein kinase-C-irreversible activator) induced a gradual, prolonged, and dose-dependent increase in basal GHRH secretion which lasted for at least 4 h. Additionally, phorbol 12-myristate 13-acetate enhanced KC1- induced GHRH secretion. In conclusion, our data suggest that the GHRH gene is expressed in the rat placenta. The placental GHRH transcript and its peptide products appear to have the same size as their hypothalamic counterparts, while the site of its placental GHRH synthesis is the cytotrophoblast. Finally, the secretion of placental GHRH seems to be regulated by both the adenyl cyclase and the protein kinase-C pathways. (Endocrinology126: 151–158, 1990)

Living organisms are highly complex systems that must maintain a dynamic equilibrium or homeostasis that requires energy to be sustained. Stress is a state in which several extrinsic or intrinsic disturbing stimuli, the stressors, threaten, or are perceived as threatening, homeostasis. To achieve homeostasis against the stressors, organisms have developed a highly sophisticated system, the stress system, which provides neuroendocrine adaptive responses, to restore homeostasis. These responses must be appropriate in terms of size and/or duration; otherwise, they may sustain life but be associated with detrimental effects on numerous physiologic functions of the organism, leading to a state of disease-causing disturbed homeostasis or cacostasis. In addition to facing a broad spectrum of external and/or internal stressors, organisms are subject to recurring environmental changes associated with the rotation of the planet around itself and its revolution around the sun. To adjust their homeostasis and to synchronize their activities to day/night cycles, organisms have developed an evolutionarily conserved biologic system, the "clock" system, which influences several physiologic functions in a circadian fashion. Accumulating evidence suggests that the stress system is intimately related to the circadian clock system, with dysfunction of the former resulting in dysregulation of the latter and vice versa. In this review, we describe the functional components of the two systems, we discuss their multilevel interactions, and we present how excessive or prolonged activity of the stress system affects the circadian rhythm of glucocorticoid secretion and target tissue effects.

Chronic fatigue syndrome is characterized by persistent or relapsing debilitating fatigue for at least 6 months in the absence of a medical diagnosis that would explain the clinical presentation. Because primary glucocorticoid deficiency states and affective disorders putatively associated with a deficiency of the arousal-producing neuropeptide CRH can be associated with similar symptoms, we report here a study of the functional integrity of the various components of the hypothalamic-pituitary-adrenal axis in patients meeting research case criteria for chronic fatigue syndrome. Thirty patients and 72 normal volunteers were studied. Basal activity of the hypothalamic-pituitary-adrenal axis was estimated by determinations of 24-h urinary free cortisol-excretion, evening basal plasma total and free cortisol concentrations, and the cortisol binding globulin-binding capacity. The adrenal cortex was evaluated indirectly by cortisol responses during ovine CRH (oCRH) stimulation testing and directly by cortisol responses to graded submaximal doses of ACTH. Plasma ACTH and cortisol responses to oCRH were employed as a direct measure of the functional integrity of the pituitary corticotroph cell. Central CRH secretion was assessed by measuring its level in cerebrospinal fluid. Compared to normal subjects, patients demonstrated significantly reduced basal evening glucocorticoid levels (89.0 ± 8.7 us. 148.4 ± 20.3 nmol/L; P < 0.01) and low 24-h urinary free cortisol excretion (122.7 ± 8.9 us. 203.1 ± 10.7 nmol/24 h; P < 0.0002), but elevated basal evening ACTH concentrations. There was increased adrenocortical sensitivity to ACTH, but a reduced maximal response [F(3.26, 65.16) = 5.50; P = 0.0015). Patients showed attenuated net integrated ACTH responses to oCRH (128.0 ± 26.4 us. 225.4 ± 34.5 pmol/Lmin, P < 0.04). Cerebrospinal fluid CRH levels in patients were no different from control values (8.4 ± 0.6 us. 7.7 ± 0.5 pmol/L; P = NS). Although we cannot definitively account for the etiology of the mild glucocorticoid deficiency seen in chronic fatigue syndrome patients, the enhanced adrenocortical sensitivity to exogenous ACTH and blunted ACTH responses to oCRH are incompatible with a primary adrenal insufficiency. A pituitary source is also unlikely, since basal evening plasma ACTH concentrations were elevated. Hence, the data are most compatible with a mild central adrenal insufficiency secondary to either a deficiency of CRH or some other central stimulus to the pituitary-adrenal axis. Whether a mild glucocorticoid deficiency or a putative deficiency of an arousal-producing neuropeptide such as CRH is related to the clinical symptomatology of the chronic fatigue syndrome remains to be determined.

