Cognitive correlates of under-ambiguity and under-risk decision making in high-functioning patients with relapsing remitting multiple sclerosis

Introduction: Impairment of decision making in relapsing remitting multiple sclerosis is still controversial, and its neuropsychological correlates have never been explored thoroughly, especially in patients with minimal physical and cognitive deficits. In the present study we investigated the cognitive underpinnings of decision making under ambiguous and explicit conditions in patients with very mild relapsing remitting multiple sclerosis, using a dice and a card gambling game. Method: The study sample included 60 patients and 35 healthy subjects. In the Game of Dice Task, winning and losing probabilities are obvious to the subject, while in the Iowa Gambling Task they are initially ambiguous and have to be gradually identified. Performance at the two tasks was correlated with scores obtained at tests investigating cognitive processing speed, memory, language and executive functions. Results: Patients’ performance did not differ from that of controls at either gambling task. There was only a trend for them to be significantly slower than healthy subjects in progressively recognizing advantageous decks in the Iowa Gambling Task. While the Game of Dice was unrelated to neuropsychological tests, predictors of performance at the Iowa task were Letter Fluency and the Symbol Digit Modalities Test for the initial, under-ambiguity, trials and the Wisconsin Card Sorting Test for the last, purely under-risk, trials. Conclusions: Our results suggest that high-functioning patients with relapsing remitting multiple sclerosis are substantially capable of making advantageous decisions, even if they may be slower in processing options and shifting strategy when selection criteria are not explicit.     

Endothelial Cilia Are Essential for Developmental Vascular Integrity in Zebrafish

The cilium is a signaling platform of the vertebrate cell. It has a critical role in polycystic kidney disease and nephronophthisis. Cilia have been detected on endothelial cells, but the function of these organelles in the vasculature remains incompletely defined. In this study, using genetic and chemical genetic tools in the model organism zebrafish, we reveal an essential role of cilia in developmental vascular integrity. Embryos expressing mutant intraflagellar transport genes, which are essential and specific for cilia biogenesis, displayed increased risk of developmental intracranial hemorrhage, whereas the morphology of the vasculature remained normal. Moreover, cilia were present on endothelial cells in the developing zebrafish vasculature. We further show that the involvement of cilia in vascular integrity is endothelial autonomous, because endothelial-specific re-expression of intraflagellar transport genes in respective mutants rescued the intracranial hemorrhage phenotype. Finally, whereas inhibition of Hedgehog signaling increased the risk of intracranial hemorrhage in ciliary mutants, activation of the pathway rescued this phenotype. In contrast, embryos expressing an inactivating mutation in pkd2, one of two autosomal dominant cystic kidney disease genes, did not show increased risk of developmental intracranial hemorrhage. These results suggest that Hedgehog signaling is a major mechanism for this novel role of endothelial cilia in establishing vascular integrity.     

Risk of Adverse Pregnancy Outcomes in Women with CKD

CKD is increasingly prevalent in pregnancy. In the Torino-Cagliari Observational Study (TOCOS), we assessed whether the risk for adverse pregnancy outcomes is associated with CKD by comparing pregnancy outcomes of 504 pregnancies in women with CKD to outcomes of 836 low-risk pregnancies in women without CKD. The presence of hypertension, proteinuria (>1 g/d), systemic disease, and CKD stage (at referral) were assessed at baseline. The following outcomes were studied: cesarean section, preterm delivery, and early preterm delivery; small for gestational age (SGA); need for neonatal intensive care unit (NICU); new onset of hypertension; new onset/doubling of proteinuria; CKD stage shift; “general” combined outcome (preterm delivery, NICU, SGA); and “severe” combined outcome (early preterm delivery, NICU, SGA). The risk for adverse outcomes increased across stages (for stage 1 versus stages 4–5: “general” combined outcome, 34.1% versus 90.0%; “severe” combined outcome, 21.4% versus 80.0%; P<0.001). In women with stage 1 CKD, preterm delivery was associated with baseline hypertension (odds ratio [OR], 3.42; 95% confidence interval [95% CI], 1.87 to 6.21), systemic disease (OR, 3.13; 95% CI, 1.51 to 6.50), and proteinuria (OR, 3.69; 95% CI, 1.63 to 8.36). However, stage 1 CKD remained associated with adverse pregnancy outcomes (general combined outcome) in women without baseline hypertension, proteinuria, or systemic disease (OR, 1.88; 95% CI, 1.27 to 2.79). The risk of intrauterine death did not differ between patients and controls. Findings from this prospective study suggest a “baseline risk” for adverse pregnancy-related outcomes linked to CKD.     

The isoprenoid end product N6-isopentenyladenosine reduces inflammatory response through the inhibition of the NFκB and STAT3 pathways in cystic fibrosis cells

Objective

N6-isopentenyladenosine (iPA) is an intermediate of the mevalonate pathway that exhibits various anti-cancer effects. However, studies on its anti-inflammatory activity are scarce and underlying molecular mechanisms are unknown. Therefore, we aimed to investigate the ability of iPA to exert anti-inflammatory effects in the human cystic fibrosis (CF) cell model of exacerbated inflammation.

Materials and methods

TNFα-stimulated CF cells CuFi-1 and its normal counterpart NuLi-1 were pre-treated with increasing concentrations of iPA and cell viability and proliferation were assessed by MTT and BrdU assays. The effect of iPA on IL-8 and RANTES secretion was determined by ELISA, and the activation and expression of signaling molecules and selenoproteins were studied by Western blot. To assess the direct effect of iPA on NFκB activity, luciferase assay was performed on TNFα-stimulated HEK293/T cells transfected with a NFκB reporter plasmid.

Results

We demonstrated for the first time that iPA prevents IL-8 and RANTES release in TNFα-stimulated CF cells and this effect is mediated by increasing the expression of the direct NFκB inhibitor IκBα and decreasing the levels of STAT3. Consistent with this, we showed that iPA inhibited TNFα-mediated NFκB activation in HEK/293T cells. Finally, we also found that iPA improved the levels of glutathione peroxidase 1 and thioredoxin reductase 1 only in CF cells suggesting its ability to maintain sufficient expression of these anti-oxidant selenoproteins.

Conclusions

Our findings indicate that iPA can exert anti-inflammatory activity especially in the cases of excessive inflammatory response as in CF.

     

Digital breast tomosynthesis and contrast‐enhanced dual‐energy digital mammography alone and in combination compared to 2D digital synthetized mammography and MR imaging in breast cancer detection and classification

To compare diagnostic performance of contrast‐enhanced dual‐energy digital mammography (CEDM) and digital breast tomosynthesis (DBT) alone and in combination compared to 2D digital mammography (MX) and dynamic contrast‐enhanced MRI (DCE‐MRI) in women with breast lesions. We enrolled 100 consecutive patients with breast lesions (BIRADS 3‐5 at imaging or clinically suspicious). CEDM, DBT, and DCE‐MRI 2D were acquired. Synthetized MX was obtained by DBT. A total of 134 lesions were investigated on 111 breasts of 100 enrolled patients: 53 were histopathologically proven as benign and 81 as malignant. Nonparametric statistics and receiver operating characteristic (ROC) curve were performed. Two‐dimensional synthetized MX showed an area under ROC curve (AUC) of 0.764 (sensitivity 65%, specificity 80%), while AUC was of 0.845 (sensitivity 80%, specificity 82%) for DBT, of 0.879 (sensitivity 82%, specificity 80%) for CEDM, and of 0.892 (sensitivity 91%, specificity 84%) for CE‐MRI. DCE‐MRI determined an AUC of 0.934 (sensitivity 96%, specificity 88%). Combined CEDM with DBT findings, we obtained an AUC of 0.890 (sensitivity 89%, specificity 74%). A difference statistically significant was observed only between DCE‐MRI and CEDM (P = .03). DBT, CEDM, CEDM combined to tomosynthesis, and DCE‐MRI had a high ability to identify multifocal and bilateral lesions with a detection rate of 77%, 85%, 91%, and 95% respectively, while 2D synthetized MX had a detection rate for multifocal lesions of 56%. DBT and CEDM have superior diagnostic accuracy of 2D synthetized MX to identify and classify breast lesions, and CEDM combined with DBT has better diagnostic performance compared with DBT alone. The best results in terms of diagnostic performance were obtained by DCE‐MRI. Dynamic information obtained by time‐intensity curve including entire phase of contrast agent uptake allows a better detection and classification of breast lesions.