Polymorphism at the 17q21 gene locus and wheezing responses to rhinovirus (RV) early in childhood conspire to increase the risk of developing asthma. However, the mechanisms mediating this ...gene-environment interaction remain unclear. In this study, we investigated the impact of one of the 17q21-encoded genes,
(orosomucoid-like 3), on RV replication in human epithelial cells.
knockdown inhibited RV-A16 replication in HeLa, BEAS-2B, A549, and NCI-H358 epithelial cell lines and primary nasal and bronchial epithelial cells. Inhibition varied by RV species, as both minor and major group RV-A subtypes RV-B52 and RV-C2 were inhibited but not RV-C15 or RV-C41.
siRNA did not affect expression of the major group RV-A receptor ICAM-1 or initial internalization of RV-A16. The two major outcomes of ORMDL3 activity, SPT (serine palmitoyl-CoA transferase) inhibition and endoplasmic reticulum (ER) stress induction, were further examined: silencing
decreased RV-induced ER stress and IFN-β mRNA expression. However, pharmacologic induction of ER stress and concomitant increased IFN-β inhibited RV-A16 replication. Conversely, blockade of ER stress with tauroursodeoxycholic acid augmented replication, pointing to an alternative mechanism for the effect of
knockdown on RV replication. In comparison, the SPT inhibitor myriocin increased RV-A16 but not RV-C15 replication and negated the inhibitory effect of
knockdown. Furthermore, lipidomics analysis revealed opposing regulation of specific sphingolipid species (downstream of SPT) by myriocin and
siRNA, correlating with the effect of these treatments on RV replication. Together, these data revealed a requirement for ORMDL3 in supporting RV replication in epithelial cells via SPT inhibition.
After EoE treatment, association of platelets with blood eosinophils, as reported by CD41, predicted esophageal eosinophil count. Percentage CD41+ circulating eosinophils is a potential non-invasive ...biomarker for EoE disease activity.
Background
The presence of eosinophils in the airway is associated with asthma severity and risk of exacerbations. Cell‐free eosinophil granules are found in tissues in eosinophilic diseases, ...including asthma. This suggests that eosinophils have lysed and released cellular content, likely harming tissues.
Objective
The present study explores the mechanism of CD32‐ and αMß2 integrin‐dependent eosinophil cytolysis of IL3‐primed blood eosinophils seeded on heat‐aggregated immunoglobulin G (HA‐IgG).
Methods
Cytoskeletal events and signalling pathways potentially involved in cytolysis were assessed using inhibitors. The level of activation of the identified events and pathways involved in cytolysis was measured. In addition, the links between these identified pathways and changes in degranulation (exocytosis) and adhesion were analysed.
Results
Cytolysis of IL3‐primed eosinophils was dependent on the production of reactive oxygen species (ROS) and downstream phosphorylation of p‐38 MAPK. In addition, formation of microtubule (MT) arrays was necessary for cytolysis and was accompanied by changes in MT dynamics as measured by phosphorylation status of stathmin and microtubule‐associated protein 4 (MAP4), the latter of which was regulated by ROS production. Reduced ROCK signalling preceded cytolysis, which was associated with eosinophil adhesion and reduced migration.
Conclusion and Clinical Relevance
In this CD32‐ and αMß2 integrin‐dependent adhesion model, lysing eosinophils exhibit reduced migration and ROCK signalling, as well as both MT dynamic changes and p‐38 phosphorylation downstream of ROS production. We propose that interfering with these pathways would modulate eosinophil cytolysis and subsequent eosinophil‐driven tissue damage.
IL-33 is a Potent Stimulus for Eosinophil Activation McKernan, Elizabeth M.; Angulo, Evelyn L.; Fichtinger, Paul S. ...
Journal of allergy and clinical immunology,
February 2018, 2018-02-00, 20180201, Letnik:
141, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Methods Fresh blood eosinophils were purified from human subjects 18-55 years old, most with an allergic rhinitis diagnosis with or without mild asthma, and who were genotyped at the 17q21 locus ...(rs7216389). ...when subjects were examined by genotype at the 17q21 locus (rs7216389 SNP), the eosinophil chemotaxis to IL-33 from TT subjects approached statistical significance (p=0.078), while CT subjects did not (p=0.82).
Based on excellent outcomes from high-volume centres, laparoscopic liver resection is increasingly being adopted into nationwide practice which typically includes low-medium volume centres. It is ...unknown how the use and outcome of laparoscopic liver resection compare between high-volume centres and low-medium volume centres. This study aimed to compare use and outcome of laparoscopic liver resection in three leading European high-volume centres and nationwide practice in the Netherlands.
An international, retrospective multicentre cohort study including data from three European high-volume centres (Oslo, Southampton and Milan) and all 20 centres in the Netherlands performing laparoscopic liver resection (low-medium volume practice) from January 2011 to December 2016. A high-volume centre is defined as a centre performing >50 laparoscopic liver resections per year. Patients were retrospectively stratified into low, moderate- and high-risk Southampton difficulty score groups.
