Publications

Snow White and the Seven Dwarfs: a fairytale for endocrinologists

‘Snow White and the Seven Dwarfs’, a fairytale that is widely known across the Western world, was originally written by the Brothers Grimm, and published in 1812 as ‘Snow White’. Though each dwarf was first given an individual name in the 1912 Broadway play, in Walt Disney ’s 1937 film ‘Snow White and the Seven Dwarfs’ , they were renamed, and the dwarfs have become household names. It is well known that myths, fables, and fairytales, though appearing to be merely children’s tales about fictional magical beings and places, have, more often than not, originated from real facts. Therefore, the presence of the seven brothers with short stature in the story is, from an endocrinological point of view, highly intriguing, in fact, thrilling. The diversity of the phenotypes among the seven dwarfs is also stimulating, although puzzling. We undertook a differential diagnosis of their common underlying disorder based on the original Disney production’s drawings and the unique characteristics of these little gentlemen, while we additionally evaluated several causes of short stature and, focusing on endocrine disorders that could lead to these clinical features among siblings, we have, we believe, been able to reveal the underlying disease depicted in this archetypal tale.

Inflammation in Posttraumatic Stress Disorder: Dysregulation or Recalibration?

Abstract: Despite ample experimental data indicating a role of inflammatory mediators in the behavioral and neurobiological manifestations elicited by exposure to physical and psychologic stressors, causative associations between systemic low-grade inflammation and central nervous system inflammatory processes in posttraumatic stress disorder (PTSD) patients remain largely conceptual. As in other stress-related disorders, pro-inflammatory activity may play an equivocal role in PTSD pathophysiology, one that renders indiscriminate employment of anti-inflammatory agents of questionable relevance. In fact, as several pieces of preclinical and clinical research convergingly suggest, timely and targeted potentiation rather than inhibition of inflammatory responses may actually be beneficial in patients who are characterized by suppressed microglia function in the face of systemic low-grade inflammation. The deleterious impact of chronic stress-associated inflammation on the systemic level may, thus, need to be held in context with the - often not readily apparent - adaptive payoffs of low-grade inflammation at the tissue level.

Plasma and Cerebrospinal Fluid Interleukin-6 Concentrations in Posttraumatic Stress Disorder

<i>Background:</i> Interleukin-6 (IL-6) secretion is suppressed by glucocorticoids and stimulated by catecholamines. Patients with posttraumatic stress disorder (PTSD) have decreased cortisol and increased catecholamine secretion. The purpose of this study was to assess the relation of IL-6 levels and hypothalamic-pituitary-adrenal and noradrenergic activity in patients with well-characterized PTSD. <i>Methods:</i> Cerebrospinal fluid (CSF) was withdrawn via a lumbar subarachnoid catheter over 6 h from 11 combat veterans with PTSD and 8 age- and sex-matched healthy controls. Blood was withdrawn concurrently. We measured IL-6, CRH and norepinephrine concentrations in the CSF and IL-6, ACTH, cortisol and norepinephrine in plasma. <i>Results:</i> Mean and median CSF IL-6 concentrations were higher in PTSD than in controls (mean = 24.0 vs. 14.6, p = 0.05; median = 26.7 vs. 14.3, p < 0.03): plasma IL-6 concentrations, however, were not different between the two groups. Plasma IL-6 and norepinephrine were positively correlated in the PTSD group (r = +0.74, p < 0.04), but not in normals (r = –0.55, p = 0.20).<i> Conclusions:</i> PTSD patients have increased CSF concentrations of IL-6. Their plasma IL-6 is not elevated but is more tightly associated with noradrenergic output in these patients than in normals. Both findings might be explained by the low cortisol secretion previously reported in PTSD as a result of lowered glucocorticoid suppression of IL-6 secretion. High levels of CSF IL-6 may reflect neurodegeneration or compensatory neuroprotection.

Preliminary Seismic Risk Assessment of Monolithic Columns of the Aphaia Temple in Aegina

No abstract is provided for this article.

The human glucocorticoid receptor: Molecular basis of biologic function

Reliability and Validity of the Greek Migraine Disability Assessment (MIDAS) Questionnaire

