Serum Neuron-Specific Enolase as a Biomarker of Neonatal Brain Injury-New Perspectives for the Identification of Preterm Neonates at High Risk for Severe Intraventricular Hemorrhage.

Neonatal brain injury (NBI) is a critical condition for preterm neonates with potential long-term adverse neurodevelopmental outcomes. This prospective longitudinal case-control study aimed at investigating the levels and prognostic value of serum neuron-specific enolase (NSE) during the first 3 days of life in preterm neonates (<34 weeks) that later developed brain injury in the form of either periventricular leukomalacia (PVL) or intraventricular hemorrhage (IVH) during their hospitalization. Participants were recruited from one neonatal intensive care unit, and on the basis of birth weight and gestational age, we matched each case (n = 29) with a neonate who had a normal head ultrasound scan (n = 29). We report that serum NSE levels during the first three days of life do not differ significantly between control and preterm neonates with NBI. Nevertheless, subgroup analysis revealed that neonates with IVH had significantly higher concentrations of serum NSE in comparison to controls and neonates with PVL on the third day of life (p = 0.014 and p = 0.033, respectively). The same pattern on the levels of NSE on the third day of life was also observed between (a) neonates with IVH and all other neonates (PVL and control; p = 0.003), (b) neonates with II-IV degree IVH and all other neonates (p = 0.003), and (c) between control and the five (n = 5) neonates that died from the case group (p = 0.023). We conclude that NSE could be an effective and useful biomarker on the third day of life for the identification of preterm neonates at high risk of developing severe forms of IVH.

Biophysical Studies and In Vitro Effects of Tumor Cell Lines of Cannabidiol and Its Cyclodextrin Inclusion Complexes.

Phytocannabinoids possess anticancer properties, as established in vitro and in vivo. However, they are characterized by high lipophilicity. To improve the properties of cannabidiol (CBD), such as solubility, stability, and bioavailability, CBD inclusion complexes with cyclodextrins (CDs) might be employed, offering targeted, faster, and prolonged CBD release. The aim of the present study is to investigate the in vitro effects of CBD and its inclusion complexes in randomly methylated ß-CD (RM-ß-CD) and 2-hyroxypropyl-ß-CD (HP-ß-CD). The enhanced solubility of CBD upon complexation with CDs was examined by phase solubility study, and the structure of the inclusion complexes of CBD in 2,6-di-O-methyl-ß-CD (DM-ß-CD) and 2,3,6-tri-O-methyl-ß-CD (TM-ß-CD) was determined by X-ray crystallography. The structural investigation was complemented by molecular dynamics simulations. The cytotoxicity of CBD and its complexes with RM-ß-CD and HP-ß-CD was tested on two cell lines, the A172 glioblastoma and TE671 rhabdomyosarcoma cell lines. Methylated ß-CDs exhibited the best inclusion ability for CBD. A dose-dependent effect of CBD on both cancer cell lines and improved efficacy of the CBD-CDs complexes were verified. Thus, cannabinoids may be considered in future clinical trials beyond their palliative use as possible inhibitors of cancer growth.

Alterations in cortisol and interleukin-6 secretion in patients with COVID-19 suggestive of neuroendocrine-immune adaptations.

