Publications

THE HYPOTHALAMIC‐PITUITARY‐ADRENAL AXIS IN INFANTILE MALNUTRITION

SUMMARY We studied the circadian rhythm and the response of the hypothalamic‐pituitary‐adrenal (HPA) axis to ovine corticotrophin releasing hormone (oCRH) stimulation and dexamethasone suppression in 32 children with grade II‐III marasmus. Children were studied prior to and after nutritional rehabilitation. Mean baseline plasma cortisol concentrations were elevated at admission and decreased significantly after nutritional rehabilitation. Mean±SEM plasma cortisol response to oCRH increased from a basal of 480 ±41 to a peak of 582 ± 58 nmol/1 at the time of admission, and from a basal of 234±27 to a peak of 532±41 nmol/1 after caloric rehabilitation. Dexamethasone suppression in the malnourished group was associated with a decrease in the mean±SEM basal plasma cortisol concentration from 397±44 to 171 ±44 nmol/1. After caloric rehabilitation, basal cortisol levels decreased from 259±27 to 22±5 nmol/l following dexamethasone. Our results support the concept that malnutrition is associated with decreased responsiveness to oCRH and incomplete dexamethasone suppression, and that these abnormalities are restored after nutritional rehabilitation.

Disparities of infant and neonatal mortality trends in Greece during the years of economic crisis by ethnicity, place of residence and human development index: a nationwide population study

Objective To study trends of infant mortality rate (IMR) and neonatal mortality rate in Greece during the period 2004–2016 and explore the role of sociodemographic factors in the years of crisis. Design Nationwide individual data for live births and infant (0–11 months) deaths provided by the Hellenic Statistical Authority were examined using Poisson, joinpoint regression and interrupted time series (ITS) analyses. Setting Greece. Participants All infant deaths (n=4862) over the 13-year period, of which 87.2% were born to Greek mothers, and respective live births. Main outcome measures Evolution of IMR (0–364 days), early (<7 days) neonatal mortality rate (ENMR), late (7–27 days) neonatal mortality rate (LNMR) and post neonatal (28–364 days) mortality rate (PNMR) trends, by maternal nationality, place of residence and Human Development Index (HDI). Results By Poisson regression, overall, during the study period, among infants of Greek mothers, IMR and PNMR declined significantly (−0.9%; 95% CI −1.7% to −0.1% and −1.6%; −3.0% to −0.2% annually, respectively), although differentially by place of residence (IMR urban : −2.1%; −2.9% to −1.3%, IMR rural : +10.6%; 7.6% to 13.6%). By contrast, among infants of non-Greek mothers, the low starting IMR/ENMR/LNMR/PNMR increased significantly (max ENMR:+12.5%; 8.6% to 16.5%) leading to a non-significant time–trend pattern overall in Greece. The inverse associations of HDI with IMR, ENMR and PNMR were restricted to Greek mothers’ infants. Joinpoint regression analyses among Greek mothers’ infants indicated non-significant increasing trends of IMR and ENMR following the crisis (+9.3%, 2012–2016, p=0.07 and +10.2%, 2011–2016, p=0.06, respectively). By contrast, the high (+17.1%; 8.1% to 26.9%, p=0.002) IMR increases among non-Greek infants were restricted to 2004–2011 and equalised to those of Greek mothers’ infants thereafter. ITS analyses in preset years (2008, 2010, 2012) identified significantly increasing trends in IMR, LNMR and PNMR after 2012, and in ENMR after 2010, among Greek mothers’ infants. Conclusions HDI and rural residence were significantly associated with IMR. The strongly decreasing IMR trends among Greek-mothers’ infants were stagnated after a lag time of ~4 years of crisis approximating the previously sharply increasing trends among non-Greeks.

Hyperandrogenism in Women with Polycystic Ovary Syndrome Persists after Menopause

