Activator Protein-1 Transcriptional Activity Drives Soluble Micrograft-Mediated Cell Migration and Promotes the Matrix Remodeling Machinery

Impaired wound healing and tissue regeneration have severe consequences on the patient's quality of life. Micrograft therapies are emerging as promising and affordable alternatives to improve skin regeneration by enhancing the endogenous wound repair processes. However, the molecular mechanisms underpinning the beneficial effects of the micrograft treatments remain largely unknown. In this study, we identified the active protein-1 (AP-1) member Fos-related antigen-1 (Fra-1) to play a central role in the extracellular signal-regulated kinase- (ERK-) mediated enhanced cell migratory capacity of soluble micrograft-treated mouse adult fibroblasts and in the human keratinocyte cell model. Accordingly, we show that increased micrograft-dependent in vitro cell migration and matrix metalloprotease activity is abolished upon inhibition of AP-1. Furthermore, soluble micrograft treatment leads to increased expression and posttranslational phosphorylation of Fra-1 and c-Jun, resulting in the upregulation of wound healing-associated genes mainly involved in the regulation of cell migration. Collectively, our work provides insights into the molecular mechanisms behind the cell-free micrograft treatment, which might contribute to future advances in wound repair therapies

Nonfunctional adrenal adenomas and impaired glucose metabolism: a systematic review and meta-analysis

Purpose: Evidence on nonfunctioning adrenal incidentaloma’s (NFAI) associated comorbidities and in particular, glucose disorders, is unclear in contrast to adrenal tumors with mild autonomous cortisol secretion. The current systematic review and meta-analysis aimed to assess the burden of impaired glucose metabolism including diabetes mellitus type 2 (T2DM), fasting blood glucose (FBG), and fasting blood insulin (FBI) levels in patients with NFAI and 1-mg overnight dexamethasone suppression test (ODST) ≤ 1.8 μg/dl across published studies. Methods: We searched PubMed, Cochrane, and Scopus databases for identifying studies published between 1956 and March 2021. Twenty-five studies met the selection criteria including prospective, retrospective, and case–control studies. Two reviewers independently extracted studies, participants’ characteristics and outcome data in a total pooled sample of 1548 patients. Results: Patients with NFAI had twofold [(odds ratio (OR) (95% confidence interval (CI)): 2.03 (1.39–2.98)] increased odds to present T2DM as well as higher FBG [weighted mean difference (WMD) (95% CI): 3.85 (1.96–5.74)] and homeostasis model assessment (HOMA) [WMD (95% CI): 0.68 (0.23–1.12)] with respect to controls. On the contrary, the WMD of FBI levels did not differ between the two groups. The incidence of T2DM in a subgroup analysis of patients with NFAI without glucose disorders at baseline was 6% [pooled incidence (95% CI): 0.06 (0.04–0.09)]. Conclusions: Patients with NFAI and 1-mg ODST ≤ 1.8 μg/dl presented higher odds of T2DM and higher levels of FBG and HOMA index than healthy controls. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature

Mini-Mental State Examination: Greek Normative Data Stratified by Age and Education in a Large Sample of 925 Community-Dwelling Healthy Participants

Background: Cognitive screening measures are widely administered in everyday clinical practice in different geriatric settings. Despite the presence of several extended-like screening tests, Mini-Mental State Examination (MMSE) continues to be largely used not only by neuropsychologists, neurologists, and psychiatrists but also by general practitioners and other health-related specialties. Aim: We herein provide normative data for the MMSE in a large sample of community-dwelling healthy participants aged over 50 years old stratified by age and education. Material and Methods: The sample included 925 community-dwelling healthy participants (age range: 50–91 years) of both genders (231 males/694 females) with different educational level (range: 1–16 years). Demographic-related effects were examined for the total MMSE score using hierarchical regression analysis; normative data are presented in mean ± standard deviation and percentile ranks and divided into seven overlapping age tables with different midpoints at 55, 60, 65, 70, 75, 80, and 85 years using the overlapping cell procedure. Results: Initial analysis did not show any effect of gender but revealed significant correlation between age, education, and total MMSE. Hierarchical regression analysis revealed that education significantly accounted for 17.3% of the total variance in the MMSE with age adding a significant 7.4% to the final model (adjusted R2 = 0.246, F = 151.872, p < 0.001; age: β = −0.286, p < 0.001; education: β = 0.332, p < 0.001). The sample was stratified according to the overlapping cell procedure with regard to age (age groups: 50–60, 55–65, 60–70, 65–75, 70–80, 75–85, 80–91); four educational levels were considered: 1–5, 6–9, 10–12, and 13–16 years. Conclusions: Current normative data for the Greek version of the MMSE are provided as a useful set of norms for clinical and research practice. © Springer Nature Switzerland AG 2020

The role of immunohistochemical markers for the diagnosis and prognosis of adrenocortical neoplasms

Adrenal cortical carcinoma (ACC) is a rare cancer with poor prognosis that needs to be dis-tinguished from adrenocortical adenomas (ACAs). Although, the recently developed transcriptome analysis seems to be a reliable tool for the differential diagnosis of adrenocortical neoplasms, it is not widely available in clinical practice. We aim to evaluate histological and immunohistochemical markers for the distinction of ACCs from ACAs along with assessing their prognostic role. Clinical data were retrospectively analyzed from 37 patients; 24 archived, formalin-fixed, and paraffin-embedded ACC samples underwent histochemical analysis of reticulin and immunohistochemical analysis of p27, p53, Ki-67 markers and were compared with 13 ACA samples. Weiss and Helsinki scores were also considered. Kaplan−Meier and univariate Cox regression methods were implemented to identify prognostic effects. Altered reticulin pattern, Ki-67% labelling index and overexpression of p53 protein were found to be useful histopathological markers for distinguishing ACAs from ACCs. Among the studied markers, only pathological p53 nuclear protein expression was found to reach statistically significant association with poor survival and development of metastases, although in a small series of patients. In conclusion, altered reticulin pattern and p53/Ki-67 expression are useful markers for distinguishing ACCs from ACAs. Immunohistopathology alone cannot discrim-inate ACCs with different prognosis and it should be combined with morphological criteria and transcriptome analysis. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Τriglycerides-glucose (TyG) index is a sensitive marker of insulin resistance in Greek children and adolescents