PURPOSE: The beneficial effect of glucocorticoids in coronavirus disease (COVID-19) is established, but whether adrenal cortisol secretion is impaired in COVID-19 is not fully elucidated. In this case-control study, we investigated the diurnal free bioavailable salivary cortisol secretion in COVID-19 patients. METHODS: Fifty-two consecutive COVID-19 patients-before dexamethasone treatment in cases required-recruited between April 15 to June 15, 2021, (NCT04988269) at Laikon Athens University-Hospital, and 33 healthy age- and sex-matched controls were included. Diurnal salivary cortisol (8 a.m., 12, 6, and 10 p.m.), plasma adrenocorticotropin (ACTH) and aldosterone, and serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels were assessed. Diurnal salivary dehydroepiandrosterone (DHEA) and IL-6 were also assessed in subgroups of patients. RESULTS: Median CRP and IL-6 measurements were about sixfold higher in patients than controls (both p < 0.001) Morning salivary cortisol levels did not differ between the two groups, but patients exhibited higher median levels of evening and nocturnal salivary cortisol compared to controls [0.391 (0.054, 0663) vs. 0.081 (0.054, 0.243) µg/dl, p < 0.001 and 0.183 (0.090, 0.834) vs. 0.054 (0.054, 0.332) µg/dl, p < 0.001, respectively], resulting in higher time-integrated area under the curve (AUC) (4.81 ± 2.46 vs. 2.75 ± 0.810, respectively, p < 0.001). Circulating ACTH, DHEA, and aldosterone levels were similar in patients and controls. Serum IL-6, but not ACTH levels, was strongly correlated with nocturnal cortisol salivary levels (ρ = 0.555, p < 0.001) in patients. CONCLUSIONS: Increased evening and nocturnal but not morning cortisol secretion may occur in even clinically mild COVID-19. In the context of acute viral infection (COVID-19), IL-6 may partially replace ACTH as a stimulus of the glucocorticoid-secreting adrenal zona-fasciculata without influencing the secretion of DHEA and aldosterone. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04988269?term=yavropoulou&draw=2&rank=3 (NCT04988269).

Association of total and neutralizing SARS-CoV-2 spike -receptor binding domain antibodies with epidemiological and clinical characteristics after immunization with the 1st and 2nd doses of the BNT162b2 vaccine.

BACKGROUND: Data regarding the association of antibody levels elicited after immunization with the BNT162b2 mRNA COVID-19 vaccine with epidemiological and clinical parameters are limited. METHODS: We prospectively measured the total (TAbs-RBD) and the neutralizing antibodies (NAbs-RBD) against the receptor binding domain (RBD) of SARS-CoV-2 spike protein in a cohort of 268 Healthcare workers before immunization, 20 days after the 1st dose and 30 days after the 2nd dose of the BNT162b2 vaccine. A statistical analysis for possible association of antibodies' levels with epidemiological and clinical parameters was performed. RESULTS: The mean age (±SD) of the participants was 45.45 years (±11.93) (range: 24-70 years) and 211 (79.9%) were females. Statistically significant differences were detected regarding both TAbs-RBD and NAbs-RBD between the first and second doses of the vaccine (P < 0.001). The median (IQR) percentage (%) of NAbs-RBD after the 1st dose was 51.07% (31.60%) and after the 2nd dose 95.31% (3.70%) (P < 0.001). The correlation between the TAbs-RBD and NAbs-RBD was after the 1st dose, Spearman's, rho: 0.861 (P < 0.001) and after the 2nd dose rho: 0.989 (P < 0.001). Twenty days after the 1st dose, 56/264 (21.2%) of the participants had low levels of NAbs-RBD, while one month after the 2nd dose all of them had protective levels of NAbs-RBD. After the 2nd vaccine dose, a statistically significant negative association of TAbs-RBD was detected for age (P < 0.001), smoking (P = 0.011), and immunosuppressive medications (P < 0.001), while a positive association was detected for BMI (P = 0.004) and systemic adverse events after immunization (P = 0.001). CONCLUSION: A significant correlation of TAbs-RBD and NAbs-RBD was detected after both vaccine doses. Older age, smoking, and immunosuppressive medications negatively affected the final antibody level after SARS-CoV-2 immunization. Our findings emphasize the significance of the 2nd vaccine dose especially in the older age groups.

Clinical value of amyloid-beta1-40 as a marker of thrombo-inflammation in antiphospholipid syndrome.