Ovarian and adrenal hyperandrogenism characterize premenopausal women with polycystic ovary syndrome (PCOS). Androgens decline with age in healthy and PCOS women.The objective of the study was to investigate hyperandrogenism in PCOS after menopause.This was a case-control, cross-sectional study.The study was conducted at a university hospital endocrinology unit.Twenty postmenopausal women with PCOS and 20 age- and body mass index-matched controls participated in the study.Serum cortisol, 17-hydroxyprogesterone (17-OHP), Δ(4)-androstenedione (Δ(4)A), dehydroepiandrosterone sulfate (DHEAS), total testosterone (T), and free androgen index (FAI) levels were measured at baseline, after ACTH stimulation, and after 3-d dexamethasone suppression. The ACTH and cortisol levels were measured during the CRH test.Androgen profile at baseline, after ACTH stimulation, and 3-d dexamethasone suppression tests were the main outcome measures.Postmenopausal PCOS women had higher 17-OHP, Δ(4)A, DHEAS, total T, FAI (P < 0.05) and lower SHBG (P < 0.05) baseline levels than control women. ACTH and cortisol responses during the CRH test were similar in the two groups. After ACTH stimulation, Δ(4)A, DHEAS, and total T levels were equally increased in both groups. After dexamethasone suppression, LH levels did not change in either group; 17-OHP-, Δ(4)A-, and FAI-suppressed levels remained higher in PCOS than in control women (P < 0.05), whereas total T and DHEAS levels were suppressed to similar values in both groups.In postmenopausal PCOS women, ACTH and cortisol responses to CRH are normal. Androgen levels at baseline are higher in PCOS than control women and remain increased after ACTH stimulation. The dexamethasone suppression results in postmenopausal PCOS women suggest that DHEAS and total T are partially of adrenal origin. Although the ovarian contribution was not fully assessed, increased Δ(4)A production suggests that the ovary also contributes to hyperandrogenism in postmenopausal PCOS women. In conclusion, postmenopausal PCOS women are exposed to higher adrenal and ovarian androgen levels than non-PCOS women.

Replication Data for: Pythagorean Self-Awareness serves effectively for Stress Management on Freshmen

Adjustment to conditions surrounding the first year of studies in tertiary education can be highly stressful. Because of the pertinent challenges, University freshmen evidently run risks for developing mental and physical ailments probably undermining their entire wellbeing. Aims: This study evaluates effects of two preventive or/and corrective intervention methods dealing with their difficulties. Sample: Freshmen (N=60). Methods: In a parallel quasi-experimental design the above freshmen were randomly sub-grouped for attending to 8 consecutive weekly sessions of either Pythagorean Self-Awareness Intervention (PSAI) or Stress Management Techniques Intervention (SMTI). Several self-report measures were administered at pre- and post-intervention phases. Assessment included various factors: (a) psychological: stress, anxiety, depression, anger, emotionality, (b) physiological: Body-Mass-Index (BMI) via engaging in healthy habits, lifestyle, sleep, (c) basic cognitive: visuospatial memory, verbal learning and (d) complex mental: fatigue-vs-coherence, speed processing, self-efficacy. Results: Significant post-intervention improvements were noted for most dimensions, irrespective of group allocation. SMTI was superior to PSAI for reducing BMI and improving basic cognitive features, whereas PSAI was superior for improving psychological and complex mental processes. Conclusions: Results are encouraging to suggest these interventions be introduced in academic settings as effective meta-cognitive multifaceted procedures for stress management, to help students become more successful in their personal as well as academic lives.

Sex-specific correlation of IGFBP-2 and IGFBP-3 with vitamin D status in adults with obesity: a cross-sectional serum proteomics study

Abstract Objective Subjects with low vitamin D levels are at risk of cardiometabolic disease. The aim of this study was to identify novel serological markers linking vitamin D status with cardiometabolic profile in non-diabetic adults with obesity. Methods For the discovery phase, we used quantitative serum proteomics in sex-matched, age-matched and BMI-matched subjects with obesity [BMI: 25–35 kg/m 2 ] and low [25(OH)D &lt; 50 nmol/L] vs. high vitamin D status [25(OH)D &gt; 50 nmol/L] ( n = 16). For the validation phase, we performed ELISA in a larger cohort with similar characteristics ( n = 179). Results We identified 423 and 549 differentially expressed proteins in the high vs. low vitamin D groups of the male and female cohorts, respectively. The small molecule biochemistry protein networks and the glycolysis|gluconeogenesis pathway were significantly enriched in the DEPs of both sexes. As surrogate markers to these processes, the insulin-like growth factor binding protein -2 (IGFBP-2) was upregulated in males, whereas IGFBP-3 was upregulated in females from the high Vitamin D status. This sex-specific trend was confirmed using Luminex ELISA to an independent but clinically analogous cohort of males ( n = 84, p = 0.002) and females ( n = 95, p = 0.03). Conclusions The high Vitamin D status correlated with the serological upregulation of IGFBP-2 in males and IGFBP-3 in females with obesity and may constitute surrogate markers of risk reduction of cardiometabolic disease.