Purpose: To investigate the association between Triglyceride-glucose (TyG) index and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Matsuda indices in Greek obese children and adolescents, in order to assess whether it could be used as a predictor of insulin resistance. Methods: 367 children (47.7% boys) with mean age of 9.9 ± 2.3 years, who were investigated for obesity, were included. After overnight fasting, TyG and HOMA-IR indices were calculated in all participants. In a subpopulation of 72 children Matsuda index was also calculated. Results: 48.8% and 36.1% of the participants had insulin resistance according to HOMA-IR and Matsuda index respectively. TyG was significantly and positively correlated with BMI, ΗΟΜΑ-IR, lipid profile and Matsuda index. ROC curve analysis for TyG showed that the optimal cutoff value for the prediction of insulin resistance (HOMA-IR) was 7.96 with sensitivity 65% and specificity 58%. The area under the curve (AUC) was 0.65 which significantly differs from 0.5 (p < 0.001). Similarly, the optimal cutoff value of TyG index for predicting insulin resistance as evidenced by Matsuda was 7.91 with sensitivity 85% and specificity 61%. The AUC was 0.75 (p < 0.001). The odds for insulin resistance (with HOMA-IR) was 2.54 times greater for subjects with TyG higher than 7.96, while the odds for insulin resistance (with Matsuda) was 8.56 times greater for subjects with TyG more than 7.91. Conclusions: TyG index shows a positive correlation with insulin resistance among children and adolescents, however further studies are needed to clarify its predictive ability. © 2020, Springer Science+Business Media, LLC, part of Springer Nature

Prolactin as a predictor of endothelial dysfunction and arterial stiffness progression in menopause

Postmenopausal women are at increased risk for progression of arteriosclerosis and hypertension. Recent cross-sectional evidence suggests that high normal circulating prolactin levels may accelerate vascular ageing in menopause. Postmenopausal women (n=201) were consecutively recruited from a Menopause Clinic and re-evaluated in at least one follow-up visit within the next 3 years. Baseline circulating prolactin levels were measured while both baseline and follow-up vascular and biochemical measurements were performed. Endothelial function was assessed by flow-mediated dilation (FMD), aortic stiffness by pulse-wave velocity (PWV) and arterial wave reflections by applanation tonometry. Baseline prolactin significantly correlated with lower FMD at follow-up (P=0.005). After multivariable adjustment for age, follow-up time, blood pressure (BP), body mass index, smoking and medication, this correlation remained significant (P=0.003). In addition, baseline circulating prolactin levels were independently associated with changes in mean BP (β=0.131, P=0.021), peripheral diastolic BP (β=0.169, P=0.004) and new-onset hypertension (OR=1.235, P=0.001). Owing to significant interaction between baseline prolactin and age for changes in PWV over time (P=0.036), a subgroup analysis based on median age was performed. This analysis revealed that in women younger than 55 years, prolactin was an independent predictor of changes in PWV over time (P=0.008). In conclusion, high normal circulating prolactin levels predict changes in haemodynamic indices and worsening endothelial function in healthy postmenopausal women. Particularly in young postmenopausal women, prolactin predicts accelerated arterial stiffening. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved

Free androgen index as a determinant of arterial stiffness in menopause: A mediation analysis

Objective: Associations of endogenous androgens in menopause with blood pressure (BP) and indices of arterial stiffness are reported, but directional relationships are not clear. Structural equation modeling is a contemporary statistical method, which allows assessment of such relationships and improves pathway understanding. Methods: We recruited 411 consecutive apparently healthy postmenopausal women who underwent noninvasive vascular evaluation. This included pulse wave analysis (aortic pressures and arterial wave reflections [augmentation index]), measurement of aortic stiffness by pulse wave velocity (PWV), stiffness index (SI), and flow-mediated dilatation. A cumulative marker combining PWV and SI (combined local and aortic arterial stiffness [CAS]) was also assessed. Free androgen index (FAI) was calculated from circulating total testosterone and sex hormone-binding globulin. Results: FAI was an independent determinant of systolic BP (SBP) (P=0.032), SI (P=0.042), and PWV (P=0.027). Under structural equation modeling analysis, FAI was a direct predictor for PWV (beta=0.149, P=0.014), SI (beta=0.154, P=0.022), and CAS (beta=0.193, P=0.02), whereas SBP was a parallel mediator of androgen's vascular effects on PWV (beta=0.280, P<0.001) and CAS (beta=0.248, P=0.004), but not SI (beta=0.024, P=0.404). FAI-induced increase in arterial stiffness via flow-mediated dilatation was not established. FAI was not a determinant of augmentation index. Conclusions: In healthy postmenopausal women, FAI was directly associated with PWV, SI, and CAS. FAI also directly correlated with SBP, which in turn concurrently increased PWV and CAS. The directional correlations found herein, imply that endogenous androgens may be causally associated with indices of arterial stiffness both directly and indirectly. This hypothesis should be confirmed in further studies with causal design. © 2017 by The North American Menopause Society