Cut-off points of the visceral adiposity index (VAI) identifying a visceral adipose dysfunction associated with cardiometabolic risk in a Caucasian Sicilian population

<p>Abstract</p> <p>Background</p> <p>The Visceral Adiposity Index (VAI) is a sex-specific mathematical index, based on Waist Circumference (WC), Body Mass Index (BMI), triglycerides (TG) and HDL cholesterol (HDL) levels, indirectly expressing visceral adipose function and insulin sensitivity. Our aim was to find the optimal cut-off points of VAI identifying a visceral adipose dysfunction (VAD) associated with cardiometabolic risk in a Caucasian Sicilian population.</p> <p>Methods</p> <p>Medical check-up data of 1,764 Primary Care patients (PC patients) were retrospectively and cross-sectionally examined using a receiver-operating characteristic (ROC) curve to determine appropriate stratified-for-age cut-off of VAI, for the identification of PC patients with Metabolic Syndrome (MetS) according to the NCEP-ATP III criteria. The PC patients with higher VAI scores were subdivided into three groups according to VAI tertiles (i.e. PC patients with mild VAD, moderate VAD or severe VAD). Finally, VAD classes were compared to classical cardio- and cerebrovascular risk factors as independent predictors of coronary heart disease and/or myocardial infarction, transient ischemic attack and/or ischemic stroke.</p> <p>Results</p> <p>Moderate and severe VADs proved to be independently associated with cardiovascular events [(OR: 5.35; 95% CI: 1.92-14.87; p = 0.001) and (OR: 7.46; 95% CI: 2.64-21.05; p < 0.001) respectively]. Mild, moderate and severe VADs were found to be independently associated with cerebrovascular events [(OR: 2.73; 95% CI: 1.12-6.65; p = 0.027), (OR: 4.20; 95% CI: 1.86-9.45; p = 0.001) and (OR: 5.10; 95% CI: 2.14-12.17; p < 0.001) respectively].</p> <p>Conclusions</p> <p>Our study suggests that among Caucasian Sicilian subjects there are clear cut-off points of VAI able to identify a VAD strongly associated with cardiometabolic risk.</p

Circulating Irisin Levels as a Marker of Osteosarcopenic-Obesity in Cushing’s Disease

Purpose: To evaluate circulating irisin levels in patients with active and controlled Cushing’s disease (CD). Design: Forty-four patients with CD evaluated during the active phase and after 12 months of biochemical remission and 40 controls were recruited. Methods: Phenotypic, anthropometric, hormonal and metabolic parameters, including insulin sensitivity estimation by homeostatic model of insulin resistance, Matsuda index and oral disposition index and circulating irisin levels were evaluated. Results: Patients with active CD showed lower irisin levels compared to controls (p&lt;0.001) and controlled CD (p&lt;0.001). The independent variables significantly associated with irisin were waist circumference (WC) (p=0.025), body fat percentage (BF%) (p=0.009), PTH (p=0.007) and chair rising test (CRT) (p&lt;0.001) in active CD and WC (p=0.013), BF% (p=0.014), PTH (p=0.038), CRT (p=0.029) and urinary-free cortisol (p&lt;0.001) in controlled CD. Conclusion: Circulating irisin levels tend to be lower in patients with active CD compared to those with controlled CD and controls. They are strongly associated with osteosarcopenia and central obesity in CD and therefore may be a possible marker of diagnosi

Irisin: A Possible Marker of Adipose Tissue Dysfunction in Obesity

Adipose tissue (AT) secretes pro- and anti-inflammatory cytokines involved in AT homeostasis, including tumor necrosis factor-α (TNFα) and irisin. The functionality of AT is based on a regulated equilibrium between adipogenesis and extracellular matrix (ECM) remodeling. We investigated the contributions of adipose progenitors (ASCs) and adipocytes (AMCs) to TNFα-induced ECM remodeling and a possible implication of irisin in AT impairment in obesity. ASCs and AMCs were exposed to TNFα treatment and nuclear factor–kappa (NF-kB) pathway was investigated: Tissue Inhibitor of Metalloproteinase (TIMP-1), Twist Family Transcription Factor 1 (TWIST-1), and peroxisome proliferator-activated receptor-γ (PPARγ) expression levels were analyzed. The proteolytic activity of matrix metalloproteinases (MMPs) -2 and -9 was analyzed by zymography, and the irisin protein content was measured by ELISA. In inflamed AMCs, a TIMP-1/TWIST-1 imbalance leads to a drop in PPARγ. Adipogenesis and lipid storage ability impairment come with local tissue remodeling due to MMP-9 overactivation. In vitro and ex vivo measurements confirm positive correlations among inflammation, adipose secreting irisin levels, and circulating irisin levels in patients with visceral obesity. Our findings identify the NF-kB downstream effectors as molecular initiators of AT dysfunction and suggest irisin as a possible AT damage and obesity predictive factor

