The p66Shc Protein Mediates Insulin Resistance and Secretory Dysfunction in Pancreatic ß-Cells Under Lipotoxic Conditions.

We evaluated the role of the p66Shc redox adaptor protein in pancreatic ß-cell insulin resistance that develops under lipotoxic conditions and with excess body fat. Prolonged exposure to palmitate in vitro or the presence of overweight/obesity augmented p66Shc expression levels and caused an impaired ability of exogenous insulin to increase cellular insulin content and secreted C-peptide levels in INS-1E cells and human and murine islets. In INS-1E cells, p66Shc knockdown resulted in enhanced insulin-induced augmentation of insulin content and C-peptide secretion and prevented the ability of palmitate to impair these effects of insulin. Conversely, p66Shc overexpression impaired insulin-induced augmentation of insulin content and C-peptide secretion in both the absence and presence of palmitate. Under lipotoxic condition, the effects of p66Shc are mediated by a p53-induced increase in p66Shc protein levels and JNK-induced p66Shc phosphorylation at Ser36 and appear to involve the phosphorylation of the ribosomal protein S6 kinase at Thr389 and of insulin receptor substrate 1 at Ser307, resulting in the inhibition of insulin-stimulated protein kinase B phosphorylation at Ser473. Thus, the p66Shc protein mediates the impaired ß-cell function and insulin resistance induced by saturated fatty acids and excess body fat.

Irisin increases the expression of anorexigenic and neurotrophic genes in mouse brain.

BACKGROUND: Irisin, a newly discovered muscle-derived hormone, acts in different organs and tissues, improving energy homeostasis. In this study, we assessed, for the first time, the effects of intraperitoneal irisin injections on circulating levels of leptin and ghrelin, mRNA expression of the major hypothalamic appetite regulators and brain neurotrophic factors, as well as feeding behaviour in healthy mice. METHODS: Twelve male 6-week-old C57BL/6 mice were randomized into two groups and intraperitoneally injected daily with irisin (0.5 µg/g body weight) or vehicle (phosphate-buffered saline [PBS]) for 14 days. On the last day of observation, leptin and ghrelin levels were measured with an enzyme-linked immunosorbent assay (ELISA). mRNA levels of genes of interest were analysed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in brain extracts. RESULTS: Irisin administration did not change leptin or ghrelin serum concentrations. However, irisin injection increased CART, POMC, NPY, and BDNF mRNA levels, without affecting the mRNA expression of AgRP, orexin, PMCH, and UCP2. Finally, over the time frame of irisin treatment, body weight and feeding behaviour were unaltered. CONCLUSIONS: These results suggest that intraperitoneal injection of irisin, although without effects on feeding behaviour and body weight, can increase the expression of anorexigenic and neurotrophic genes in mouse brain.

Clinical biomarkers for cancer recognition and prevention: A novel approach with optical measurements.

Cancer is the most important cause of death worldwide, and early cancer detection is the most fundamental factor for efficacy of treatment, prognosis, and increasing survival rate. Over the years great effort has been devoted to discovering and testing new biomarkers that can improve its diagnosis, especially at an early stage. Here we report the potential usefulness of new, easily applicable, non-invasive and relatively low-cost clinical biomarkers, based on abnormalities of oral mucosa spectral reflectance and fractal geometry of the vascular networks in several different tissues, for identification of hereditary non-polyposis colorectal cancer carriers as well for detection of other tumors, even at an early stage. In the near future the methodology/technology of these procedures should be improved, thus making possible their applicability worldwide as screening tools for early recognition and prevention of cancer.

Exposure to di-2-ethylhexyl phthalate, di-n-butyl phthalate and bisphenol A through infant formulas.

