Phenotype of ARDS alveolar and blood neutrophils

RATIONALE: Acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease's complex pathophysiology, yet these cells have been little studied. OBJECTIVES: To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared with healthy volunteer cells, and to define their sensitivity to phosphoinositide 3-kinase inhibition. METHODS: Twenty-three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis, and adhesion molecules were quantified by flow cytometry, and oxidase responses were quantified by chemiluminescence. Cytokine and transcriptional profiling were used in multiplex and GeneChip arrays. MEASUREMENTS AND MAIN RESULTS: Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed constitutive apoptosis, and primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype, and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the prosurvival phenotype of patient cells was resistant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal, and cell death pathways in patient cells, aligning closely to sepsis and burns datasets but not to phosphoinositide 3-kinase signatures. CONCLUSIONS: Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed prosurvival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells.This work was funded by a non-commercial grant from GSK, with additional support from The Wellcome Trust, Papworth Hospital, The British Lung Foundation and the NIHR Cambridge Biomedical Research Centre. DMLS holds a Gates Cambridge Scholarship; CS is in receipt of a Wellcome Trust Early Postdoctoral Research Fellowship for Clinician Scientists [WT101692MA].This is the author accepted manuscript. The final version is available from ATS Journals via http://dx.doi.org/10.1164/rccm.201509-1818O

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Evaluating compliance to a low glycaemic index (GI) diet in women with polycystic ovary syndrome (PCOS)

<p>Abstract</p> <p>Background</p> <p>A low Glycaemic Index (GI) diet may decrease some long-term health risks in Polycystic Ovary Syndrome (PCOS) such as endometrial cancer. This study was performed to assess compliance to a low GI diet in women with PCOS. Food diaries prospectively collected over 6 months from women on a low GI diet or healthy eating diet were analysed retrospectively. The women were recruited for a pilot randomised control trial investigating whether a low GI diet decreased the risk of Endometrial Cancer. Nine women with PCOS completed 33 food diaries (17 from women on a low GI diet and 16 from women on a healthy eating diet) recording 3023 food items (low GI group:n = 1457; healthy eating group:n = 1566). Data was analysed using Foster-Powell international values inserted into an SPSS database as no scientifically valid established nutrition software was found. The main outcome measures were mean item GI and Glyacemic Load (GL), mean meal GL, percentage high GI foods and mean weight loss.</p> <p>Findings</p> <p>Women allocated the low GI diet had a statistically significant lower GI of food items (33.67 vs 36.91, p < 0.05), lower percentage of high GI foods (4.3% vs 12.1%, p < 0.05) and lower GL of food items and meals.</p> <p>Conclusion</p> <p>Women with PCOS on a low GI diet consumed food items with a significantly lower mean GI and GL compared to the healthy eating diet group. Longer term compliance needs evaluation in subsequent studies to ascertain that this translates to reduced long term health risks.</p> <p>Trial Registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN86420258">ISRCTN86420258</a></p

Generalised max entropy classifiers

In this paper we propose a generalised maximum-entropy classification framework, in which the empirical expectation of the feature functions is bounded by the lower and upper expectations associated with the lower and upper probabilities associated with a belief measure. This generalised setting permits a more cautious appreciation of the information content of a training set. We analytically derive the KarushKuhn-Tucker conditions for the generalised max-entropy classifier in the case in which a Shannon-like entropy is adopted

The Immune Cell Composition in Barrett's Metaplastic Tissue Resembles That in Normal Duodenal Tissue

BACKGROUND AND OBJECTIVE: Barrett's esophagus (BE) is characterized by the transition of squamous epithelium into columnar epithelium with intestinal metaplasia. The increased number and types of immune cells in BE have been indicated to be due to a Th2-type inflammatory process. We tested the alternative hypothesis that the abundance of T-cells in BE is caused by a homing mechanism that is found in the duodenum. PATIENTS AND METHODS: Biopsies from BE and duodenal tissue from 30 BE patients and duodenal tissue from 18 controls were characterized by immmunohistochemistry for the presence of T-cells and eosinophils(eos). Ex vivo expanded T-cells were further phenotyped by multicolor analysis using flowcytometry. RESULTS: The high percentage of CD4(+)-T cells (69±3% (mean±SEM/n = 17, by flowcytometry)), measured by flowcytometry and immunohistochemistry, and the presence of non-activated eosinophils found in BE by immunohistochemical staining, were not different from that found in duodenal tissue. Expanded lymphocytes from these tissues had a similar phenotype, characterized by a comparable but low percentage of αE(CD103) positive CD4(+)cells (44±5% in BE, 43±4% in duodenum of BE and 34±7% in duodenum of controls) and a similar percentage of granzyme-B(+)CD8(+) cells(44±5% in BE, 33±6% in duodenum of BE and 36±7% in duodenum of controls). In addition, a similar percentage of α4β7(+) T-lymphocytes (63±5% in BE, 58±5% in duodenum of BE and 62±8% in duodenum of controls) was found. Finally, mRNA expression of the ligand for α4β7, MAdCAM-1, was also similar in BE and duodenal tissue. No evidence for a Th2-response was found as almost no IL-4(+)-T-cells were seen. CONCLUSION: The immune cell composition (lymphocytes and eosinophils) and expression of intestinal adhesion molecule MAdCAM-1 is similar in BE and duodenum. This supports the hypothesis that homing of lymphocytes to BE tissue is mainly caused by intestinal homing signals rather than to an active inflammatory response