A note on preconditioning weighted linear least squares, with consequences for weakly-constrained variational data assimilation

The effect of preconditioning linear weighted least-squares using an approximation of the model matrix is analyzed, showing the interplay of the eigenstructures of both the model and weighting matrices. A small example is given illustrating the resulting potential inefficiency of such preconditioners. Consequences of these results in the context of the weakly-constrained 4D-Var data assimilation problem are finally discussed.Comment: 10 pages, 2 figure

Growth and Osteogenic Differentiation of Discarded Gingiva-Derived Mesenchymal Stem Cells on a Commercial Scaffold

Background: In periodontal patients with jawbone resorption, the autologous bone graft is considered a “gold standard” procedure for the placing of dental prosthesis; however, this procedure is a costly intervention and poses the risk of clinical complications. Thanks to the use of adult mesenchymal stem cells, smart biomaterials, and active biomolecules, regenerative medicine and bone tissue engineering represent a valid alternative to the traditional procedures. Aims: In the past, mesenchymal stem cells isolated from periodontally compromised gingiva were considered a biological waste and discarded during surgical procedures. Conclusion: Matriderm represents a biocompatible scaffold able to support the in vitro cell growth and osteodifferentiation ability of gingival mesenchymal stem cells isolated from waste gingiva, and could be employed to develop low-cost and painless strategy of autologous bone tissue regeneration. This study aims to test the osteoconductive activity of FISIOGRAFT Bone Granular and Matriderm collagen scaffolds on mesenchymal stem cells isolated from periodontally compromised gingiva as a low-cost and painless strategy of autologous bone tissue regeneration. Materials and Methods: We isolated human mesenchymal stem cells from 22 healthy and 26 periodontally compromised gingival biopsy tissues and confirmed the stem cell phenotype by doubling time assay, colony-forming unit assay, and expression of surface and nuclear mesenchymal stem cell markers, respectively by cytofluorimetry and realtime quantitative PCR. Healthy and periodontally compromised gingival mesenchymal stem cells were seeded on FISIOGRAFT Bone GranularR and MatridermR scaffolds, and in vitro cell viability and bone differentiation were then evaluated. Results: Even though preliminary, the results demonstrate that FISIOGRAFT Bone GranularR is not suitable for in vitro growth and osteogenic differentiation of healthy and periodontally compromised mesenchymal stem cells, which, instead, are able to grow, homogeneously distribute, and bone differentiate in the MatridermR collagen scaffold

Identification of Novel Wsf1 Mutations in a Sicilian Child with Wolfram Syndrome

Wolfram Syndrome (WS) is a rare hereditary disease with autosomal recessive inheritance with incomplete penetrance. It is characterized by diabetes mellitus associated with progressive optic atrophy. The diagnosis is essentially clinical and mutation analysis is used to confirm the diagnosis. In the present study we describe the clinical and molecular features of a diabetic child carrying two novel WFS1 mutations. The Sicilian proband and his non-affected family were studied. Ophthalmologic examination included: visual acuity determination and funduscopy, optical coherent tomography, retinal fluorangiography, perimetry and electroretinogram. Molecular methods: automatic sequencing of PCR amplified WFS1 gene fragments and qRT-PCR analysis of WFS1 transcripts. 3 WSF1 mutations have been identified in the proband. One allele carries 2 paternally inherited mutations (c.1332 C>G and c.1631C>G) in exon-8, never annotated before, in heterozygosis with one “de novo” classic mutation (c.505 G>A) in exon-5. In addition, we report an unexpected molecular feature: higher WFS1 mRNA levels in the proband compared to the father

Anaplastic Thyroid Carcinoma: A ceRNA Analysis Pointed to a Crosstalk between SOX2