An updated evolutionary and structural study of TBK1 reveals highly conserved motifs as potential pharmacological targets in neurodegenerative diseases

Abstract TANK binding kinase 1 protein (TBK1) is a kinase that belongs to the IκB (IKK) family. TBK1, also known as T2K, FTDALS4, NAK, IIAE8 and NF-κB, is responsible for the phosphorylation of the amino acid residues Serine and Threonine. This enzyme is involved in various key biological processes, including interferon activation and production, homeostasis, cell growth, autophagy, insulin production and the regulation of TNF-α, IFN-β and IL-6. Mutations in the TBK1 gene alter the protein’s normal function and may lead to an array of pathological conditions, including disorders of the Central Nervous System. The present study sought to elucidate the role of the TBK1 protein in Amyotrophic Lateral Sclerosis (ALS), a human neurodegenerative disorder. A broad evolutionary and phylogenetic analysis of TBK1 was performed across numerous organisms to distinguish conserved regions important for the protein’s function. Subsequently, mutations and SNPs were explored and their potential effect on the enzyme’s function was investigated. These analytical steps, in combination with the study of the secondary, tertiary, and quaternary structure of TBK1, enabled the identification of conserved motifs, which can function as novel pharmacological targets and inform therapeutic strategies for Amyotrophic Lateral Sclerosis.

Cushing's Disease

Is There a Role for Glucocorticoid Receptor Beta in Glucocorticoid-dependent Asthmatics?

Endocrinology of Male Reproduction

Gestational weight gain charts for different body mass index groups for women in Europe, North America, and Oceania

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS

ESTIMATION OF THE SEISMIC RISK WITH CONSIDERATION OF CAPACITY DEGRADATION OVER TIME

The dependence of mankind on the urban built environment is an integral part of culture that is so firmly embedded in our daily life that we are mostly unaware of its existence, as long as functionality is provided. The aging of our structures and the action of natural hazards, such as earthquakes, threaten the functionality of our urban environment and extraordinary expenditures are required to just maintain the status quo. Throughout the world, buildings are reaching the end of their useful life and develop new pathologies that increase their seismic risk, an effect that we aim to capture. In the paper, first, a methodology for structural performance assessment with consideration of capacity degradation over time is presented, utilizing IN2 analysis and an extension of the PEER probabilistic framework to rapidly achieve accurate estimates of limit-state exceedance probabilities of deteriorated structures. In the second part the methodology is applied to an example of a three-storey asymmetric reinforced concrete building. At this stage of the study only an influence of corrosion on longitudinal and transverse reinforcement of the structural elements is considered in the estimation of the seismic risk. The N2 method is used for seismic performance assessment of the structure. It is shown that the capacity in terms of the maximum base shear, as well as in terms of the maximum ground acceleration corresponding to limit states in the nonlinear range, is reduced over time, since the corrosion affects the capacity of both the beams and columns. Consequently, the expected frequency of violating life-safety or near-collapse limit states over the time interval increases in comparison to the typical case where the strength deterioration is neglected.

Petrosal sinus sampling for Cushing syndrome: anatomical and technical considerations. Work in progress.

ACTH-producing microadenomas of the pituitary gland drain unilaterally into the adjacent cavernous sinus; therefore, petrosal sinus sampling to distinguish pituitary from ectopic-ACTH syndromes must always be performed bilaterally. A negative finding from a unilateral petrosal sinus sample does not exclude the presence of a contralateral ACTH-producing microadenoma. Hemiresection of the pituitary gland based on results of bilateral sampling can be performed if the adenoma is too small to be recognized at surgery. Large pituitary adenomas produce elevated ACTH levels in the petrosal sinuses bilaterally. However, if plain radiographs or CT scans provide unequivocally positive findings in Cushing syndrome (less than 20%), inferior petrosal sinus sampling is not indicated.

Prevalence of Primary Aldosteronism Across the Stages of Hypertension Based on a New Combined Overnight Test

Primary aldosteronism (PA) is the most common endocrine cause of arterial hypertension. Despite the increasing incidence of hypertension worldwide, the true prevalence of PA in hypertension was only recently recognized. The objective of the work was to estimate the prevalence of PA in patients at different stages of hypertension based on a newly developed screening-diagnostic overnight test. This is a prospective study with hypertensive patients (n=265) at stage I (n=100), II (n=88), and III (n=77) of hypertension. A group of 103 patients with essential hypertension without PA was used as controls. PA diagnosis was based on a combined screening-diagnostic overnight test, the Dexamethasone-Captopril-Valsartan Test (DCVT) that evaluates aldosterone secretion after pharmaceutical blockade of angiotensin-II and adrenocorticotropic hormone. DCVT was performed in all participants independently of the basal aldosterone to renin ratio (ARR). The calculated upper normal limits for post-DCVT aldosterone levels [3 ng/dl (85 pmol/l)] and post-DCVT ARR [0.32 ng/dl/μU/ml (9 pmol/IU)] from controls, were applied together to establish PA diagnosis. Using these criteria PA was confirmed in 80 of 265 (30%) hypertensives. The prevalence of PA was: 21% (21/100) in stage I, 33% (29/88) in stage II, and 39% (30/77) in stage III. Serum K+ levels were negatively correlated and urinary K+ was positively correlated in PA patients with post-DCVT ARR (r=-0.349, p <0.01, and r=0.27, p <0.05 respectively). In conclusion, DCVT revealed that PA is a highly prevalent cause of hypertension. DCVT could be employed as a diagnostic tool in all subjects with arterial hypertension of unknown cause.

