Could Fractional Exhaled Nitric Oxide Test be Useful in Predicting Inhaled Corticosteroid Responsiveness in Chronic Cough? A Systematic Review

© 2016 Background Fractional exhaled nitric oxide (FENO) is a safe and convenient test for assessing T H 2 airway inflammation, which is potentially useful in the management of patients with chronic cough. Objective To summarize the current evidence on the diagnostic usefulness of FENO for predicting inhaled corticosteroid (ICS) responsiveness in patients with chronic cough. Methods A systematic literature review was conducted to identify articles published in peer-reviewed journals up to February 2015, without language restriction. We included studies that reported the usefulness of FENO (index test) for predicting ICS responsiveness (reference standard) in patients with chronic cough (target condition). The data were extracted to construct a 2 × 2 accuracy table. Study quality was assessed with Quality Assessment of Diagnostic Accuracy Studies 2. Results We identified 5 original studies (2 prospective and 3 retrospective studies). We identified considerable heterogeneities in study design and outcome definitions, and thus were unable to perform a meta-analysis. The proportion of ICS responders ranged from 44% to 59%. Sensitivity and specificity ranged from 53% to 90%, and from 63% to 97%, respectively. The reported area under the curve ranged from abou t 0.60 to 0.87; however, studies with a prospective design and a lower prevalence of asthma had lower area under the curve values. None measured placebo effects or objective cough frequency. Conclusions We did not find strong evidence to support the use of FENO tests for predicting ICS responsiveness in chronic cough. Further studies need to have a randomized, placebo-controlled design, and should use validated measurement tools for cough. Standardization would facilitate the development of clinical evidence

Patients with systemic lupus erythematosus have abnormally elevated Epstein–Barr virus load in blood

Various genetic and environmental factors appear to be involved in systemic lupus erythematosus (SLE). Epstein–Barr virus (EBV) is among the environmental factors that are suspected of predisposing to SLE, based on the characteristics of EBV itself and on sequence homologies between autoantigens and EBV antigens. In addition, higher titers of anti-EBV antibodies and increased EBV seroconversion rates have been observed in SLE patients as compared with healthy control individuals. Serologic responses do not directly reflect EBV status within the body. Clarification of the precise status of EBV infection in SLE patients would help to improve our understanding of the role played by EBV in this disease. In the present study we determined EBV types in SLE patients (n = 66) and normal control individual (n = 63) by direct PCR analysis of mouthwash samples. We also compared EBV load in blood between SLE patients (n = 24) and healthy control individuals (n = 29) using semiquantitative PCR assay. The number of infections and EBV type distribution were similar between adult SLE patients and healthy control individuals (98.5% versus 94%). Interestingly, the EBV burden in peripheral blood mononuclear cells (PBMCs) was over 15-fold greater in SLE patients than in healthy control individuals (mean ± standard deviation: 463 ± 570 EBV genome copies/3 μg PBMC DNA versus 30 ± 29 EBV genome copies/3 μg PBMC DNA; P = 0.001), suggesting that EBV infection is abnormally regulated in SLE. The abnormally increased proportion of EBV-infected B cells in the SLE patients may contribute to enhanced autoantibody production in this disease

Biochemical Markers as Predictors of In-Hospital Mortality in Patients with Severe Trauma: A Retrospective Cohort Study

Background Initial evaluation of injury severity in trauma patients is an important and challenging task. We aimed to assess whether easily measurable biochemical parameters (hemoglobin, pH, and prothrombin time/international normalized ratio [PT/INR]) can predict in-hospital mortality in patients with severe trauma. Methods This retrospective study involved review of the medical records of 315 patients with severe trauma and an injury severity score >15 who were managed at Gyeongsang National University Hospital between January 2005 and December 2015. We extracted the following data: in-hospital mortality, injury severity score, and initial hemoglobin level, pH, and PT/INR. The predictive values of these variables were compared using receiver operation characteristic curves. Results Of the 315 patients, 72 (22.9%) died. The in-hospital mortality rates of patients with hemoglobin levels <8.4 g/dl and ≥8.4 g/dl were 49.8% and 9.9%, respectively (P < 0.001). At a cutoff hemoglobin level of 8.4 g/dl, the sensitivity and specificity values for mortality were 81.9% and 86.4%, respectively. At a pH cutoff of 7.25, the sensitivity and specificity values for mortality were 66.7% and 77.8%, respectively; 66.7% of patients with a pH <7.25 died versus 22.2% with a pH ≥7.25 (P < 0.001). The in-hospital mortality rates for patients with PT/INR values ≥1.4 and <1.4 were 37.5% and 16%, respectively (P < 0.001; sensitivity, 37.5%; specificity, 84%). Conclusions Using the suggested cutoff values, hemoglobin level, pH, and PT/INR can simply and easily be used to predict in-hospital mortality in patients with severe trauma

Natural Form of Noncytolytic Flexible Human Fc as a Long-Acting Carrier of Agonistic Ligand, Erythropoietin

