CAAP48, a New Sepsis Biomarker, Induces Hepatic Dysfunction in an in vitro Liver-on-Chip Model

Sepsis is a leading cause of mortality in the critically ill, characterized by life-threatening organ dysfunctions due to dysregulation of the host response to infection. Using mass spectrometry, we identified a C-terminal fragment of alpha-1-antitrypsin, designated CAAP48, as a new sepsis biomarker that actively participates in the pathophysiology of sepsis. It is well-known that liver dysfunction is an early event in sepsis-associated multi-organ failure, thus we analyzed the pathophysiological function of CAAP48 in a microfluidic-supported in vitro liver-on-chip model. Hepatocytes were stimulated with synthetic CAAP48 and several control peptides. CAAP48-treatment resulted in an accumulation of the hepatocyte-specific intracellular enzymes aspartate- and alanine-transaminase and impaired the activity of the hepatic multidrug resistant-associated protein 2 and cytochrome P450 3A4. Moreover, CAAP48 reduced hepatic expression of the multidrug resistant-associated protein 2 and disrupted the endothelial structural integrity as demonstrated by reduced expression of VE-cadherin, F-actin and alteration of the tight junction protein zonula occludens-1, which resulted in a loss of the endothelial barrier function. Furthermore, CAAP48 induced the release of adhesion molecules and pro- and anti-inflammatory cytokines. Our results show that CAAP48 triggers inflammation-related endothelial barrier disruption as well as hepatocellular dysfunction in a liver-on-chip model emulating the pathophysiological conditions of inflammation. Besides its function as new sepsis biomarker, CAAP48 thus might play an important role in the development of liver dysfunction as a consequence of the dysregulated host immune-inflammatory response in sepsis

Metabonomics and Intensive Care

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901

Regional and large-scale patterns in Amazon forest structure and function are mediated by variations in soil physical and chemical properties

Forest structure and dynamics have been noted to vary across the Amazon Basin in an east-west gradient in a pattern which coincides with variations in soil fertility and geology. This has resulted in the hypothesis that soil fertility may play an important role in explaining Basin-wide variations in forest biomass, growth and stem turnover rates. To test this hypothesis and assess the importance of edaphic properties in affect forest structure and dynamics, soil and plant samples were collected in a total of 59 different forest plots across the Amazon Basin. Samples were analysed for exchangeable cations, C, N, pH with various Pfractions also determined. Physical properties were also examined and an index of soil physical quality developed. Overall, forest structure and dynamics were found to be strongly and quantitatively related to edaphic conditions. Tree turnover rates emerged to be mostly influenced by soil physical properties whereas forest growth rates were mainly related to a measure of available soil phosphorus, although also dependent on rainfall amount and distribution. On the other hand, large scale variations in forest biomass could not be explained by any of the edaphic properties measured, nor by variation in climate. A new hypothesis of self-maintaining forest dynamic feedback mechanisms initiated by edaphic conditions is proposed. It is further suggested that this is a major factor determining forest disturbance levels, species composition and forest productivity on a Basin wide scale

Branch xylem density variations across Amazonia

International audienceMeasurements of branch xylem density, Dx, were made for 1466 trees representing 503 species, sampled from 80 sites across the Amazon basin. Measured values ranged from 240 kg m?3 for a Brosimum parinarioides from Tapajos in West Pará, Brazil to 1130 kg m?3 for an Aiouea sp. from Caxiuana, Central Pará, Brazil. Analysis of variance showed significant differences in average Dx across the sample plots as well as significant differences between families, genera and species. A partitioning of the total variance in the dataset showed that geographic location and plot accounted for 33% of the variation with species identity accounting for an additional 27%; the remaining "residual" 40% of the variance accounted for by tree to tree (within species) variation. Variations in plot means, were, however, hardly accountable at all by differences in species composition. Rather, it would seem that variations of xylem density at plot level must be explained by the effects of soils and/or climate. This conclusion is supported by the observation that the xylem density of the more widely distributed species varied systematically from plot to plot. Thus, as well as having a genetic component branch xylem density is a plastic trait that, for any given species, varies according to where the tree is growing and in a predictable manner. Exceptions to this general rule may be some pioneers belonging to Pourouma and Miconia and some species within the genera Brosimum, Rinorea and Trichillia which seem to be more constrained in terms of this plasticity than most species sampled as part of this study

The weight of complications: high and low BMI have disparate modes of failure in total hip arthroplasty

Abstract Background Body mass index (BMI) has been shown to influence risk for revision total hip arthroplasty (rTHA), but few studies have specifically examined which causes of rTHA are most likely in different BMI classes. We hypothesized that patients in different BMI classes would undergo rTHA for disparate reasons. Methods Ninety-eight thousand six hundred seventy patients undergoing rTHA over 2006–2020 were identified in the National Inpatient Sample. Patients were classified as underweight, normal-weight, overweight/obese, or morbidly obese. Multivariable logistic regression was used to analyze the impact of BMI on rTHA for periprosthetic joint infection (PJI), dislocation, periprosthetic fracture (PPF), aseptic loosening, or mechanical complications. Analyses were adjusted for age, sex, race/ethnicity, socioeconomic status, insurance, geographic region, and comorbidities. Results Compared to normal-weight patients, underweight patients were 131% more likely to have a revision due to dislocation and 63% more likely due to PPF. Overweight/obese patients were 19% less likely to have a revision due to dislocation and 10% more likely due to PJI. Cause for revision in morbidly obese patients was 4s1% less likely to be due to dislocation, 8% less likely due to mechanical complications, and 90% more likely due to PJI. Conclusions Overweight/obese and morbidly obese patients were more likely to undergo rTHA for PJI and less likely for mechanical reasons compared to normal weight patients. Underweight patients were more likely to undergo rTHA for dislocation or PPF. Understanding the differences in cause for rTHA among the BMI classes can aid in patient-specific optimization and management to reduce postoperative complications. Level of evidence III