The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the ...inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction.
Summary
Background Psoriasis is characterized by epidermal infiltration of neutrophils that destroy invading microorganisms via a potent antimicrobial arsenal of oxidants and antimicrobial agents. ...In contrast to atopic dermatitis, psoriasis exhibits low levels of skin infections due to the presence of antimicrobial agents, including cathelicidin LL‐37. LL‐37 kills a broad spectrum of microbes, and activates neutrophil chemotaxis.
Objective To determine whether or not LL‐37 could regulate additional neutrophil functions such as production of cytokines/chemokines, reactive oxygen species and release of neutrophil antimicrobial peptides.
Methods Human peripheral blood neutrophils were used in this study. The production of interleukin (IL)‐8 and release of α‐defensins were analysed by enzyme‐linked immunosorbent assay, and real‐time polymerase chain reaction (PCR) was used to quantify α‐defensin gene expression. Phosphorylation of mitogen‐activated protein kinase (MAPK) was determined by Western blotting. The generation of reactive oxygen species was examined using flow cytometry, and intracellular Ca2+ mobilization was measured using a calcium assay kit.
Results LL‐37 enhanced the production of IL‐8 under the control of MAPK p38 and extracellular signal regulated kinase (ERK), as evidenced by the inhibitory effects of p38 and ERK1/2 inhibitors on LL‐37‐mediated IL‐8 production. Furthermore, LL‐37 induced phosphorylation of p38 and ERK. We also revealed that LL‐37 stimulated the generation of reactive oxygen species dose‐ and time‐dependently, most probably via NADPH oxidase activation and intracellular Ca2+ mobilization. Finally, LL‐37 induced both mRNA expression and protein release of α‐defensins, known as human neutrophil peptide 1–3.
Conclusion Taken together, we suggest that in addition to its microbicidal properties, LL‐37 may contribute to innate immunity by enhancing neutrophil host defence functions at inflammation and/or infection sites.
Abstract
Funding Acknowledgements
Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Co., Ltd.
OnBehalf
ANAFIE Registry Group
Backgrounds
Benefits of catheter ablation ...(CA) have been shown for patients with atrial fibrillation (AF). However, data in elderly patients aged ≥75 years who have undergone CA for non-valvular AF (NVAF) are insufficient.
Purpose
The All Nippon Atrial Fibrillation In the Elderly (ANAFIE) Registry is a prospective, multicenter, observational study, which was designed to collect the real-world data on the clinical status and prognosis in 30,000 over Japanese patients (aged ≥75 years) with NVAF. This cross-sectional subanalysis of the ANAFIE registry assessed the 2-year outcomes and anticoagulant treatment in elderly NVAF patients with a history of CA.
Methods
A total of the 32,275 patients from the ANAFIE registry were divided into two groups by a history of CA: the CA and No-CA groups. Kaplan-Meier analysis was used to evaluate the annualized incidences of stroke/systemic embolic event (SEE), major bleeding, intracranial hemorrhage (ICH), heart failure requiring hospitalization (HF), and all-cause mortality. Hazard ratio (HR) for each event was analyzed using the Cox proportional-hazards model.
Results
Of all patients, 2,970 patients (9.2%) were included in the CA group and 29,305 (90.8%) were included in the No-CA group. The CA group had lower age (mean 78.9 vs 81.7 years), higher prevalence of paroxysmal AF (73.0 vs 39.0%), higher creatinine clearance (mean 53.1 vs 47.9 mL/min) and lower CHA2DS2-VASc (mean 4.2 vs 4.5) and HAS-BLED scores (mean 1.8 vs 1.9) than the No-CA group. Oral anticoagulants (OACs) were administered in 87.3% of the CA group (warfarin, 16.8%; direct OAC, 70.5%) and 92.9% of the No-CA group (warfarin, 26.4%; direct OAC, 66.5%). Compared with the No-CA group, the CA group had lower the annualized incidences (/100 patient-year 95%confidence intervals) of stroke/SEE (0.74 0.52, 0.96 vs 1.72 1.61, 1.83), major bleeding (0.63 0.43, 0.84 vs 1.12 1.03, 1.21), ICH (0.49 0.31, 0.67 vs 0.78 0.71, 0.86), HF (2.54 2.12, 2.96 vs 4.44 4.26, 4.62), and all-cause mortality (1.45 1.14, 1.77 vs 3.95 3.78, 4.11).