OBJECTIVE: Amyloid-beta1-40 (Aß40) is a pro-inflammatory peptide under investigation as a novel biomarker of vascular inflammation, endothelial dysfunction and atherothrombosis in the general population. Herein we tested the hypothesis that Aß40 is deregulated in APS, a systemic autoimmune disease characterized by a thrombo-inflammatory state. METHODS: Between January 2016 and July 2017, we consecutively recruited 80 regularly followed thrombotic APS patients (44 primary, 36 SLE/APS) and 80 age- and sex-matched controls. Plasma Aß40 levels were measured using ELISA and APS-related clinical and laboratory characteristics were recorded. The adjusted Global Anti-Phospholipid Syndrome Score (aGAPSS), a validated risk score in APS, was calculated as a comparator to Aß40 performance to detect arterial thrombotic APS-related events. RESULTS: Higher Aß40 levels were significantly associated with the presence of APS [odds ratio (OR) 1.024 per 1 pg/ml (95% CI 1.007, 1.041)] after adjustment for cardiovascular risk factors (CVRFs), including smoking, arterial hypertension, dyslipidaemia and BMI, and for estimated glomerular filtration rate (eGFR). Among APS patients, increased high-sensitivity CRP (hs-CRP) serum levels was the only independent determinant of Aß40 levels. Importantly, Aß40 levels above the optimal receiver operating characteristics (ROC)-derived cut-off value were independently associated with recurrent arterial events [OR 4.93 (95% CI 1.31, 18.51)] after adjustment for age, sex, CVRFs, hs-CRP and high anti-ß2 glycoprotein I IgG titres. Finally, by ROC curve analysis, Aß40 provided incremental additive value over the aGAPSS by significantly improving its discrimination ability for recurrent arterial thromboses. CONCLUSION: In APS, Aß40 plasma levels are elevated and associated with an adverse thrombo-inflammatory profile. The pathophysiological and prognostic role of Aß40 in APS merits further investigation.

Associations of maternal oestradiol, cortisol, and TGF-ß1 plasma concentrations with thyroid autoantibodies during pregnancy and postpartum.

BACKGROUND: Thyroid physiology and autoimmunity are altered in pregnancy. While oestradiol, cortisol, and TGF-ß1 are implicated in these phenomena outside pregnancy, their associations with thyroid autoantibodies during pregnancy and postpartum are not thoroughly examined. This study aimed to unravel their eventual associations during pregnancy and postpartum in the same cohort of 93 pregnant women studied prospectively from 2015 to 2017. METHODS: Blood samples were drawn at the 24th and the 36th gestational week and at the 1st postpartum week for measurements of thyroid hormones, TSH, anti-TPO, anti-Tg, oestradiol, cortisol, and TGF-ß1. RESULTS: Serum anti-TPO was greater (P < 0.05) at the 1st postpartum than at the 24th and 36th gestational weeks. At the 36th gestational week, cortisol was greater (P < 0.05) and TGF-ß1 lower (P < 0.05) than at the 24th gestational and the 1st postpartum weeks. At the 1st postpartum week, cortisol correlated negatively with anti-Tg (r = -0.419) (P < 0.05). ΔTGF-ß1 was the best negative and Δoestradiol the best positive predictor of the 1st postpartum week anti-TPO (P < 0.05, b = -0.509; P < 0.05, b = 0.459 respectively). CONCLUSIONS: At postpartum, increased TGF-ß1 is related to a less pronounced anti-TPO increase as compared to the 3rd trimester, suggesting an immunosuppressive role for TGF-ß1. During pregnancy and postpartum, oestradiol, cortisol, and TGF-ß1 are associated with suppression of thyroid autoantibodies.

Body height in paediatric inflammatory bowel diseases: A structural equation model analysis.

BACKGROUND: Linear growth restriction is a unique feature of paediatric inflammatory bowel diseases (IBD), and reduced insulin-like growth factor (IGF-1) is a major determinant of short stature. We aimed to assess factors influencing somatic height in children suffering from IBD. MATERIALS AND METHODS: This was a retrospective, cross-sectional study conducted after approval by Institutional authorities. Anthropometric data, disease-related factors, biochemical and clinical indices of inflammation and endocrine parameters were recorded and considered as explanatory covariates. A structural equation model analysis was utilized. Somatic height was the outcome of interest, and possible associations of explanatory covariates directly or through the mediation effect of IGF-1 were assessed. RESULTS: Systemic inflammation, as expressed by high-sensitivity intereukin-6 (IL-6), and nutritional status described by body mass index (BMI) were the pathways that significantly affected stature through the mediation effect of IGF-1. Cortisol showed a direct, positive and independent of IGF-1 association with height. CONCLUSIONS: Insulin-like growth factor-1 is a key player in the process that results in impaired linear growth. Malnutrition and systemic inflammation have a restrictive action on growth by reducing circulating IGF-1. The positive relation of serum cortisol to height could correspond to suppressed pituitary-adrenal axis due to long-term use of glucocorticoids.

