Publications

CRH is a main regulator of the stress response. This neuropeptide and its specific receptors, CRHR-1 and CRHR-2, are disseminated throughout the central nervous system. There is a significant interspecies difference in the distribution of CRHR within the central nervous system. CRH-R1 antagonists may attenuate stress-related behavior in rats without compromising adrenal function, but few studies have addressed the same question in higher mammals. Antalarmin (AA) is a specific CRHR-1 antagonist suitable for oral administration. Social separation is a potent stressor for rhesus monkeys. Therefore, we sought to investigate the hormonal responses to chronic administration of AA using a primate stress model. Eight preadolescent (4–6 kg) male rhesus monkeys received AA (20 mg/kg·d) or placebo (PBO) orally. All animals were on a regular day/light cycle and were fed with standard monkey chow daily. The study (114 d) was comprised of the following consecutive phases: adaptation, baseline, separation (stress), recovery, and cross-over. During social separation, solid panels separated the individuals. Cerebrospinal fluid (CSF) and femoral venous blood samples were obtained once a week on the fourth day of separation under ketamine anesthesia. Serum samples were also obtained 1 and 2 h after separation. CSF samples were assayed for CRH, AA, norepinephrine (NE) and epinephrine (EPI). Plasma was assayed for ACTH, cortisol, NE, and EPI. AA was detected in the plasma of each monkey while they were taking the active drug and in none of the animals on PBO. Among the behaviors assessed, environmental exploration, a behavior inhibited by stress, was increased during AA administration. However, AA at this dose did not affect other anxiety-related behavioral end points, including self-directed behavior, vocalization, or locomotion. We also observed that: 1) ACTH decreased between adaptation and baseline, indicating that the animals had adjusted to the novel environment; 2) ACTH and cortisol increased significantly after social separation, indicating that social separation was an adequate model for acute stress; 3) NE and EPI increased significantly during acute stress in the AA and PBO groups (P < 0.005, NE; P < 0.001, EPI); 4) after chronic stress, by d 4 of separation, ACTH levels were no longer significantly different from baseline, and NE and EPI remained slightly elevated when compared with baseline (P < 0.05, NE; P < 0.01, EPI); and 5) all the animals remained healthy and gained the expected weight during the study. In summary, oral chronic administration of a specific CRH-R1 antagonist to rhesus monkeys does not blunt the sympathoadrenal response to stress while increasing environmental exploration, a behavior that is normally suppressed during stressful events. Taken together, these findings suggest that CRHR-1 antagonists may be a valid treatment for stressrelated disorders.

The availability of single nucleotide polymorphisms (SNPs) that have been identified in a given gene and have been related to several diseases provides the opportunity to study complex biological pathways and can assist researchers in better associating genes and disease‑linked terms in the areas of genetics, genomics and epigenetics. The study of the glucocorticoid receptor (GR) interactome through SNP observations in 'key‑player' genes will provide researcher with the opportunity to draw the 'genomic grammar' of the complex biological mechanisms associated with GR function and will open new horizons in biology, medicine, pharmacology and even extend to personalized medicine. The GR interactome is extensive, and is involved in several physiological and pathological processes of the organism. Glucocorticoids are the final product of the hypothalamic‑pituitary‑adrenal axis and an inextricable part of the stress system. These hormones are implicated in various critical systems and processes for the human organism, such as the immune system, development, metabolism and several others. GR is the protein that mediates their actions and is involved in several interactions with specific genes and proteins. In the present study, in order to unravel new beneficial knowledge on genetic targets regarding the GR interactome, a data mining and semantic pipeline was performed using the available literature. More specifically, through bioinformatics tools and methods, the most relevant SNPs and genes connected to the GR interactome were extracted. Subsequently, the outcome SNPs were filtered, annotated, classified and evaluated in order to create the 'genomic grammar' and identify the related disease with the interactome of GR. Genomic background and heredity play a significant role in the GR interactome. A more in‑depth understanding of the biological pathways and complex actions of the GR may lead to the design and development of more effective treatments for inflammatory and autoimmune diseases, as well as cancers.