The Migraine Disability Assessment (MIDAS) Questionnaire is a reliable and valid instrument for migraine-related disability. Such a tool is needed to quantify migraine-related disability in the Greek population.This validation study aims to assess the test-retest reliability, internal consistency, item discriminant and convergent validity of the Greek translation of the MIDAS.Adults diagnosed with migraine completed the MIDAS Questionnaire on two occasions 3 weeks apart to assess reliability, and completed the RAND-36 to assess validity.Participants (n = 152) had a median MIDAS score of 24 and mostly severe disability (58% were grade IV). The test-retest reliability analysis (N = 59) revealed excellent reliability for the total score. Internal consistency was α = 0.71 for initial and α = 0.82 for retest completion. For item discriminant validity, the correlations between each question and the total score were significant, with high correlations for questions 2-5 (range 0.67 ≤ r ≤ 0.79; p < 0.01). For convergent validity, there was significant negative correlation between the total score and all RAND-36 subscales except for 'emotional wellbeing'. The negative correlation indicates that patients with a lower degree of disability according to their MIDAS score tended to have better wellbeing. Psychometric properties are comparable with those of other published validation studies of the MIDAS and the original. Findings on question 1 show that missing work/school days may be closely related with increased affect issues.The Greek version of the MIDAS Questionnaire has good reliability and validity. This study allowed for cross-cultural comparability of research findings.

Hypothalamic-Pituitary-Adrenal Axis Activity in Obese Men with and without Sleep Apnea: Effects of Continuous Positive Airway Pressure Therapy

Previous studies on the association between the hypothalamic-pituitary-adrenal axis activity and sleep apnea (SA) and obesity are inconsistent and/or limited.In this study, we evaluated the activity of the hypothalamic-pituitary-adrenal axis in nonpsychologically distressed obese subjects with and without SA and examined the impact of continuous positive airway pressure (CPAP) in SA patients.In study I, four-night sleep laboratory recordings and serial 24-h plasma measures of cortisol were obtained in 45 obese men with and without apnea and nonobese controls. Sleep apneic patients were reassessed after 3 months of CPAP use. In study II, 38 obese men with and without sleep apnea and nonobese controls were challenged with ovine CRH administration after four nights in the sleep laboratory.The sleep patterns were similar between obese and nonobese controls. Twenty-four-hour plasma cortisol levels were highest in nonobese controls, intermediate in obese apneic patients, and lowest in obese controls (8.8 +/- 0.4 vs. 8.1 +/- 0.3 vs. 7.5 +/- 0.3 microg/dl, P < 0.05). CPAP tended to reduce cortisol levels in the apneic patients (difference -0.7 +/- .4 microg/dl, P = 0.1). CRH administration resulted in a higher ACTH response in both obese groups, compared with nonobese controls; the three groups were not different in cortisol response.Nonpsychologically distressed, normally sleeping, obese men had low cortisol secretion. The cortisol secretion was slightly activated by SA and returned to low by CPAP use. The low cortisol secretion in obesity through its inferred hyposecretion of hypothalamic CRH might predispose the obese to sleep apnea.

Adrenal 11-hydroxylase activity in a hypercortisolemic new world primate: Adaptive intra adrenal changes

Rapid Eye Movement Sleep Correlates with the Overall Activities of the Hypothalamic-Pituitary-Adrenal Axis and Sympathetic System in Healthy Humans

To assess the association of the overall amount of rapid eye movement (REM) sleep and the activities of the hypothalamic-pituitary-adrenal axis and sympathetic system, we performed polysomnography and measured 24-h urinary free cortisol and catecholamine excretion in 21 healthy adults. After an adaptation night, each subject was recorded in the sleep laboratory for 3 consecutive nights while 24-h urine specimens were collected. Urinary free cortisol, epinephrine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid levels were significantly and positively correlated with the average values of percent REM sleep (P < 0.05). There were no correlations between hormone values and REM latency, other variables of REM distribution, or REM density, an index of phasic activity during REM sleep. The positive correlations between stress system activity and REM sleep are consistent with hormonal and sleep alterations in melancholic depression, a state characterized by increased cortisol and catecholamine secretion.

Validation of the Greek version of the Adolescent Sleep Hygiene Scale (ASHS)

Transition from childhood to adolescence is known to bring about many changes in the lifestyle and psycho-emotional state of adolescents. One of the major lifestyle factors that affect adolescents' physical and mental health is sleep. The aim of this study was to validate the Adolescent Sleep Hygiene Scale (ASHS), a tool that measures sleep hygiene, in an adolescent sample living in Greece. The study's sample consisted of 146 Greek adolescents aged 12-18 years. The Adolescent Stress Questionnaire was used for convergent validity and correlation with adolescents' stress. The pilot and the main study demonstrated sufficient internal consistency. Exploratory Factor Analysis showed an adequate adaptation of the original ASHS questionnaire to the Greek adolescents. The findings of this study support the use of ASHS as a reliable and valid tool for evaluating sleep-facilitating and sleep-inhibiting practices of Greek adolescents.