Serum irisin concentrations in lean adolescents with polycystic ovary syndrome.

OBJECTIVE: To explore differences in irisin concentrations between lean adolescents with PCOS and age- and body mass index (BMI)-matched controls and examine the associations of irisin with core features of the syndrome. DESIGN: Cross-sectional study. PATIENTS: Lean females with PCOS, aged 13-21 years. MEASUREMENTS: Physical, hormonal and sonographic assessment. Irisin concentrations were measured with ELISA. RESULTS: Participants included in total 39 sedentary females (mean ± SD; age 17.3 ± 2.1 years, BMI 20.7 ± 1.3 Kg/m2 ), 23 adolescents with PCOS and 16 controls. Adolescents with PCOS compared to controls had significantly elevated concentrations of fasting serum irisin (mean ± SD; PCOS, 1.7 ± 1.0 µg/mL vs controls, 1.0 ± 0.4 µg/mL; P = .007), luteinizing hormone (LH), oestradiol, testosterone, Δ4-androstenedione, 17-hydroxyprogesterone, glucose, as well as free androgen index, Ferriman-Gallwey score and mean ovarian volume (MOV). For the total sample, circulating irisin was positively correlated with MOV (r = .332, P = .041), glucose (r = .428, P = .007), insulin (rs  = .369, P = .021) and HOMA-IR (rs  = .422, P = .007) and negatively correlated with QUICKI (r = -.329, P = .041). Follicle-stimulating hormone (B = 0.295, Beta = .342, P = .042) and MOV (B = 0.182, Beta = 0.821, P = .001) were positive predictors, and LH (B = -0.108, Beta = -0.523, P = .010) and testosterone (B = -0.431, Beta = -0.457, P = .032) were negative predictors of irisin concentrations, whereas irisin positively predicted fasting glucose (B = 0.262, Beta = 0.428, P = .007). In the PCOS group, irisin concentrations were positively correlated with HOMA-IR (rs  = .416, P = .048) but negatively correlated with LH (rs  = -.499, P = .015), testosterone (r = -.585, P = .003), free androgen index (r = -.426, P = .048) and Ferriman-Gallwey score (r = -.533, P = .015). CONCLUSIONS: Irisin was associated with the adolescents' metabolic and reproductive characteristics and the hyperandrogenic phenotype of the syndrome. Much research is needed to ascertain mechanisms of elevated serum irisin in adolescent PCOS.

Is there an association between thyroid function abnormalities and breast cancer?

OBJECTIVE: The aim of this study was to evaluate the association between thyroid function abnormalities and breast cancer and, in particular, the prognostic markers of breast cancer.. SUBJECTS AND METHODS: Baseline levels of thyrotropin, free triiodothyronine, free thyroxine and thyroid autoantibodies were measured in 97 women with primary breast cancer, 27 women with benign breast disease, and 4 women with atypical ductal hyperplasia. Their baseline levels were compared with those in 48 healthy women with a normal mammography in the last 2 years. RESULTS: There were no significant associations between history of thyroid disease and breast cancer (p = 0.33). The mean baseline levels of triiodothyronine and thyrotropin did not differ significantly between the compared groups. The mean baseline levels of free thyroxine were found to be significantly higher in the breast cancer group, even after adjusting for thyroid replacement therapy. The presence of thyroid antibodies did not differ significantly between the compared groups. In a subgroup analysis, breast cancer cases with thyroid disease and particularly hypothyroidism had a significantly lower incidence of lymph node metastases compared with breast cancer cases without thyroid disease. CONCLUSIONS: Our data confirmed the proliferative effect of thyroid hormones on breast cells, which had previously been shown in vitro. Additionally, thyroid disease and particularly hypothyroid function appeared to be associated with a lower incidence of lymph node metastases. Further studies to determine the prognostic role of thyroid hormones in breast cancer are warranted.

Is there an association between thyroid function abnormalities and breast cancer?