Conclusions
Elderly NVAF patients with a history of CA had lower adverse incidences compared with patients without a history of CA. A more optimal OAC therapy for elderly NVAF patients with a history of CA should be examined in the future.
In large-scale spatial surveys, such as the forthcoming ESA Euclid mission, images may be undersampled due to the optical sensors sizes. Therefore, one may consider using a super-resolution (SR) ...method to recover aliased frequencies, prior to further analysis. This is particularly relevant for point-source images, which provide direct measurements of the instrument point-spread function (PSF). We introduce SParse Recovery of InsTrumental rEsponse (SPRITE), which is an SR algorithm using a sparse analysis prior. We show that such a prior provides significant improvements over existing methods, especially on low signal-to-noise ratio PSFs.
The Heck reaction was carried out in
N,
N-dimethylacetamide (DMAc) solvent with Pd-supported zeolites as catalysts. Particular attention was paid to the influence of pretreatment conditions and the ...kind of zeolites on the catalytic activity and the elution of Pd. Pd
2+ ion-exchanged zeolites exhibited relatively high activity in the reaction. However, a considerable amount of Pd was dissolved in the solvent. Deposition of agglomerated Pd
0 was observed after the reaction, suggesting the dissolved Pd
2+ species was reduced with DMAc during reaction. Pd
0-loaded zeolites were prepared by the reduction of Pd oxide/zeolites with H
2. Among Pd
0-loaded catalysts, Pd
0/H–Y exhibited high activity. The dissolution of Pd was significantly suppressed over Pd
0/H–Y, as indicated by ICP analysis of the solution. The recycled use of Pd
0/H–Y was possible through oxidation and successive reduction with H
2. The growing process of Pd clusters in H–Y was followed by energy-dispersive XAFS (partly Quick XAFS) during temperature-programmed reduction in diluted H
2. It was found that stable Pd
13 clusters that interacted with Brønsted acid sites were generated in the pore of H–Y. The Pd
13 clusters were ascribed to the active and insoluble species in the Heck reaction.
We have developed an FX-architecture digital spectro-correlator for the Atacama Compact Array of the Atacama Large Millimeter/submillimeter Array. The correlator is able to simultaneously process ...four pairs of dual polarization signals with a bandwidth of 2 GHz, which are received by up to sixteen antennas. It can calculate auto- and cross-correlation spectra, including cross-polarization in all combinations of all the antennas, and output correlation spectra with flexible spectral configuration, such as multiple frequency ranges and multiple frequency resolutions. Its spectral dynamic range is estimated to be higher than 10
$^{4}$
relative to
$T_{\rm sys}$
from processing results of thermal noise for eight hours with a typical correlator configuration. The sensitivity loss is also confirmed to be 0.9% with the same configuration. In this paper, we report on the detailed design of the correlator and the verification results of the developed hardware.
Background
Many perforated peptic ulcers (PPUs) require surgical repair due to diffuse peritonitis. However, few studies have examined the clinical effects of postoperative drainage after PPU repair. ...This study aimed to investigate the drain insertion rates in patients who underwent PPU repair in Japan, and to clarify the impact of drain insertion on the postoperative clinical course.
Methods
A retrospective nationwide cohort study was performed using administrative claims data of patients who had undergone PPU repair between 2010 and 2016. These patients were divided into two groups based on whether or not they had received a postoperative abdominal drain. Using propensity score matching, we compared the incidences of postoperative interventions for abdominal complications between both groups.
Results
A total of 4869 patients from 324 hospitals were analyzed. At the hospital level, drains were placed in all PPU repair patients in 229 (70.7%) hospitals. At the patient level, 4401 patients (90.4%) had drains inserted. The drain group was associated with a higher emergency admission rate, poorer preoperative shock status, longer anesthetic time, and a higher amount of intra-abdominal irrigation. In the propensity score-matched patients, the drain group had a significantly lower incidence of postoperative interventions than the no-drain group (1.9 vs. 5.6%; risk ratio = 0.35; 95% confidence interval 0.16–0.73;
P
= 0.003).
Conclusion
Postoperative drainage was performed in the majority of patients who underwent PPU repair in Japan. Drainage following PPU repair may facilitate patient recovery by reducing the need for postoperative interventions.
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