Mechanisms of antidiarrhoeal effects by diosmectite in human intestinal cells

Rotavirus (RV) induces diarrhoea through a sequence of enterotoxic and cytotoxic effects. The former are NSP4-dependent, induce calcium-dependent chloride secretion and involve oxidative stress. Diosmectite (DS) is a natural clay that has been recommended as an active therapy for diarrhoea, but the mechanism of its effect is not clear. Electrical parameters may be used to measure the direct enterotoxic and cytotoxic effects in polar epithelial intestinal cells. To investigate the effects of DS on RV-induced enterotoxic and cytotoxic damage. Caco-2 cells were used as a model of RV infection to evaluate chloride secretion, epithelial integrity, oxidative stress and viral infectivity in Ussing chambers

Performance of the pediatric index of mortality 2 (PIM-2) in cardiac and mixed intensive care units in a tertiary children's referral hospital in Italy

Background: Mortality rate of patients admitted to Intensive Care Units is a widely adopted outcome indicator. Because of large case-mix variability, comparisons of mortality rates must be adjusted for the severity of patient illness at admission. The Pediatric Index of Mortality 2 (PIM-2) has been widely adopted as a tool for adjusting mortality rate by patients' case mix. The objective of this study was to assess the performance of PIM-2 in children admitted to intensive care units after cardiac surgery, other surgery, or for other reasons. Methods: This was a prospective cohort study, conducted in a 607 inpatient-bed tertiary-care pediatric hospital in Italy, with three pediatric intensive care Units (PICUs) and one cardiac Unit (CICU). In 2009-11, all consecutive admissions to PICUs/CICU of children aged 0-16 years were included in the study. Discrimination and calibration measures were computed to assess PIM-2 performance. Multivariable logistic regression analysis was used to assess the association of patients' main reason for intensive care admission (cardiac-surgical, other-surgical, medical), age, Unit and year with observed mortality, adjusting for PIM-2 score. Results: PIM-2 data collection was completed for 91.2% of total PICUs/CICU patient admissions (2912), and for 94.8% of patients who died in PICUs/CICU (129). Overall observed mortality was 4.4% (95% CI, 3.7-5.2), compared to 6.4% (95% CI, 5.5-7.3) expected mortality. Standardised mortality ratio was 0.7 (95% CI: 0.6-0.8). PIM-2 discrimination was fair (area under the curve, 0.79; 95% CI: 0.75-0.83). Calibration was less satisfactory, mainly because of the over two-fold overprediction of deaths in the highest risk group (114.7 vs 53; p < 0.001), and particularly in cardiac-surgical patients. Multivariable logistic analysis showed that risk of death was significantly reduced in cardiac-surgical patients and in those aged 1 month to 12 years, independently from PIM-2. Conclusions: The children age distribution and the proportion of cardiac-surgical patients should be taken into account when interpreting SMRs estimated using the PIM-2 prediction model in different Units. A new calibration study of PIM-2 score might be needed, and more appropriate cardiac-focused risk-adjustment models should be developed. The role of age on risk of death needs to be further explored

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele