CD40 ligation prevents onset of tolerogenic properties in human dendritic cells treated with CTLA-4-Ig

The synthetic immunomodulator cytotoxic T lymphocyte antigen 4-Ig (CTLA-4-Ig) initiates effects in human monocyte-derived dendritic cells (DC) that rely on immunosuppressive tryptophan catabolism. However, it is unable to induce suppressive properties in DC matured by CD40 engagement. Thus, CD40-driven events may physiologically set human DC free from restraint by regulatory cells expressing surface CTLA-4.     

Suppression of hypothalamic deiodinase type II activity blunts TRH mRNA decline during fasting

Fasting is characterized by disrupted thyroid feedback, with suppressed levels of thyroid hormones and paraventricular thyrotropin releasing hormone (TRH). We found that third ventricle administration of the deiodinase inhibitor, iopanoic acid, dose-dependently reduced deiodinase type II (DII) activity selectively in the hypothalamus. This suppression of DII by iopanoic acid during fasting prevented elevated DII activity and blunted the decline in hypothalamic TRH mRNA levels. Because fasting-induced elevation in hypothalamic DII activity is paralleled by increased hypothalamic T3 concentration, our study suggests that T3 formation by DII in the hypothalamus is the cause of disrupted thyroid feedback during fasting.     

Ostracoda and Mollusca biodiversity and hydrochemical features in Late Miocene brackish basins of Italy

Late Miocene brackish ostracods and molluscs collected in three Italian basins show noticeable differences in their taxonomic composition, despite their capability of dispersing across wide geographic areas. In the Venetian-Friulian Basin (northern Italy), the upper Tortonian sediments contain oligotypic ostracod assemblages including Hemicyprideis dacica dacica, Hemicytheria pejinovicensis, and Loxoconcha cf. L. josephi and few gastropods referable to Planorbidae and Stenothyroides, which are typical of the central Paratethys. In central Italy, the brackish ostracods and molluscs recovered from upper Tortonian-lower Messinian deposits from four Tuscan basins (Volterra-Radicondoli, Velona, Baccinello-Cinigiano, and Valdelsa) display high affinity at a generic level but strong endemicity at a specific level. At Cessaniti (southern Italy), the upper Tortonian unit contains oligotypic brackish ostracods and molluscs: Mediocytherideis (Sylvestra) posterobursa, Cyprideis ruggierii, Loxoconcha cf. L. biformata, and Zonocypris membranae quadricella characterise the ostracod fauna, while Granulolabium bicinctum and Hydrobia frauenfeldi are the dominant molluscs. The recovered ostracods have a strong affinity with brackish species from central and eastern Palaeo-Mediterranean areas, whereas the molluscs present a Paratethyan origin. Despite the fact that the basins are all brackish and partly coeval, the systematics of these assemblages highlights the absence of common species among the three studied areas. Geochemical analyses (stable isotopes and trace elements) are performed on ostracods, and ⁸⁷Sr/⁸⁶Sr ratios are established in molluscs and echinoids. The results suggest brackish environments with different compositions and origins of solutes in the three different areas. The Tuscan basins are characterised by brackish waters, with NaCl-enriched waters coming from aquifers of Triassic evaporite bedrock. The brackish deposits of the Venetian-Friulian Basin and Cessaniti are true marginal marine environments, although the northern basin may have been influenced by both the Paratethyan Sava Basin and the northern portion of the Palaeo-Mediterranean water bodies.     