Modulation of miRNA Expression by Dietary Polyphenols in apoE Deficient Mice: A New Mechanism of the Action of Polyphenols

Background: Polyphenols are the most abundant antioxidants in the human diet and are widespread constituents of fruits and beverages, such as tea, coffee or wine. Epidemiological, clinical and animal studies support a role of polyphenols in the prevention of various diseases, such as cardiovascular diseases, cancers or neurodegenerative diseases. Recent findings suggest that polyphenols could interact with cellular signaling cascades regulating the activity of transcription factors and consequently affecting the expression of genes. However, the impact of polyphenol on the expression of microRNA, small non-coding RNAs, has not yet been studied. The aim of this study was to investigate the impact of dietary supplementation with polyphenols at nutritional doses on miRNA expression in the livers of apolipoprotein E-deficient mice (apoE(-/-)) jointly with mRNA expression profiling. [br/] Methodology/Principal Findings: Using microarrays, we measured the global miRNA expression in the livers of wild-type (C57B6/J) mice or apoE(-/-) mice fed diets supplemented with one of nine different polyphenols or a control diet. This analysis revealed that knock-out of the apoE gene induced significant modulation in the expression of miRNA. Moreover, changes in miRNA expression were observed after polyphenol supplementation, and five miRNAs (mmu-miR-291b-5p, mmu-miR-296-5p, mmu-miR-30c-1*, mmu-miR-467b* and mmu-miR-374*) were identified as being commonly modulated by these polyphenols. We also observed that these polyphenols counteracted the modulation of miRNA expression induced by apoE mutation. Pathway analyses on these five miRNA-target genes revealed common pathways, some of which were also identified from a pathway analysis on mRNA profiles. [br/] Conclusion:This in vivo study demonstrated for the first time that polyphenols at nutritional doses modulate the expression of miRNA in the liver. Even if structurally different, all polyphenols induced a similar miRNA expression profile. Common pathways were identified from both miRNA-target and mRNA analysis, revealing cellular functions that could be regulated by polyphenols at both the miRNA and mRNA level

Bioactive Compounds of Rambutan (Nephelium lappaceum L.)

Rambutan, a widely popular tropical fruit encompasses rich amount of bioactive compounds. All parts of this plant (leaves, bark, root, fruits, fruit skin, pulp and seeds) finds traditional usage, and are linked with high therapeutic values. Rambutan fruits parts like that of peel, pulp and seeds have been scientifically investigated in-depth and is reported to encompass high amounts of bioactive compounds (such as polyphenol, flavonoid, alkaloid, essential mineral, dietary fiber). These compounds contribute towards antioxidant, antimicrobial, anticancer, antidiabetic and anti-obesity activities. However, literature pertaining towards potential industrial applications (food, cosmetics, pharmaceutical) of rambutan fruits are limited. In the present chapter, it is intended to document some of the interesting research themes published on rambutan fruits, and identify the existing gaps to open up arena for future research work.This chapter theme is based on our ongoing project—VALORTECH, which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 810630

A concept for integrated care pathways for atopic dermatitis-A GA2 LEN ADCARE initiative

INTRODUCTION: The integrated care pathways for atopic dermatitis (AD-ICPs) aim to bridge the gap between existing AD treatment evidence-based guidelines and expert opinion based on daily practice by offering a structured multidisciplinary plan for patient management of AD. ICPs have the potential to enhance guideline recommendations by combining interventions and aspects from different guidelines, integrating quality assurance, and describing co-ordination of care. Most importantly, patients can enter the ICPs at any level depending on AD severity, resources available in their country, and economic factors such as differences in insurance reimbursement systems. METHODS: The GA2 LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD-ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2 EN ADCARE centres. RESULTS: The AD-ICPs outline the diagnostic procedures, possible co-morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD. CONCLUSION: The AD-ICPs provide a multidisciplinary plan for improved diagnosis, treatment, and patient feedback in AD management, as well as addressing critical unmet needs, including improved access to care, training specialists, implementation of educational programs, assessment on the impact of climate change, and fostering a personalised treatment approach. By focusing on these key areas, the initiative aims to pave the way for a brighter future in the management of AD