Roles of IL-6-gp130 Signaling in Vascular Inflammation

Interleukin-6 (IL-6) is a well-established, independent indicator of multiple distinct types of cardiovascular disease and all-cause mortality. In this review, we present current understanding of the multiple roles that IL-6 and its signaling pathways through glycoprotein 130 (gp130) play in cardiovascular homeostasis. IL-6 is highly inducible in vascular tissues through the actions of the angiotensin II (Ang II) peptide, where it acts in a paracrine manner to signal through two distinct mechanisms, the first being a classic membrane receptor initiated pathway and the second, a trans-signaling pathway, being able to induce responses even in tissues lacking the IL-6 receptor. Recent advances and new concepts in how its intracellular signaling pathways operate via the Janus kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) are described. IL-6 has diverse actions in multiple cell types of cardiovascular importance, including endothelial cells, monocytes, platelets, hepatocytes and adipocytes. We discuss central roles of IL-6 in endothelial dysfunction, cellular inflammation by affecting monocyte activation/differentiation, cellular cytoprotective functions from reactive oxygen species (ROS) stress, modulation of pro-coagulant state, myocardial growth control, and its implications in metabolic control and insulin resistance. These multiple actions indicate that IL-6 is not merely a passive biomarker, but actively modulates adaptive and pathological responses to cardiovascular stress

Causative agent distribution and antibiotic therapy assessment among adult patients with community acquired pneumonia in Chinese urban population

<p>Abstract</p> <p>Background</p> <p>Knowledge of predominant microbial patterns in community-acquired pneumonia (CAP) constitutes the basis for initial decisions about empirical antimicrobial treatment, so a prospective study was performed during 2003–2004 among CAP of adult Chinese urban populations.</p> <p>Methods</p> <p>Qualified patients were enrolled and screened for bacterial, atypical, and viral pathogens by sputum and/or blood culturing, and by antibody seroconversion test. Antibiotic treatment and patient outcome were also assessed.</p> <p>Results</p> <p>Non-viral pathogens were found in 324/610 (53.1%) patients among whom <it>M. pneumoniae </it>was the most prevalent (126/610, 20.7%). Atypical pathogens were identified in 62/195 (31.8%) patients carrying bacterial pathogens. Respiratory viruses were identified in 35 (19%) of 184 randomly selected patients with adenovirus being the most common (16/184, 8.7%). The nonsusceptibility of <it>S. pneumoniae </it>to penicillin and azithromycin was 22.2% (Resistance (R): 3.2%, Intermediate (I): 19.0%) and 79.4% (R: 79.4%, I: 0%), respectively. Of patients (312) from whom causative pathogens were identified and antibiotic treatments were recorded, clinical cure rate with β-lactam antibiotics alone and with combination of a β-lactam plus a macrolide or with fluoroquinolones was 63.7% (79/124) and 67%(126/188), respectively. For patients having mixed <it>M. pneumoniae </it>and/or <it>C. pneumoniae </it>infections, a better cure rate was observed with regimens that are active against atypical pathogens (e.g. a β-lactam plus a macrolide, or a fluoroquinolone) than with β-lactam alone (75.8% vs. 42.9%, <it>p </it>= 0.045).</p> <p>Conclusion</p> <p>In Chinese adult CAP patients, <it>M. pneumoniae </it>was the most prevalent with mixed infections containing atypical pathogens being frequently observed. With <it>S. pneumoniae</it>, the prevalence of macrolide resistance was high and penicillin resistance low compared with data reported in other regions.</p

Transgene expression in various organs post BM-HSC transplantation

Gene therapy mediated by bone marrow-derived hematopoietic stem cells (BM-HSC) has been widely used in treating genetic deficiencies in both pre-clinical and clinical settings. Using mitotically inactive cell-targeting lentivirus with separate promoters for our gene of interest (the murine MHC class II (MHCII) chaperone, invariant chain (Ii)) and a GFP reporter, we monitored the expression and function of introduced Ii in various types of professional antigen presenting cells (B cells, macrophages and DC) from different organs (spleen, pancreatic lymph nodes (PLN), BM and blood). Ii and GFP were detected. Ii levels correlated with GFP levels only in macrophages and monocytes from spleen, monocytes from PLN and macrophage precursors from blood. By cell type, Ii levels in PLN cells were more similar to those in spleen cells than to those in blood or BM cells. Functionally, Ii expressed in PLN or spleen had more effect on MHCII abundance than Ii expressed in BM or blood. The results have implications for analysis of the outcomes of gene therapy when both therapeutic and reporter genes are introduced. The findings also have implications for understanding the development of immune molecule function

SiGra: single-cell spatial elucidation through an image-augmented graph transformer

Abstract Recent advances in high-throughput molecular imaging have pushed spatial transcriptomics technologies to subcellular resolution, which surpasses the limitations of both single-cell RNA-seq and array-based spatial profiling. The multichannel immunohistochemistry images in such data provide rich information on the cell types, functions, and morphologies of cellular compartments. In this work, we developed a method, single-cell spatial elucidation through image-augmented Graph transformer (SiGra), to leverage such imaging information for revealing spatial domains and enhancing substantially sparse and noisy transcriptomics data. SiGra applies hybrid graph transformers over a single-cell spatial graph. SiGra outperforms state-of-the-art methods on both single-cell and spot-level spatial transcriptomics data from complex tissues. The inclusion of immunohistochemistry images improves the model performance by 37% (95% CI: 27–50%). SiGra improves the characterization of intratumor heterogeneity and intercellular communication and recovers the known microscopic anatomy. Overall, SiGra effectively integrates different spatial modality data to gain deep insights into spatial cellular ecosystems