ABSTRACT Objective The aim of this study was to evaluate the association between thyroid function abnormalities and breast cancer and, in particular, the prognostic markers of breast cancer.. Subjects and methods Baseline levels of thyrotropin, free triiodothyronine, free thyroxine and thyroid autoantibodies were measured in 97 women with primary breast cancer, 27 women with benign breast disease, and 4 women with atypical ductal hyperplasia. Their baseline levels were compared with those in 48 healthy women with a normal mammography in the last 2 years. Results There were no significant associations between history of thyroid disease and breast cancer (p = 0.33). The mean baseline levels of triiodothyronine and thyrotropin did not differ significantly between the compared groups. The mean baseline levels of free thyroxine were found to be significantly higher in the breast cancer group, even after adjusting for thyroid replacement therapy. The presence of thyroid antibodies did not differ significantly between the compared groups. In a subgroup analysis, breast cancer cases with thyroid disease and particularly hypothyroidism had a significantly lower incidence of lymph node metastases compared with breast cancer cases without thyroid disease. Conclusions Our data confirmed the proliferative effect of thyroid hormones on breast cells, which had previously been shown in vitro. Additionally, thyroid disease and particularly hypothyroid function appeared to be associated with a lower incidence of lymph node metastases. Further studies to determine the prognostic role of thyroid hormones in breast cancer are warranted.

Circulating levels of TNF-like cytokine 1A correlate with reflected waves and atherosclerosis extent and may predict cardiac death in patients with stable coronary artery disease.

BACKGROUND: TNF-like cytokine 1A (TL1A)-mediated interactions are involved in atheromatic plaque formation. In stable coronary artery disease (CAD) we examined whether circulating TL1A levels correlate with coronary and/or peripheral atherosclerosis extent and predict future cardiovascular events. METHODS: In this cross-sectional study, peripheral vascular studies and TL1A serum measurements were performed in 122 consecutive patients with angiographically confirmed CAD who were followed for a median of 41.9 months. TL1A levels were compared against controls (n = 63) and 20 patients with acute coronary syndrome (ACS). RESULTS: TL1A was higher in ACS than the 2 other groups (p < 0.001). In stable CAD, after adjustment for traditional risk factors independent positive correlations between TL1A serum levels and reflected waves (p = 0.049), and carotid atheromatic plaque score (p = 0.049) were evident. In stable patients with a history of ACS, TL1A levels correlated with worse endothelial function (p = 0.006), extent of CAD assessed by Gensini score (p = 0.042), and cardiac mortality (p = 0.051). CONCLUSIONS: This pilot study suggests that serum TL1A measurements are of clinical value in CAD. Studies on the pathogenetic role of TL1A in atherosclerosis and its sequelae are warranted.

The correlation of right 2D:4D finger length ratio to the low-grade inflammation marker IL-6 in children. The Healthy Growth Study.

BACKGROUND: Second to fourth digit ratio (2D:4D) is associated with cardiometabolic risk in adults. AIM: To examine the association of right 2D:4D with cardiovascular disease risk factors in children. STUDY DESIGN: Cross-sectional study. SUBJECTS: A sample of 301 children (53.5% girls) aged 9-13 in Greece and their parents. Children who were sick during the previous week of examination (n=44) were excluded from the analyses. OUTCOME MEASURES: Socio-demographic (gestational age, birth weight, age, gender, maternal education level), anthropometric (body weight and height, finger length), clinical (pubertal stage, sickness during the previous week of the examination), blood [serum high sensitivity C-reactive protein (CRP), serum high sensitivity interleukin-6 (IL-6), serum leptin], lifestyle (dietary intake, maternal smoking during pregnancy) and physical fitness (handgrip strength) data were collected. CRP, IL-6 and leptin were measured with ELISA, using standard equipment and procedures, in accordance with manufacturers' instructions. RESULTS: Full data were available for 257 children (52.1% girls). The rank values of right 2D:4D and IL-6 were included in the analyses. Right 2D:4D was correlated only with IL-6 at a bivariate level (r=0.216, p=0.012) in girls. At a linear multivariate level, this association remained significant, even after adjusting for several potential confounders such as age, Tanner stage, maternal education level, body mass index, maternal smoking during pregnancy, duration of pregnancy, protein-, carbohydrate-, fat-intake and physical fitness (ß±SE=0.220±0.066, p=0.001). CONCLUSIONS: Right 2D:4D was found to be associated with IL-6 in girls. Right 2D:4D may be a valuable, simple screening tool of low-grade inflammation in children.