Phthalates and bisphenol A (BPA) are ubiquitous contaminants identified as endocrine disruptors. Phthalates are worldwide used as plasticizers, in particular to improve the mechanical properties of polymers such as polyvinyl chloride. Because they are not chemically bound to the polymer, they tend to leach out with time and use. Di-2-ethylhexyl phthalate (DEHP) and di-n-butyl phthalate (DnBP) are the two most common phthalates. BPA is an estrogenic compound used to manufacture polycarbonate containers for food and drink, including baby bottles. It can migrate from container into foods, especially at elevated temperatures. Diet is a predominant source of exposure for phthalates and BPA, especially for infants. The aim of this study was to test the presence of DEHP, DnBP, and BPA in infant formulas. DEHP, DnBP, and BPA concentrations were measured in 22 liquid and 28 powder milks by gas chromatography with flame ionization detection and high performance liquid chromatography with fluorimetric detection, respectively. DEHP concentrations in our samples were between 0.005 and 5.088 µg/g (median 0.906 µg/g), DnBP concentrations were between 0.008 and 1.297 µg/g (median 0.053 µg/g), and BPA concentrations were between 0.003 and 0.375 µg/g (median 0.015 µg/g). Concentrations of the investigated contaminants in liquid and powder milks were not significantly different, even though samples were packed in different types of containers. These data point out potential hazards for infants fed with baby formulas. Contamination seems more related to the production of formulas than to a release from containers.

First day of life reference values for pleth variability index in spontaneously breathing term newborns.

BACKGROUND: The perfusion index (PI), derived from the pulse oximetry signal, has been shown to be an accurate predictor for identifying high illness severity in neonates. The plethysmographic variability index (PVI) is a measure of the dynamic change in PI occurring during a complete respiratory cycle. OBJECTIVES: The aim of this study was to establish the reference range of PVI in spontaneously breathing term newborns. METHODS: PI and PVI values were assessed in 242 term newborns during the first day of life. RESULTS: The median PVI value on the first day of life was 20% [95% confidence interval (CI) for the mean 19-20%; inter-quartile range 15 (95% CI 15-16) - 24 (95% CI 23-24)]. The 10th and 90th percentile cutoff values were 12% (95% CI 11-12) and 28% (95% CI 27-29), respectively, with the 97.5th percentile of 35% (95% CI 34-38). PVI was also significantly influenced by the behavioral status of the newborn, and was positively correlated with PI and pulse rate, while it was inversely correlated with oxygen saturation (p < 0.0001). CONCLUSIONS: Our findings suggest: (1) evaluation of PVI values is an easily applicable, noninvasive procedure for monitoring early postnatal respiratory changes in newborns, and (2) the feasibility of a noninvasive pulse-oximeter postnatal screening for early identification of adverse neonatal cardiorespiratory outcomes.

Indications and limitations for a neonatal pulse oximetry screening of critical congenital heart disease.

AIMS: Critical congenital cardiovascular malformations (CCVMs) require surgical correction during the first month of life, physical examination is unable to detect >50% of affected infants. An oximetry screening has been previously proposed. Our aim was to verify the usefulness and consistency of a pulse oximetry screening for early detection of CCVMs in a small size nursery. METHODS: A single determination of SpO2 was performed on 5292 consecutive apparently healthy newborns, discharged from nursery at a median age of 72 h during the period May 1, 2000 and November 30, 2004. Infants showing signs of congenital heart disease before the screening and those with a prenatal diagnosis were excluded. Cardiac ultrasound was performed on all infants with SpO2< or =95% at >24 h. The accuracy of the screening in identifying CCVMs was assessed by receiver-operating characteristic (ROC) curves analysis. RESULTS: We found 2 (0.038%) true positives, 1 (0.019%) false negative, 1 (0.019%) false positive, and 5288 (99.92%) true negatives. Prevalence of critical CCVMs was 1 in 1764. Clinical follow-up showed no evidence of CCVMs in the negative cases. A pulse-oximetry cut-off value of < or =95% showed 66.7% sensitivity (95% CI: 11.6-94.5), 100% specificity (95% CI: 99.9-100.0), 50% positive predictive value, 100% negative predictive value and AUC of 0.833 (standard error: 0.145) (95% CI: 0.823 to 0.843) in identifying CCVMs. CONCLUSIONS: Our findings indicate that pulse oximetry is a non-invasive and specific screening tool for an early detection of CCVMs, and is easily applicable to a small size nursery.