Adrenarche is a developmental change of the adrenal gland that results in increased secretion of adrenal androgens. This maturational process generally begins several years before activation of the hypothalamic-pituitary-gonadal axis (gonadarche). To study further the relationship between adrenarche and gonadarche, we examined adrenarche in patients with precocious puberty and in patients with isolated hypogonadotropic hypogonadism. Plasma dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and cortisol were measured basally and during an infusion of ACTH in 50 children with precocious puberty, 5 patients with isolated hypogonadotropic hypogonadism, 7 preadrenarchal children with constitutional short stature, 44 normal pubertal children, and 40 normal adults. Children with precocious puberty did not have a corresponding advance in the timing of adrenarche. Their basal and ACTH-stimulated adrenal androgen levels were markedly lower than those of normal children matched for pubertal stage (P < 0.05) and were only slightly greater than those reported for normal children of the same age. Similarly, patients with isolated hypogonadotropic hypogonadism and delayed puberty had no corresponding delay of adrenarche. Their adrenal androgen levels were appropriate for chronological age. Thus, these data provide further support for the hypothesis that adrenarche and gonadarche are independent maturational events controlled by separate mechanisms.

Objective: Cardiovascular disease is the principal cause of death worldwide. Although the dose-response relationship between stress and hypertension is well established, there is a paucity of non-pharmaceutical intervention programs. The purpose of this study was to investigate the effectiveness of a stress management and lifestyle change program on blood pressure (BP) control and psychosocial wellbeing. Design and method: This was a quasi-experimental design with a waitlist control group in Attica, Greece, which was funded from EPANAD 2007–2013 (N = 553, 50% women and mean age 52.4 ± 8.46 years). The study comprised of an 8-week stress management and lifestyle change program including weekly sessions of stress management, dietary counseling, physical exercise and psychoeducation. Pre- and post- intervention BP measurements and psychosocial wellbeing factors were assessed. Results: Post-intervention there was a statistically significant reduction in systolic BP levels (mean: 126.05 vs 129.37, p < 0.001, intervention (IG) and control (CG) group, respectively). A 35.7% of the IG receded BP category vs. 17.5% of the CG (p < 0.001). After controlling for gender, age, educational level and BP cutoffs, we found significant improvements in stress, anxiety, self-esteem, spirituality, body weight, hours of sleep and in the subscales of the Healthy Lifestyle and Personal Control Questionnaire. Concerning the sub-categories of chance and powerful others in the health locus of control scale, improvements were recorded for the individuals of tertiary education. Conclusions: This non-pharmaceutical stress management and lifestyle change program resulted in significant benefits for regulation of BP, as well as for body weight, lifestyle and the psychosocial wellbeing of the participants. Future non-pharmaceutical programs are strongly encouraged both for the clinical and the community settings.

The operational status of an oil refinery (type and scale of operations that take place at any time instance) largely determines the amount of fuel produced, circulated within the facility, and stored in tanks. This status is affected by seasonality, periods of peak or low demand, as well as periods of routine maintenance. However, it is an aspect that is typically neglected even though it stands out among the factors that determine the seismic performance of several critical industrial assets, such as the storage tanks, as well as the consequences of any potential failure. An open-source refinery testbed is employed herein to demonstrate the effect of the refinery's operational status on the seismic risk estimates. Alternative realistic operational scenarios are developed following typical industry practices and are arranged over a time period between two refinery major maintenance shutdown events. The most probable damage state is selected for each asset to identify the most vulnerable ones. Based on the type and importance of the impacted assets, the potential consequences are determined at the facility level. Resulting estimates are very different if an earthquake strikes during a regular/high/low-demand period, or a maintenance period. The framework can be utilized to identify the locations within the refinery that may trigger cascading failures and secondary damages, should their assets be damaged by a seismic event. The outcomes can be exploited by stakeholders, risk engineers, and emergency action planners for developing customized and businesslike procedures to enhance the seismic resilience of the facility.

Objective Studies in obesity have implicated adipocytokines in the development of insulin resistance, which in turn may lead to accelerated aging. In this study, we determined associations of chromosomal telomere length (TL) to markers of obesity and insulin resistance in middle-aged adult male and female Arabs with and without diabetes mellitus type 2 (DMT2). Design and methods One hundred and ninety-three non-diabetic and DMT2 subjects without complications (97 males and 96 females) participated in this cross-sectional study. Clinical data, as well as fasting blood samples, were collected. Serum glucose and lipid profile were determined using routine laboratory methods. Serum insulin, leptin, adiponectin, resistin, tumor necrosis factor-α, and PAI-1 were quantified using customized multiplex assay kits. High sensitive C-reactive protein (hsCRP) and angiotensin II (ANG II) were measured using ELISAs. Circulating leukocyte TL was examined by quantitative real-time PCR. Results Circulating chromosomal leukocyte TL had significant inverse associations with body mass index (BMI), systolic blood pressure, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), low-density lipoprotein (LDL)- and total cholesterol, ANG II and hsCRP levels. Adiponectin, BMI, systolic blood pressure, and LDL cholesterol predicted 47% of the variance in TL ( P &lt;0.0001). HOMA-IR was the most significant predictor for TL in males, explaining 35% of the variance ( P =0.01). In females, adiponectin accounted for 28% of the variance in TL ( P =0.01). Conclusion Obesity and insulin resistance are associated with chromosomal TL among adult Arabs. Evidence of causal relations needs further investigation. The positive association of adiponectin to TL has clinical implications as to the possible protective effects of this hormone from accelerated aging.