Effect of dietary docosahexaenoic acid on biosynthesis of docosahexaenoic acid from alpha-linolenic acid in young rats

Docosahexaenoic acid (DHA), a crucial nervous system n-3 PUFA, may be obtained in the diet or synthesized in vivo from dietary alpha-linolenic acid (LNA). We addressed whether DHA synthesis is regulated by the availability of dietary DHA in artificially reared rat pups, during p8 to p28 development. Over 20 days, one group of rat pups was continuously fed deuterium-labeled LNA (d5-LNA) and no other n-3 PUFA (d5-LNA diet), and a second group of rat pups was fed a d5-LNA diet with unlabeled DHA (d5-LNA + DHA diet). The rat pups were then euthanized, and the total amount of deuterium-labeled docosahexaenoic acid (d5-DHA) (synthesized DHA) as well as other n-3 fatty acids present in various body tissues, was quantified. In the d5-LNA + DHA group, the presence of dietary DHA led to a marked decrease (3- to 5-fold) in the total amount of d5-DHA that accumulated in all tissues that we examined, except in adipose. Overall, DHA accretion from d5-DHA was generally diminished by availability of dietary preformed DHA, inasmuch as this was found to be the predominant source of tissue DHA. When preformed DHA was unavailable, d5-DHA and unlabeled DHA were preferentially accreted in some tissues along with a net loss of unlabeled DHA from other organs.     

Protein unlocking procedures of formalin-fixed paraffin-embedded tissues: application to MALDI-TOF imaging MS investigations

Archival formalin-fixed paraffin-embedded (FFPE) tissues are a powerful tool for examining the clinical course of diseases. These specimens represent an incredible mine of valuable clinical and biological information for proteomic investigation. MALDI-TOF imaging MS (MALDI-IMS) is a protein profiling technique which enables the direct sampling of histological section; however, the quality of molecular data are strongly influenced by the tissue preparation condition. In fact, in previous years most of the studies employing such a technological platform have been conducted using cryo-preserved tissues. We have developed an in vitro approach using "tissue surrogate" samples in order to explore different protein unlocking procedures which might enable a suitable recovery of polypeptides for MS analysis. The developed protocols have been compared both by MALDI-TOF MS and nLC-MS(E) analysis either on surrogate samples or on FFPE specimen from human breast cancer. The collected evidence has been applied for the preparation of FFPE tissue sections following MALDI-IMS analysis. Our results outline the possibility to obtain valuable peptide mass spectra profiles form FFPE preparations by applying a combined two steps procedure of heat induced antigen retrieval (HIAR) in presence of EDTA and on target trypsin hydrolysis. A multivariate statistical evaluation is presented and discussed according to molecular spatial distributions and tissue morphology.     

Estimated Glomerular Filtration Rate,All-Cause Mortality and Cardiovascular Diseases Incidence in a Low Risk Population: The MATISS Study

Background

Chronic kidney disease (CKD) independently increases the risk of death and cardiovascular disease (CVD) in the general population. However, the relationship between estimated glomerular filtration rate (eGFR) and CVD/death risk in a general population at low risk of CVD has not been explored so far.

Design

Baseline and longitudinal data of 1465 men and 1459 women aged 35-74 years participating to the MATISS study, an Italian general population cohort, were used to evaluate the role of eGFR in the prediction of all-cause mortality and incident CVD.

Methods

Bio-bank stored sera were used to evaluate eGFR at baseline. Serum creatinine was measured on thawed samples by means of an IDMS-calibrated enzymatic method. eGFR was calculated by the CKD-EPI formula.

Results

At baseline, less than 2% of enrolled persons had eGFR < 60 mL/min/1.73m² and more than 70% had a 10-year cardiovascular risk score < 10%. In people 60 or more years old, the first and the last eGFR quintiles (<90 and ≥109 mL/min/1.73m², respectively) were associated to an increased risk for both all-cause mortality (hazard ratio 1.6, 95% confidence interval 1.2-2.1 and 4.3, 1.6-11.7, respectively) and incident CVD (1.6, 1.0-2.4 and 7.0, 2.2-22.9, respectively), even if adjusted for classical risk factors.

Conclusions

These findings strongly suggest that in an elderly, general population at low risk of CVD and low prevalence of reduced renal filtration, even a modest eGFR reduction is related to all-cause mortality and CVD incidence, underlying the potential benefit to this population of considering eGFR for their risk prediction.