Regulatory effects of interleukin‐11 during acute lung inflammatory injury

The role of interleukin‐11 (IL‐11) was evaluated in the IgG immune complex model of acute lung injury in rats. IL‐11 mRNA and protein were both up‐regulated during the course of this inflammatory response. Exogenously administered IL‐11 substantially reduced, in a dose‐dependent manner, the intrapulmonary accumulation of neutrophils and the lung vascular leak of albumin. These in vivo anti‐inflammatory effects of IL‐11 were associated with reduced NF‐κB activation in lung, reduced levels of tumor necrosis factor α (TNF‐α) in bronchoalveolar lavage (BAL) fluids, and diminished up‐regulation of lung vascular ICAM‐1. It is interesting that IL‐11 did not affect BAL fluid content of the CXC chemokines, macrophage inflammatory protein‐2 (MIP‐2) and cytokine‐inducible neutrophil chemoattractant (CINC); the presence of IL‐11 did not affect these chemokines. However, BAL content of C5a was reduced by IL‐11. These data indicate that IL‐11 is a regulatory cytokine in the lung and that, like other members of this family, its anti‐inflammatory properties appear to be linked to its suppression of NF‐κB activation, diminished production of TNF‐α, and reduced up‐regulation of lung vascular ICAM‐1. J. Leukoc. Biol. 66: 151–157; 1999.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141937/1/jlb0151.pd

Visualization of fluoride ions in vivo using a gadolinium(III)-coumarin complex-based fluorescence/MRI dual-modal probe

A new Gadolinium(III)-coumarin complex, DO3A-Gd-CA, was designed and prepared as a dual-modal probe for simultaneous fluorescence and relaxivity responses to fluoride ions (F-) in aqueous media and mice. DO3A-Gd-CA was designed by using Gd(III) center as an MRI signal output unit and fluoride binding site, and the 4-(diethylamino)-coumarin-3-carboxylic acid (CA) as a fluorescence reporter. Upon the addition of fluoride ions to the solution of DO3A-Gd-CA, the liberation of the coordinated CA ligand led to a 5.7-fold fluorescence enhancement and a 75% increase in the longitudinal relaxivity (r₁). The fluorescent detection limit for fluoride ions was determined to be 8 μM based on a 3σ/slope. The desirable features of the proposed DO3A-Gd-CA, such as high sensitivity and specificity, reliability at physiological pH and low cytotoxicity enable its application in visualization of fluoride ion in mice. The successful in vivo imaging indicates that DO3A-Gd-CA could be potentially used in biomedical diagnosis fields

Efficacy and safety of Vilobelimab (IFX-1), a novel monoclonal anti-C5a antibody, in patients with early severe sepsis or septic shock — a randomized, placebo-controlled, double-blind, multicenter, phase IIa Trial (SCIENS Study)