The study aimed to assess the total prevalence of functional gastrointestinal disorders (FGID), and separately, irritable bowel syndrome (IBS) among adults and to determine their potential association with fructose consumption. Data from the Hellenic National Nutrition and Health Survey were included (3798 adults; 58·9 % females). Information regarding FGID symptomatology was assessed using self-reported physician diagnosis questionnaires the reliability of which were screened using the ROME III, in a sample of the population. Fructose intake was estimated from 24 h recalls, and the MedDiet score was used to assess adherence to the Mediterranean diet. The prevalence of FGID symptomatology was 20·2 %, while 8·2 % had IBS (representing 40·2 % of total FGID). The likelihood of FGID was 28 % higher (95 %CI: 1·03-1·6) and of IBS 49 % (95 %CI: 1·08-2·05) in individuals with higher fructose intake than with lower intake (3rd tertile compared with 1st). When area of residence was accounted for, individuals residing in the Greek islands had a significantly lower probability of FGID and IBS compared with those residing in Mainland and the main Metropolitan areas, with Islanders also achieving a higher MedDiet score and lower added sugar intake, comparatively to inhabitants of the main metropolitan areas. FGID and IBS symptomatology was most prominent among individuals with higher fructose consumption, and this was most conspicuous in areas with a lower Mediterranean diet adherence, suggesting that the dietary source of fructose rather than total fructose should be examined in relation to FGID.

A crude oil refinery is employed as a benchmark to test a fundamental assumption in the seismic risk assessment of asset portfolios, i.e., that a fragility function can characterize an asset (or class thereof) with negligible loss of fidelity. Although this is often taken as granted, it also implies that one should not care about breaking the correlation in response that should exist between similar assets subjected to the same ground motion. After all, this is a direct consequence of the summarization of multiple structural analysis results into a single fragility curve that is only parameterized by the (typically scalar) intensity measure. The alternative is to separately consider individual ground motion records and only aggregate per-record results at the final level of impact metrics. Stacking the deck against the conventional approach, a refinery offers an ideal testbed of interconnected assets and multiple refining processes. The results highlight that wherever multiple similar or identical assets are involved in a system disruption, breaking their record-to-record response correlation can severely bias the assessment results.

In recent years, research on exosomes and their content has been intensive, which has revealed their important role in cell‑to‑cell communication, and has implicated exosomal biomolecules in a broad spectrum of physiological processes, as well as in the pathogenesis of various diseases. Pregnancy and its normal progression rely highly on the efficient communication between the mother and the fetus, mainly mediated by the placenta. Recent studies have established the placenta as an important source of circulating exosomes and have demonstrated that exosome release into the maternal circulation gradually increases during pregnancy, starting from six weeks of gestation. This orchestrates maternal‑fetal crosstalk, including maternal immune tolerance and pregnancy‑associated metabolic adaptations. Furthermore, an increased number of secreted exosomes, along with altered patterns of exosomal non‑coding RNAs (ncRNAs), especially microRNAs and long non‑coding RNAs (lncRNAs), have been observed in a number of pregnancy complications, such as gestational diabetes mellitus and preeclampsia. The early detection of exosomes and specific exosomal ncRNAs in various biological fluids during pregnancy highlights them as promising candidate biomarkers for the diagnosis, prognosis and treatment of numerous pregnancy disorders in adolescents and adults. The present review aimed to provide insight into the current knowledge regarding the potential, only partially elucidated, role of exosomes and exosomal cargo in the regulation and progression of normal pregnancy, as well as their potential dysregulation and contribution to pathological pregnancy situations.