It has been suggested that cancer stem cells (CSC) may play a central role in oncogenesis, especially in undifferentiated tumours. Anaplastic thyroid carcinoma (ATC) has characteristics suggestive of a tumour enriched in CSC. Previous studies suggested that the stem cell factor SOX2 has a preeminent hierarchical role in determining the characteristics of stem cells in SW1736 ATC cell line. In detail, silencing SOX2 in SW1736 is able to suppress the expression of the stem markers analysed, strongly sensitizing the line to treatment with chemotherapeutic agents. Therefore, in order to further investigate the role of SOX2 in ATC, a competing endogenous RNA (ceRNA) analysis was conducted in order to isolate new functional partners of SOX2. Among the interactors, of particular interest are genes involved in the biogenesis of miRNAs (DICER1, RNASEN, and EIF2C2), in the control cell cycle (TP53, CCND1), and in mitochondrial activity (COX8A). The data suggest that stemness, microRNA biogenesis and functions, p53 regulatory network, cyclin D1, and cell cycle control, together with mitochondrial activity, might be coregulated

Myristic acid is associated to low plasma HDL cholesterol levels in a Mediterranean population and increases HDL catabolism by enhancing HDL particles trapping to cell surface proteoglycans in a liver hepatoma cell model

Background: HDL-C plasma levels are modulated by dietary fatty acid (FA), but studies investigating dietary supplementation in FA gave contrasting results. Saturated FA increased HDL-C levels only in some studies. Mono-unsaturated FA exerted a slight effect while poly-unsaturated FA mostly increased plasma HDL-C. Aims: This study presents two aims: i) to investigate the relationship between HDL-C levels and plasma FA composition in a Sicilian population following a "Mediterranean diet", ii) to investigate if FA that resulted correlated with plasma HDL-C levels in the population study and/or very abundant in the plasma were able to affect HDL catabolism in an "in vitro" model of cultured hepatoma cells (HepG2). Results: plasma HDL-C levels in the population correlated negatively with myristic acid (C14:0, β = -0.24, p < 0.01), oleic acid (C18:1n9, β = -0.22, p < 0.01) and cis-11-Eicosenoic (C20:1n9, β = -0.19, p = 0.01) and positively with palmitoleic acid (C16:1, β = +0.19, p = 0.03). HepG2 cells were conditioned with FA before evaluating HDL binding kinetics, and only C14:0 increased HDL binding by a non-saturable pathway. After removal of heparan sulphate proteoglycans (HSPG) by heparinases HDL binding dropped by 29% only in C14:0 conditioned cells (p < 0.05). C14:0 showed also the highest internalization of HDL-derived cholesteryl esters (CE, +32% p = 0.01 vs. non-conditioned cells). Conclusions: C14:0 was correlated with decreased plasma HDL-C levels in a Mediterranean population. C14:0 might reduce HDL-C levels by increasing HDL trapping to cell surface HSPG and CE stripping from bound HDL. Other mechanisms are to be investigated to explain the effects of other FA on HDL metabolism

In vitro generation of pancreatic endocrine cells from human adult fibroblast-like limbal stem cells

Stem cells might provide unlimited supply of transplantable cells for β-cell replacement therapy in diabetes. The human limbus is a highly specialized region hosting a well-recognized population of epithelial stem cells, which sustain the continuous renewal of the cornea, and the recently identified stromal fibroblast-like stem cells (f-LSCs), with apparent broader plasticity. However, the lack of specific molecular markers for the identification of the multipotent limbal subpopulation has so far limited the investigation of their differentiation potential. In this study we show that the human limbus contains uncommitted cells that could be potentially harnessed for the treatment of diabetes. Fourteen limbal biopsies were obtained from patients undergoing surgery for ocular diseases not involving the conjunctiva or corneal surface. We identified a subpopulation of f-LSCs characterized by robust proliferative capacity, expressing several pluripotent stem cell markers and exhibiting self-renewal ability. We then demonstrated the potential of f-LSCs to differentiate in vitro into functional insulin-secreting cells by developing a four-step differentiation protocol that efficiently directed f-LSCs towards the pancreatic endocrine cell fate. The expression of specific endodermal, pancreatic, islet, and β-cell markers, as well as functional properties of f-LSC-derived insulin-producing cells, were evaluated during differentiation. With our stage-specific approach, up to 77% of f-LSCs eventually differentiated into cells expressing insulin (also assessed as C-peptide) and exhibited phenotypic features of mature β-cells, such as expression of critical transcription factors and presence of secretory granules. Although insulin content was about 160-fold lower than what observed in adult islets, differentiated cells processed ∼98% of their proinsulin content, similar to mature β-cells. Moreover, they responded in vitro in a regulated manner to multiple secretory stimuli, including glucose. In conclusion, f-LSCs represent a possible relevant source of autologous, transplantable, insulin-producing cells that could be tested for the reversal of diabetes