IMPORTANCE:. Anaphylatoxin C5a, a proinflammatory complement split product, plays a central role in mediating organ dysfunction. OBJECTIVES:. This phase II clinical trial was conducted to study safety, tolerability, pharmacokinetics, and pharmacodynamics of vilobelimab, a recombinant monoclonal antibody against C5a, in patients with severe sepsis or septic shock. DESIGN:. Multicenter, randomized, and placebo-controlled study. SETTING AND PARTICIPANTS:. Eleven multidisciplinary ICUs across Germany. Adult patients with severe sepsis or septic shock and with early onset of infection-associated organ dysfunction. MAIN OUTCOMES AND MEASURES:. Patients were randomly assigned in a ratio of 2:1 to three subsequent dosing cohorts for IV vilobelimab or placebo receiving either 2 × 2 mg/kg (0 and 12 hr), 2 × 4 mg/kg (0 and 24 hr), and 3 × 4 mg/kg (0, 24, and 72 hr). Co-primary endpoints were pharmacodynamics (assessed by C5a concentrations), pharmacokinetics (assessed by vilobelimab concentrations), and safety of vilobelimab. Preliminary efficacy was evaluated by secondary objectives. RESULTS:. Seventy-two patients were randomized (16 patients for each vilobelimab dosing cohort and eight patients for each placebo dosing cohort). Vilobelimab application was associated with dosing dependent decrease in C5a compared with baseline (p < 0.001). Duration of C5a decrease increased with more frequent dosing. Membrane attack complex lysis capacity measured by 50% hemolytic complement was not affected. Vilobelimab was well tolerated with similar safety findings in all dose cohorts. No vilobelimab-specific adverse events emerged. For vilobelimab-treated patients, investigators attributed less treatment-emergent adverse events as related compared with placebo. Dosing cohorts 2 and 3 had the highest ICU-free and ventilator-free days. There was no difference in mortality, vasopressor-free days, or renal replacement therapy-free days between the groups. CONCLUSIONS AND RELEVANCE:. Administration of vilobelimab in patients with severe sepsis and septic shock selectively neutralizes C5a in a dose-dependent manner without blocking formation of the membrane attack complex and without resulting in detected safety issues. The data warrant further investigation of C5a inhibition in sepsis

A gadolinium(III) complex based dual-modal probe for MRI and fluorescence sensing of fluoride ions in aqueous medium and: in vivo

A novel Gd(iii) complex, Gd(TTA)3-DPPZ, was designed and assembled as a dual-modal probe for the simultaneous fluorescence and magnetic resonance imaging (MRI) detection of fluoride ions in aqueous media and in vivo. In this system, the Gd(iii) center is not only serving as a MRI signal output unit, but also as a binding site for fluoride ions. When appropriate equivalents of fluoride ions were added into the solution of Gd(TTA)3-DPPZ, the replacement of the coordination water led to a decrease of the longitudinal relaxivity (r1) as well as distinct spectroscopic changes, by which MRI/fluorescence dual-modal fluoride ion sensing was achieved. In the presence of fluoride ions, a 2-fold fluorescence emission enhancement of Gd(TTA)3-DPPZ, and a notable decrease of the UV-vis absorption spectrum were observed. The fluorescence detection limit for fluoride ions was established at 70 nM. Gd(TTA)3-DPPZ also exhibits about 75% decrease of the longitudinal relaxivity (r1) upon addition of fluoride ions in aqueous medium. The appropriate blood circulation time of Gd(TTA)3-DPPZ allows its potential application in MRI in vivo. The results demonstrated that Gd(TTA)3-DPPZ could serve as a potential MRI/fluorescence bimodal imaging agent for the specific and high-sensitive sensing of fluoride ions in vivo

Fluoride-specific fluorescence/MRI bimodal probe based on a gadolinium(III)-flavone complex: synthesis, mechanism and bioimaging application in vivo

Molecular imaging is a powerful tool to visualize cellular processes and activity levels of biomarkers at the cellular and molecular level, in which a molecular probe is a prerequisite for the molecular imaging technique. The present work reports a bimodal probe for the fluorescence and magnetic resonance detection of fluoride ions (F) in aqueous media and in vivo. The bimodal probe, EDTA-Gd-HF, was prepared by self-assembly of the EDTA-Gd complex with 3-hydroxyflavone (HF). In the system, HF plays the role of spectroscopic reporter and Gd(iii) serves as a MRI signal output unit as well as the fluoride ion binding site. Upon addition of fluoride ions into an aqueous solution of EDTA-Gd-HF, the replacement of one coordinated water molecule and then liberation of HF led to remarkable spectroscopic recovery and distinct changes to the longitudinal relaxivity (r), by which fluorescence/MRI bimodal fluoride ion sensing was achieved. In vivo magnetic resonance imaging (MRI) in mice indicates that EDTA-Gd-HF can be potentially used in biomedical diagnosis and therapy fields