OBJECTIVE In both normal volunteers and patients with Cushing's disease, one dominant inferior petrosal sinus (IPS) contains higher concentrations of AVP and ACTH than the contralateral (non‐dominant) IPS, but ovine corticotrophin‐releasing hormone (oCRH)‐stimulated AVP in the petrosal sinuses is greater in Cushing's disease than in normal volunteers. To distinguish whether greater oCRH‐releasable AVP might be specifically related to the presence of a pituitary corticotrophinoma, or be due to hypercortisolism per se , we compared IPS AVP in patients with Cushing's disease with those of patients with other causes of Cushing's syndrome. PATIENTS Twenty‐three patients with Cushing's disease, 16 patients with the syndrome of ectopic ACTH and seven patients with Cushing's syndrome of adrenal origin. MEASUREMENTS AVP and ACTH, measured both before and 3, 5 and 10 minutes after oCRH in the petrosal sinuses, and in a peripheral vein. RESULTS In all three groups, AVP concentrations were lateralized such that most of the AVP was found in one, dominant IPS. oCRH significantly increased IPS ACTH only in patients with Cushing's disease ( P &lt; 0.001), whereas it significantly increased dominant IPS AVP levels in all three patient groups ( P &lt; 0.01). However, neither dominant nor non‐dominant IPS AVP (basal or oCRH‐stimulated) were significantly different among patients with Cushing's disease, ectopic ACTH or Cushing's syndrome of adrenal origin. Basal and oCRH‐stimulated IPS AVP were negatively correlated with urine free cortisol. CONCLUSIONS Inferior petrosal sinus AVP levels are similar in all forms of Cushing's syndrome, and thus the higher inferior petrosal sinus AVP levels in patients with Cushing's disease compared with normal volunteers are unlikely to be related specifically to the presence of the pituitary corticotrophinoma. While AVP may play a role in pituitary corticotroph tumourigenesis or may be secreted by some pituitary corticotroph tumours, the observation that CRH‐stimulated inferior petrosal sinus AVP levels are higher in Cushing's disease than in normal volunteers appears most likely to be related to the low endogenous CRH levels induced by hypercortisolism, rather than a consequence of Cushing's disease itself. We hypothesize that low endogenous CRH leads to increased sensitivity of central nervous system CRH receptors to exogenous CRH, and thus to greater ovine CRH‐stimulated AVP.

Parathyroid hormone (PTH) plays a crucial role in calcium metabolism and skeletal development via altering vitamin D level. Besides, hypersecretion of PTH is implicated in the etiology of osteoporosis. In this study, we analyzed association between promoter region sequence variants of PTH gene and circulating 25-hydroxy-vitamin D (25(OH)D) level. Genotypes of PTH SNPs rs1459015, rs10500783 and rs10500784 and circulating serum 25(OH)D level of healthy adults (N=386) of different nationalities living in Riyadh were determined and relation between the different PTH allelic variants and corresponding mean 25(OH)D values were obtained using Analysis of Variance (ANOVA) and Bonferroni post-hoc test for multiple comparisons. We observed a high prevalence of vitamin D deficiency (<50 nmol/l) among all nationals which ranged from 59% among Indians to 82% among Yemeni. Comparison of the means of 25(OH)D levels corresponding to different genotypes of PTH SNPs indicated that the T allele of SNP rs1459015 was associated with higher 25(OH)D level in the Sudanese (P=0.03), while the T allele of SNP rs10500783 was associated with higher 25(OH)D level in Saudis (P=0.03). Analysis of results also indicated that the Sudanese carriers of the CC genotype of SNP rs1459015 had a higher risk of suffering from vitamin D deficiency (P=0.02). In conclusion, our study indicated significant association between specific PTH gene promoter region variants and altered levels of 25(OH)D and vitamin D deficiency among specific nationals.

Foetal growth monitoring is an essential component of prenatal care with postnatal impact. The aim of the study was to construct reference ranges for foetal biometric parameters in Greek foetuses and to compare them with previously published models.Measurements from 1200 Greek foetuses were used to construct normal curves for biparietal diameter (BPD), occipitofrontal diameter (OFD), head circumference (HC), abdominal circumference (AC), femoral length (FL) and the BPD/FL ratio according to the methodology described by Royston and Wright (1998). The model was validated in a second group of 1200 different foetuses using analysis of the corresponding standardized residuals (z-scores). The z-scores which were derived by our model were compared to those calculated using previously published models from other populations.BPD, OFD, HC, AC, FL and the BPD/FL ratio are accurately described by simple quadratic equations (R(2) > 0·96 for most of the parameters tested). Statistically significant differences were observed for most of the z-scores when our models were compared to previously published models. Less than 10% of our foetuses were < 5th or > 95th centile of the latter models. About 10% of our foetuses were > 95th centile for FL and HC when the INTERGROWTH-21st formulas were used.We present national foetal biometric references. Using charts from other populations (including INTERGROWTH-21st) may be unrepresentative of local populations and lead to misclassification of foetal growth status.