Antimicrobial Peptide LL-37 and IDR-1 Ameliorate MRSA Pneumonia in Vivo

Background: The only human cathelicidin, LL-37, and the innate defense regulator peptide IDR-1, which have been proven to have antimicrobial activity, represent essential elements of immunity. Our previous study showed that the peptide LL-37 was protective in vitro to attenuate LTA-induced inflammatory effects. Methicillin-resistant staphylococcus aureus (MRSA) causes a multitude of serious and sometimes life-threatening diseases around the globe. However, the effect of LL-37 and IDR-1 in MRSA-induced pneumonia is unknown. In the present study, we explored the potential of LL-37 and IDR-1 in ameliorating MRSA-induced pneumonia in vivo. Methods: C57BL/6 mice were randomly divided into four groups and perfused intratracheally with PBS, peptide, MRSA and MRSA plus peptide, respectively. Pulmonary tissue pathology, ELISA and quantitative RT-PCR were employed. The relative signal pathways were further explored by western blot analysis. Results: Pathological analysis of the lung tissue sections demonstrated that, when compared with the MRSA-treated group, both the LL-37 and IDR-1 could ameliorate the MRSA-induced pneumonia. The phosphorylation of JNK and Akt were markedly decreased in the peptide plus MRSA-treated group compared with the MRSA-treated group. Furthermore, both of them also reduced TNF-α and IL-6 production in the bronchoalveolar lavage fluid (BALF) and serum in vivo. Conclusion: We report the first evidence of peptides inhibiting inflammation, decreasing the release of inflammatory cytokines and restoring pulmonary function in vivo. The antimicrobial peptide LL-37 and IDR-1 could ameliorate MRSA-induced pneumonia by exerting an anti-inflammatory property and attenuating pro-inflammatory cytokine release, thus providing support for the hypothesis that both innate and synthetic peptides could protect against MRSA in vivo

Changes of cardiac output and velocity time integral in blood return at the end of renal replacement therapy predict fluid responsiveness in critically Ill patients with acute circulatory failure

Abstract Objectives To observe if blood return, also defined as the blood infusion test (BIT) could predict fluid responsiveness in critically ill patients with acute circulatory failure and renal replacement therapy (RRT). Methods This was a single-center, prospective, diagnostic accuracy study. Before BIT, the passive leg raise test (PLRT) was performed to record the change of cardiac output (ΔCO) by pulse contour analysis, and ΔCO >  = 10% was defined as the fluid responder. Meanwhile, the change in velocity time integral (ΔVTI) was recorded by ultrasound. Later, the ΔCO and ΔVTI during BIT were recorded 5–10 min after PLRT. The receiver-operating characteristic curves of ΔCO and ΔVTI of BIT were performed in predicting the fluid responder defined by PLRT. Results A total of 43 patients with acute circulatory failure undergoing RRT were enrolled in the present study, and 25 patients (58.1%) were recognized as responders during PLRT. According to the receiver-operating characteristic curves, the cutoff value of ΔCO was 10% and ΔVTI was 9% during BIT with the area under curve of 0.96 and 0.94, respectively. Conclusions BIT in RRT could identify fluid responsiveness in critically ill patients with shock. Trial registration ChiCTR-DDD-17010534. Registered on 30/01/2017 (retrospective registration)

Using automatic speckle tracking imaging to measure diaphragm excursion and predict the outcome of mechanical ventilation weaning

Abstract Introduction The speckle tracking ultrasound is an innovative technology enabling distinct assessment of diaphragmatic movement, yet the relative data are scarce. In this pilot study, we sought to evaluate the predictive value of the weaning outcome of automatic speckle tracking in assessing diaphragm excursion. Methods This is a prospective, multicenter, observational study. A total of 160 critically ill subjects underwent speckle-tracking ultrasonography of the right/left hemidiaphragm before the spontaneous breathing trial. Meanwhile, the diaphragm excursion and velocity values were measured manually by M-mode ultrasound. Patients were divided into weaning-failure and weaning-success groups. The correlation was assessed between automatic and manual measurement, and the diagnostic efficacy of automatic measured excursion and velocity for predicting weaning outcome was analyzed. Results A total of 88 patients completed the follow-up of the weaning outcome. The overall incidence of weaning failure was 43.18%. There was a significant correlation between the automatic measurement of mean excursion and velocity assessed by speckle tracking imaging and manual measurement (R 0.69 and 0.65, respectively). Receiver operating characteristic (ROC) curve analysis showed that the mean excursion and diaphragmatic velocity exhibited high diagnostic values for prolonged weaning [area under the ROC curve (AUROC) 0.824 and 0.786, respectively]. The diaphragmatic excursion showed moderate diagnostic value for predicting both weaning failure and in-hospital death/withdrawal of treatment (AUROC 0.659 and 0.653, respectively). Conclusion Automatic speckle tracking analysis of the diaphragm showed high consistency with conventional manual ultrasound measures. Diaphragmatic excursion and its excursion velocity helped predict mechanical ventilation weaning failure, prolonged weaning, as well as in-hospital adverse outcomes, which served as a reliable tool in guiding clinical weaning strategy. Key message Automatic speckle tracking analysis of the diaphragm showed high consistency with conventional manual ultrasound measures. Diaphragmatic excursion and its excursion velocity helped predict mechanical ventilation weaning failure, prolonged weaning, as well as in-hospital adverse outcomes