A total of 2425 patients were included (1540 high-volume; 885 low-medium volume). The median annual proportion of laparoscopic liver resection was 42.9 per cent in high-volume centres and 7.2 per cent in low-medium volume centres. Patients in the high-volume centres had a lower conversion rate (7.4 versus 13.1 per cent; P < 0.001) with less intraoperative incidents (9.3 versus 14.6 per cent; P = 0.002) as compared to low-medium volume centres. Whereas postoperative morbidity and mortality rates were similar in the two groups, a lower reintervention rate (5.1 versus 7.2 per cent; P = 0.034) and a shorter postoperative hospital stay (3 versus 5 days; P < 0.001) were observed in the high-volume centres as compared to the low-medium volume centres. In each Southampton difficulty score group, the conversion rate was lower and hospital stay shorter in high-volume centres. The rate of intraoperative incidents did not differ in the low-risk group, whilst in the moderate-risk and high-risk groups this rate was lower in high-volume centres (absolute difference 6.7 and 14.2 per cent; all P < 0.004).
High-volume expert centres had a sixfold higher use of laparoscopic liver resection, less conversions, and shorter hospital stay, as compared to a nationwide low-medium volume practice. Stratification into Southampton difficulty score risk groups identified some differences but largely outcomes appeared better for high-volume centres in each risk group.
This study evaluates the effect of preoperative macrogol on gastrointestinal recovery and functional recovery after liver surgery combined with an enhanced recovery programme in a randomized ...controlled setting.
Patients were randomized to either 1 sachet of macrogol a day, one week prior to surgery versus no preoperative laxatives. Postoperative management for all patients was within an enhanced recovery programme. The primary outcome was recovery of gastrointestinal function, defined as Time to First Defecation. Secondary outcomes included Time to Functional Recovery.
Between August 2012 and September 2016, 82 patients planned for liver resection were included in the study, 39 in the intervention group and 43 in the control group. Median Time to First Defecation was 4.0 days in the intervention group (IQR 2.8–5.0) and 4.0 days in the control group (IQR 2.9–5.0), P = 0.487. Median Time to Functional Recovery was day 6 (IQR 4.0–8.0) in the intervention group and day 5 (IQR 4.0–7.5) in the control group, P = 0.752. No significant differences were seen in complication rate, reinterventions or mortality.
This randomized controlled trial showed no advantages of 1 sachet of macrogol preoperatively combined with an enhanced recovery programme, for patients undergoing liver surgery.
The CRESST experiment is a direct dark matter search which aims to measure interactions of potential dark matter particles in an Earth-bound detector. With the current stage, CRESST-III, we focus on ...a low energy threshold for increased sensitivity towards light dark matter particles. In this paper we describe the analysis of one detector operated in the first run of CRESST-III (05/2016–02/2018) achieving a nuclear recoil threshold of 30.1 eV. This result was obtained with a 23.6 g CaWO4 crystal operated as a cryogenic scintillating calorimeter in the CRESST setup at the Laboratori Nazionali del Gran Sasso (LNGS). Both the primary phonon (heat) signal and the simultaneously emitted scintillation light, which is absorbed in a separate silicon-on-sapphire light absorber, are measured with highly sensitive transition edge sensors operated at ∼15 mK. The unique combination of these sensors with the light element oxygen present in our target yields sensitivity to dark matter particle masses as low as 160 MeV/c2.
Beta1-integrin activation (mAb N29 intensity) and 15 other eosinophil-surface markers were assayed by whole blood flow cytometry. Conclusions In this pilot study, persistent beta1-integrin activation ...on circulating eosinophils after EoE treatment was associated with residual esophageal eosinophilic inflammation, whereas a decrease in beta1-integrin activation was associated with resolution of eosinophilic inflammation.
Despite a lack of high-level evidence, current guidelines recommend laparoscopic left lateral sectionectomy (LLLS) as the routine approach over open LLS (OLLS). Randomized studies and propensity ...score matched studies on LLLS vs OLLS for all indications, including malignancy, are lacking.
This international multicenter propensity score matched retrospective cohort study included consecutive patients undergoing LLLS or OLLS in six centers from three European countries (January 2000–December 2016). Propensity scores were calculated based on nine preoperative variables and LLLS and OLLS were matched in a 1:1 ratio. Short-term operative outcomes were compared using paired tests.
A total of 560 patients were included. Out of 200 LLLS, 139 could be matched to 139 OLLS. After matching, baseline characteristics were well balanced. LLLS was associated with shorter operative time (144 (110–200) vs 199 (138–283) minutes, P < 0.001), less blood loss (100 (50–300) vs 350 (100–750) mL, P = 0.005) and a 3-day shorter postoperative hospital stay (4 (3–7) vs 7 (5–9) days, P < 0.001).
This international multicenter propensity score matched study confirms the superiority of LLLS over OLLS based on shorter postoperative hospital stay, operative time, and less blood loss thus validating current guideline advice.
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