Concise Review: Reprogramming, Behind the Scenes: Noncanonical Neural Stem Cell Signaling Pathways Reveal New, Unseen Regulators of Tissue Plasticity With Therapeutic Implications

Interest is great in the new molecular concepts that explain, at the level of signal transduction, the process of reprogramming. Usually, transcription factors with developmental importance are used, but these approaches give limited information on the signaling networks involved, which could reveal new therapeutic opportunities. Recent findings involving reprogramming by genetic means and soluble factors with well-studied downstream signaling mechanisms, including signal transducer and activator of transcription 3 (STAT3) and hairy and enhancer of split 3 (Hes3), shed new light into the molecular mechanisms that might be involved. We examine the appropriateness of common culture systems and their ability to reveal unusual (noncanonical) signal transduction pathways that actually operate in vivo. We then discuss such novel pathways and their importance in various plastic cell types, culminating in their emerging roles in reprogramming mechanisms. We also discuss a number of reprogramming paradigms (mouse induced pluripotent stem cells, direct conversion to neural stem cells, and in vivo conversion of acinar cells to β-like cells). Specifically for acinar-to-β-cell reprogramming paradigms, we discuss the common view of the underlying mechanism (involving the Janus kinase-STAT pathway that leads to STAT3-tyrosine phosphorylation) and present alternative interpretations that implicate STAT3-serine phosphorylation alone or serine and tyrosine phosphorylation occurring in sequential order. The implications for drug design and therapy are important given that different phosphorylation sites on STAT3 intercept different signaling pathways. We introduce a new molecular perspective in the field of reprogramming with broad implications in basic, biotechnological, and translational research. Reprogramming is a powerful approach to change cell identity, with implications in both basic and applied biology. Most efforts involve the forced expression of key transcription factors, but recently, success has been reported with manipulating signal transduction pathways that might intercept them. It is important to start connecting the function of the classic reprogramming genes to signaling pathways that also mediate reprogramming, unifying the sciences of signal transduction, stem cell biology, and epigenetics. Neural stem cell studies have revealed the operation of noncanonical signaling pathways that are now appreciated to also operate during reprogramming, offering new mechanistic explanations.

Gender dimorphic increase in <scp>RBP</scp>‐4 and <scp>NGAL</scp> in children born after <scp>IVF</scp>: an epigenetic phenomenon?

In vitro fertilisation (IVF) has been widely used during the last decades. Recent studies demonstrated some alterations in IVF children's metabolic profile compared with controls. The recently reported lipocalins retinol-binding protein 4 (RBP-4) and neutrophil gelatinase-associated lipocalin (NGAL), as well as visfatin, which are associated with glucose intolerance and could help in the early detection of metabolic abnormalities, have not been studied in IVF children as yet. We studied the lipocalins RBP-4 and NGAL as well as visfatin in children born after IVF.A total of 100 children born after IVF (47 boys) and 60 controls born after normal conception (30 boys), aged 4-14 year, were studied cross-sectionally. All children had a physical examination, their fasting glucose, insulin, lipid profile, RBP-4, NGAL, and visfatin were determined and their homoeostasis model assessment (HOMA) index was calculated.Children born after IVF had significantly higher RBP-4 (P = 0·009) and NGAL (P = 0·028) levels than controls. When divided by gender, RBP-4 remained higher in IVF girls (P = 0·002), whereas NGAL was higher in IVF boys (P = 0·021). Linear regression analysis had revealed that the differences are attributed to the IVF procedure per se.In our study, IVF children had significantly higher RBP-4 and NGAL levels than controls, suggesting early metabolic derangements that could be attributed to an epigenetic phenomenon. These results are in accordance with our earlier findings of higher blood pressure and triglycerides in IVF children than controls. Further prospective studies in IVF children will determine the natural course of their metabolic profile.

A MODIFIED RESPONSE SPECTRUM METHOD FOR ESTIMATING PEAK FLOOR ACCELERATION DEMANDS IN ELASTIC REGULAR FRAME STRUCTURES

In this paper an extended complete quadratic combination rule for quick assessment of peak floor acceleration demands (PFA) of elastic structures subjected to seismic excitation is proposed. The simplification from time history analysis to the response spectrum method is shown in detail. Based on a relative acceleration formulation combined with nonlinear optimization techniques cross correlation coefficients are determined to estimate relative and absolute PFA demands. For estimation of central tendency and dispersion of the seismic response, regression equations are derived to provide a simple implementation of the method in civil engineering design practice. Application of the proposed procedure to a 24-story moment resisting generic frame structure shows the improvement compared to common response spectrum methods.