Early Intra-Articular Complement Activation in Ankle Fractures

Cytokine regulation possibly influences long term outcome following ankle fractures, but little is known about synovial fracture biochemistry. Eight patients with an ankle dislocation fracture were included in a prospective case series and matched with patients suffering from grade 2 osteochondritis dissecans (OCD) of the ankle. All fractures needed external fixation during which joint effusions were collected. Fluid analysis was done by ELISA measuring aggrecan, bFGF, IL-1β, IGF-1, and the complement components C3a, C5a, and C5b-9. The time periods between occurrence of fracture and collection of effusion were only significantly associated with synovial aggrecan and C5b-9 levels (P<0.001). Furthermore, synovial expressions of both proteins correlated with each other (P<0.001). Although IL-1β expression was relatively low, intra-articular levels correlated with C5a (P<0.01) and serological C-reactive protein concentrations 2 days after surgery (P<0.05). Joint effusions were initially dominated by neutrophils, but the portion of monocytes constantly increased reaching 50% at day 6 after fracture (P<0.02). Whereas aggrecan and IL-1β concentrations were not different in fracture and OCD patients, bFGF, IGF-1, and all complement components were significantly higher concentrated in ankle joints with fractures (P<0.01). Complement activation and inflammatory cell infiltration characterize the joint biology following acute ankle fractures

Comparative Analysis of Recommendations for Timingand Frequency of Home Blood Pressure Monitoring in Clinical Practice Guidelines

Objective  To compare and analyze the recommendations for the timing and frequency of home blood pressure monitoring (HBPM) in clinical practice guidelines to help clinicians select the best recommendations and provide suggestions for the development of recommendations in the future.  Methods  Clinical practice guidelines related to hypertension published in the last five years were systematically searched and screened, and the recommendations for the timing and frequency of HBPM were extracted for statistical analysis.  Results  A total of 21 guidelines developed by institutions in 16 countries or regions were included, containing recommendations related to the timing and/or frequency of HBPM. For the HBPM timing, all guidelines recommend that blood pressure measurements be taken twice a day, in the morning and evening. In the morning blood pressure should be measured before taking antihypertensive medication (94.4%, 17/18), before breakfast (72.2%, 13/18) and after urination (55.6%, 10/18), while in the evening it should be taken before dinner (50.0%, 8/16), before bedtime (37.5%, 6/16) or 2 hours after dinner (6.3%, 1/16).For HBPM frequency, 9 (40.9%, 9/22) guidelines recommend at least 3 consecutive days of measurement in the week before the visit, and others suggest that measurements should be taken consecutively for at least 4 d (18.2%, 4/22), 5 d (13.6%, 3/22) or 7 d (27.3%, 6/22) days.  Conclusions  The guidelines of different countries and regions have great differences in recommendations on the timing and frequency of HBPM. It is recommended that future guideline developers develop the best recommendations after a thorough search, evaluation, and synthesis of the evidence, with full consideration of the balance of pros and cons, feasibility, patient preferences and values, as well as the context in which the guidelines are implemented

Highly accurate and large-scale collision cross sections prediction with graph neural networks

Abstract The collision cross section (CCS) values derived from ion mobility spectrometry can be used to improve the accuracy of compound identification. Here, we have developed the Structure included graph merging with adduct method for CCS prediction (SigmaCCS) based on graph neural networks using 3D conformers as inputs. A model was trained, evaluated, and tested with >5,000 experimental CCS values. It achieved a coefficient of determination of 0.9945 and a median relative error of 1.1751% on the test set. The model-agnostic interpretation method and the visualization of the learned representations were used to investigate the chemical rationality of SigmaCCS. An in-silico database with 282 million CCS values was generated for three different adduct types of 94 million compounds. Its source code is publicly available at https://github.com/zmzhang/SigmaCCS . Altogether, SigmaCCS is an accurate, rational, and off-the-shelf method to directly predict CCS values from molecular structures