Human IgG1 Fc has been widely used as a bioconjugate, but exhibits shortcomings, such as antibody- and complement-mediated cytotoxicity as well as decreased bioactivity, when applied to agonistic proteins. Here, we constructed a nonimmunogenic, noncytolytic and flexible hybrid Fc (hyFc) consisting of IgD and IgG4, and tested its function using erythropoietin (EPO) conjugate, EPO-hyFc. Despite low amino acid homology (20.5%) between IgD Fc and IgG4 Fc, EPO-hyFc retained “Y-shaped” structure and repeated intravenous administrations of EPO-hyFc into monkeys did not generate EPO-hyFc-specific antibody responses. Furthermore, EPO-hyFc could not bind to FcγR I and C1q in contrast to EPO-IgG1 Fc. In addition, EPO-hyFc exhibited better in vitro bioactivity and in vivo bioactivity in rats than EPO-IgG1 Fc, presumably due to the high flexibility of IgD. Moreover, the mean serum half-life of EPO-hyFc(H), a high sialic acid content form of EPO-hyFc, was approximately 2-fold longer than that of the heavily glycosylated EPO, darbepoetin alfa, in rats. More importantly, subcutaneous injection of EPO-hyFc(H) not only induced a significantly greater elevation of serum hemoglobin levels than darbepoetin alfa in both normal rats and cisplatin-induced anemic rats, but also displayed a delayed time to maximal serum level and twice final area-under-the-curve (AUClast). Taken together, hyFc might be a more attractive Fc conjugate for agonistic proteins/peptides than IgG1 Fc due to its capability to elongate their half-lives without inducing host effector functions and hindering bioactivity of fused molecules. Additionally, a head-to-head comparison demonstrated that hyFc-fusion strategy more effectively improved the in vivo bioactivity of EPO than the hyperglycosylation approach

SupCon-MPL-DP: Supervised Contrastive Learning with Meta Pseudo Labels for Deepfake Image Detection

Recently, there has been considerable research on deepfake detection. However, most existing methods face challenges in adapting to the advancements in new generative models within unknown domains. In addition, the emergence of new generative models capable of producing and editing high-quality images, such as diffusion, consistency, and LCM, poses a challenge for traditional deepfake training models. These advancements highlight the need for adapting and evolving existing deepfake detection techniques to effectively counter the threats posed by sophisticated image manipulation technologies. In this paper, our objective is to detect deepfake videos in unknown domains using unlabeled data. Specifically, our proposed approach employs Meta Pseudo Labels (MPL) with supervised contrastive learning, so-called SupCon-MPL, allowing the model to be trained on unlabeled images. MPL involves the simultaneous training of both a teacher model and a student model, where the teacher model generates pseudo labels utilized to train the student model. This method aims to enhance the adaptability and robustness of deepfake detection systems against emerging unknown domains. Supervised contrastive learning utilizes labels to compare samples within similar classes more intensively, while encouraging greater distinction from samples in dissimilar classes. This facilitates the learning of features in a diverse set of deepfake images by the model, consequently contributing to the performance of deepfake detection in unknown domains. When utilizing the ResNet50 model as the backbone, SupCon-MPL exhibited an improvement of 1.58% in accuracy compared with traditional MPL in known domain detection. Moreover, in the same generation of unknown domain detection, there was a 1.32% accuracy enhancement, while in the detection of post-generation unknown domains, there was an 8.74% increase in accuracy

The Retinal Pigment Epithelium Is a Notch Signaling Niche in the Mouse Retina

Summary: Notch signaling in neural progenitor cell is triggered by ligands expressed in adjacent cells. To identify the sources of active Notch ligands in the mouse retina, we negatively regulated Notch ligand activity in various neighbors of retinal progenitor cells (RPCs) by eliminating mindbomb E3 ubiquitin protein ligase 1 (Mib1). Mib1-deficient retinal cells failed to induce Notch activation in intra-lineage RPCs, which prematurely differentiated into neurons; however, Mib1 in post-mitotic retinal ganglion cells was not important. Interestingly, Mib1 in the retinal pigment epithelium (RPE) also contributed to Notch activation in adjacent RPCs by supporting the localization of active Notch ligands at RPE-RPC contacts. Combining this RPE-driven Notch signaling and intra-retinal Notch signaling, we propose a model in which one RPC daughter receives extra Notch signals from the RPE to become an RPC, whereas its sister cell receives only a subthreshold level of intra-retinal Notch signal and differentiates into a neuron. : Ha et al. identify a role of retinal pigment epithelium (RPE) as a Notch signaling niche in the mouse retina. The extra Notch signal derived from the RPE is especially critical to maintaining the RPC fate of cells that receive an insufficient Notch signal from their sister cells. Keywords: Notch signaling, mind bomb1, Mib1, retina, retinal pigment epithelium, RPE, retinal progenitor cell, RP

Quantitative Analysis of Sphingomyelin by High-Performance Liquid Chromatography after Enzymatic Hydrolysis

Sphingomyelin is the most abundant sphingolipid in mammalian cells and is mostly present in the plasma membrane. A new analytical method using high-performance liquid chromatography (HPLC) was developed to quantify sphingomyelin in mouse plasma and tissues, 3T3-L1 cells, rat aortic smooth muscle cells, and HT-29 cells. Sphingomyelin and dihydrosphingomyelin, an internal standard, were separated by high-performance thin-layer chromatography and simultaneously hydrolyzed with sphingolipid ceramide N-deacylase and sphingomyelinase to release sphingosine and dihydrosphingosine, respectively. Sphingomyelin content was measured by HPLC following o-phthalaldehyde derivatization. Sphingomyelin concentrations in 3T3-L1 cells, rat aortic smooth muscle cells, and HT-29 cells were 60.10±0.24, 62.69±0.08, and 58.38±0.37 pmol/μg protein, respectively, whereas those in brain, kidney, and liver of ICR mice were 55.60±0.43, 43.75±0.21, and 22.26±0.14 pmol/μg protein. The sphingomyelin concentration in mouse plasma was 407.40±0.31 μM. The limits of detection and quantification for sphingomyelin were 5 and 20 pmol, respectively, in the HPLC analysis with fluorescence detection. This sensitivity was sufficient for analyzing sphingomyelin in biological samples. In conclusion, this analytical method is a sensitive and specific technique for quantifying sphingomyelin and was successfully applied to diverse biological samples with excellent reproducibility