Neuroimmunology of Sleep

A Novel Point Mutation in the Amino Terminal Domain of the Human Glucocorticoid Receptor (hGR) Gene Enhancing hGR-Mediated Gene Expression

Context: Interindividual variations in glucocorticoid sensitivity have been associated with manifestations of cortisol excess or deficiency and may be partly explained by polymorphisms in the human glucocorticoid receptor (hGR) gene. We studied a 43-yr-old female, who presented with manifestations consistent with tissue-selective glucocorticoid hypersensitivity. We detected a novel, single, heterozygous nucleotide (G → C) substitution at position 1201 (exon 2) of the hGR gene, which resulted in aspartic acid to histidine substitution at amino acid position 401 in the amino-terminal domain of the hGRα. We investigated the molecular mechanisms of action of the natural mutant receptor hGRαD401H. Methods-Results: Compared with the wild-type hGRα, the mutant receptor hGRαD401H demonstrated a 2.4-fold increase in its ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter in response to dexamethasone but had similar affinity for the ligand (dissociation constant = 6.2 ± 0.6 vs. 6.1 ± 0.6 nm) and time to nuclear translocation (14.75 ± 0.25 vs. 14.25 ± 1.13 min). The mutant receptor hGRαD401H did not exert a dominant positive or negative effect upon the wild-type receptor, it preserved its ability to bind to glucocorticoid response elements, and displayed a normal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. Conclusions: The mutant receptor hGRαD401H enhances the transcriptional activity of glucocorticoid-responsive genes. The presence of the D401H mutation may predispose subjects to obesity, hypertension, and other manifestations of the metabolic syndrome.

Associations of tonsillar hypertrophy and snoring with history of wheezing in childhood

Reports in adults and children have correlated history of wheezing or asthma with the presence of obstructive sleep-disordered breathing but the mechanism of this epidemiologic association is unknown. The goal of the present study was to examine whether tonsillar hypertophy can explain this association.Children were recruited from the Emergency Department and the Pediatric Pulmonology Clinic. History of wheezing requiring treatment (explanatory variable) and snoring > or = 1 night/week (outcome) were recorded and presence of tonsillar hypertrophy (outcome) was assessed.Four hundred forty-two children were recruited (mean age: 7.6 + or - 3.6 years) and 210 of them had history of wheezing. History of wheezing was significantly associated with the presence of tonsillar hypertrophy and snoring even after adjustment for age, gender, obesity, and passive smoking [odds ratio (95% confidence interval): 2.23 (1.37-3.63); P = 0.001 and 1.73 (1.12-2.67); P = 0.013, respectively]. When only children with tonsillar hypertrophy were considered (n = 92), history of wheezing was significantly related to the presence of snoring, whereas in subjects without tonsillar hypertrophy (n = 350) wheezing did not affect snoring [odds ratio: 2.76 (1.10-6.93); P = 0.031 and 1.49 (0.92-2.43); P = 0.107, respectively].Children with history of wheezing have more frequently tonsillar hypertrophy than those without wheezing. Tonsillar hypertrophy may mediate at least in part the reported association between asthma and obstructive sleep-disordered breathing in childhood.

Reproductive placental corticotropin-releasing hormone and its clinical implications

Evidence of Primary Aldosteronism in a Predominantly Female Cohort of Normotensive Individuals: A Very High Odds Ratio for Progression into Arterial Hypertension

Primary aldosteronism (PA) is an established cause of hypertension, whereas high-normal serum aldosterone levels have been linked to an increased risk for hypertension.We aimed to define the post-fludrocortisone-dexamethasone suppression test (FDST) normal cutoff values of aldosterone and the aldosterone to renin ratio and evaluate the presence of PA in normotensive individuals.This study was designed as a case-control study.The study was performed in a tertiary general hospital.One hundred normotensive participants (80 females), mean age 53 years, were studied.All participants underwent baseline biochemical and hormonal evaluation, FDST, and adrenal computerized tomography. Blood pressure was assessed at baseline and after 5 years.Sixty-nine participants with normal adrenal computerized tomography who remained normotensive after 5 years were used as a control population to calculate the cutoff values of adequate aldosterone suppression. PA was defined as a combination of post-FDST aldosterone to renin ratio of 0.93 ng/dL · μU/mL or greater (100% sensitivity and 96% specificity) and post-FDST aldosterone of 2.96 ng/dL or greater (100% sensitivity and 61% specificity on receiver-operating characteristic analysis). Thirteen of 100 participants had PA at baseline and 11 (85%) developed hypertension, whereas only 20 of 87 without PA (23%) developed hypertension at 5 years [odds ratio (OR) 18.42, 95% confidence intervals (CI) 3.76-90.10, P < .0001]. Logistic regression analysis showed a positive relation of PA [odds ratio (OR) 16.30, confidence interval (CI) 1.78-150.30, P = .01] and a negative relation of serum potassium (OR 0.39, CI 0.19-0.79, P = .01) with the development of hypertension.Normotensive PA represents a clinical entity referring to normotensive individuals with PA who are at increased risk for hypertension.