Alzheimer disease and Apolipoprotein E4: meningeal brain lymphatics point to new clues in pathogenesis

ABSTRACT The role of the lymphatic system in brain function and/or dysfunction has long been an enigma. However, recent reports that meningeal lymphatic vessels exist within the mouse and human brain, as well as evidence that mouse meningeal lymphatic vessels play a role in clearing the toxic amyloid-beta peptide connected with Alzheimer’s disease (AD), may herald novel diagnostic and therapeutic avenues. Here, we explore new evidence connecting the lymphatic system of the brain with AD. In particular, we focus on new findings showing that meningeal lymphatic vessels play a role in drainage of cerebrospinal fluid and egress of immune cells from the brain, and that disrupting this vessel system leads to accumulation of amyloid - beta peptide and cognitive dysfunction. We also discuss the hypothesis that apolipoprotein E isoform e4 (APO E4) ─ the leading genetic risk for developing AD ─ is involved in meningeal lymphatic vessel function. By reanalyzing previously published RNA-Seq data, we show that APO E4 knock-in microglia cells express lower levels of genes representing lymphatic markers (a phenomenon we call “attenuated lymphaticness”) and of genes in which functional missense mutations are linked to lymphedema. Accordingly, we propose the hypothesis that APO E4 is involved in the shrinkage of lymphatic vessels. This notion could lead, if verified by additional anatomic and mechanistic data, to the concept that APO E4-related AD (such as in late onset AD or trisomy 21-related AD) is related to lymphosclerosis coupled with lymphedema.

Psychosocial Factors and Suicidal Behaviour in Adolescents

Exploring the Effects of Problematic Internet Use on Adolescent Sleep: A Systematic Review

Adolescent suse internet via several devices to gather information or communicate. Sleep, as a key factor of adolescents’ development, contributes to their physical and mental health. Over the past decades insufficient sleep among adolescents has been wide spread, and one of its attributing factors is the increased availability of technology. This review aims to investigate the body of evidence regarding the impact of problematic internet use on adolescent sleep. Extensive search of databases was performed according to PRISMA guidelines for studies published within the last decade, regarding subjects aged 10–19. The final step of the search yielded 12 original studies. The quality of extracted data was evaluated with the AXIS tool, in order to estimate the risk of bias. All studies showed a negative correlation between adolescent sleep and problematic internet use. It was found to affect sleep quality and quantity and provoke insomnia symptoms. Interestingly, adolescent’s sex, parental educational level, type of family and use for leisure or academic reasons appeared as affecting factors of the problematic internet use-sleep relationship. Problematic internet use has several effects on adolescents’ sleep. Results of relevant studies should be embedded in educational interventions addressed to adolescents as well as parents, to eliminate the negative outcomes of problematic internet use on sleep and adolescence’s health in general.

Supplementary Material for: Circulating irisin levels in preadolescents and adolescents born preterm

Introduction. Prematurity is associated with increased cardiometabolic risk later in life. The adipomyokine irisin has been acknowledged as a modulator of energy metabolism and insulin sensitivity. The aim of this study was to investigate circulating levels of irisin and their relation to anthropometric measurements and cardiometabolic phenotype in a population of preterm-born children vs. full-term-born peers. Methods. A total of 160 children (87 born preterm aged 8.1-14.8 years and 73 born full-term of similar age and gender distribution) were studied. Arterial blood pressure, anthropometry, body composition assessments with dual energy X-ray absorptiometry (DXA) and skin fold measurements were performed. Blood biochemistry and circulating levels of irisin, insulin, cortisol, leptin, and adiponectin were also determined. Results. The preterm group had higher diastolic blood pressure, triceps skin fold, subscapular skin fold (SSF) and abdominal skin fold measurements and more central adiposity than the full-term group. Irisin was significantly lower (p=0.002), whereas leptin was higher (p=0.03), in the preterm than the full-term group. Irisin correlated positively with gestational age (r=0.19, p=0.01), birthweight (r=0.23, p=0.003) and high-density lipoprotein cholesterol (r=0.20, p=0.01), and negatively with SSSF (r=-0.25 p=0.003) and chronological age (r=-0.21, p=0.008). Conclusion. Lower levels of irisin and a slightly unhealthy adiposity and cardiometabolic pattern were detected in preterm-born children in comparison to their full-term-born peers. Whether low irisin levels in preadolescents and adolescents born prematurely could be of prognostic value for the development of cardiometabolic sequelae later in life remains to be further studied.