Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase ...I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis.
Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored.
Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9 ± 2.4 μM (normal range 50-70 μM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury.
Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury.
ClinicalTrials.gov identifier NCT01434121.
A poly(ε-caprolactone) (PCL)-degrading bacterium designated as strain MRL-AN1 was isolated from soil. The bacterium was identified as Brevundimonas sp. strain MRL-AN1 through biochemical tests and ...16S rRNA gene sequencing. Scanning electron microscopy and Fourier transform infrared spectroscopy results confirmed the degradation of PCL by strain MRL-AN1. An extracellular PCL depolymerase was purified to homogeneity by column chromatography and molecular weight was estimated to be approximately 63.49 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. PCL depolymerase could degrade not only PCL but also other aliphatic polyesters. The enzyme was stable at wide range of temperature (20–45°C) and pH (5–9) as well as stable in the presence of various metal ions, surfactants and organic solvents. Phenylmethylsulfonyl fluoride inhibited enzyme activity that indicates this enzyme belongs to the serine hydrolase family. It is concluded from the results that the enzymes from strain MRL-AN1 might be applied in the process of biochemical monomer recycling in the polyester-contaminated environments.
Brevundimonas sp. strain MRL-AN1 was newly isolated from soil that could degrade various polyester based biodegradable plastics. The degradation of polyesters by this bacterium has not been studied previously.
During antiretroviral therapy (ART) that suppresses HIV replication to below the limit-of-quantification, virions produced during ART can be detected at low frequencies in the plasma, termed residual ...viremia (RV). We hypothesized that a reservoir of HIV-infected cells actively produce and release virions during ART that are potentially infectious, and that following ART-interruption, these virions can complete full-cycles of replication and contribute to rebound viremia. Therefore, we studied the dynamics of RV sequence variants in 3 participants who initiated ART after ~3 years of infection and were ART-suppressed for >6 years prior to self-initiated ART-interruptions. Longitudinal RV C2V5env sequences were compared to sequences from pre-ART plasma, supernatants of quantitative viral outgrowth assays (QVOA) of cells collected during ART, post-ART-interruption plasma, and ART-re-suppression plasma. Identical, "putatively clonal," RV sequences comprised 8-84% of sequences from each timepoint. The majority of RV sequences were genetically similar to those from plasma collected just prior to ART-initiation, but as the duration of ART-suppression increased, an increasing proportion of RV variants were similar to sequences from earlier in infection. Identical sequences were detected in RV over a median of 3 years (range: 0.3-8.2) of ART-suppression. RV sequences were identical to pre-ART plasma viruses (5%), infectious viruses induced in QVOA (4%) and rebound viruses (5%) (total n = 21/154 (14%) across the 3 participants). RV sequences identical to ART-interruption "rebound" sequences were detected 0.1-7.4 years prior to ART-interruption. RV variant prevalence and persistence were not associated with detection of the variant among rebound sequences. Shortly after ART-re-suppression, variants that had been replicating during ART-interruptions were detected as RV (n = 5). These studies show a dynamic, virion-producing HIV reservoir that contributes to rekindling infection upon ART-interruption. The persistence of identical RV variants over years suggests that a subpopulation of HIV-infected clones frequently or continuously produce virions that may resist immune clearance; this suggests that cure strategies should target this active as well as latent reservoirs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The volatility and intermittency of wind energy result in highly unpredictable wind power output, which poses challenges to the stability of the intact power system when integrating large-scale wind ...power. The accuracy of wind power prediction is critical for maximizing the utilization of wind energy, improving the quality of power supply, and maintaining the stable operation of the power grid. To address this challenge, this paper proposes a novel hybrid forecasting model, referred to as Hybrid WT–PSO–NARMAX, which combines wavelet transform, randomness operator-based particle swarm optimization (ROPSO), and non-linear autoregressive moving average with external inputs (NARMAX). The model is specifically designed for power generation forecasting in wind energy systems, and it incorporates the interactions between the wind system’s supervisory control and data acquisition’s (SCADA) actual power record and numerical weather prediction (NWP) meteorological data for one year. In the proposed model, wavelet transform is utilized to significantly improve the quality of the chaotic meteorological and SCADA data. The NARMAX techniques are used to map the non-linear relationship between the NWP meteorological variables and SCADA wind power. ROPSO is then employed to optimize the parameters of NARMAX to achieve higher forecasting accuracy. The performance of the proposed model is compared with other forecasting strategies, and it outperforms in terms of forecasting accuracy improvement. Additionally, the proposed Prediction Error-Based Power Forecasting (PEBF) approach is introduced, which retrains the model to update the results whenever the difference between forecasted and actual wind powers exceeds a certain limit. The efficiency of the developed scheme is evaluated through a real case study involving a 180 MW grid-connected wind energy system located in Shenyang, China. The proposed model’s forecasting accuracy is evaluated using various assessment metrics, including mean absolute error (MAE) and root mean square error (RMSE), with the average values of MAE and RMSE being 0.27% and 0.30%, respectively. The simulation and numerical results demonstrated that the proposed model accurately predicts wind output power.
Neutrophil recruitment to inflammation sites purportedly depends on sequential waves of chemoattractants. Current models propose that leukotriene B4 (LTB4), a secondary chemoattractant secreted by ...neutrophils in response to primary chemoattractants such as formyl peptides, is important in initiating the inflammation process. In this study we demonstrate that LTB4 plays a central role in neutrophil activation and migration to formyl peptides. We show that LTB4 production dramatically amplifies formyl peptide-mediated neutrophil polarization and chemotaxis by regulating specific signaling pathways acting upstream of actin polymerization and MyoII phosphorylation. Importantly, by analyzing the migration of neutrophils isolated from wild-type mice and mice lacking the formyl peptide receptor 1, we demonstrate that LTB4 acts as a signal to relay information from cell to cell over long distances. Together, our findings imply that LTB4 is a signal-relay molecule that exquisitely regulates neutrophil chemotaxis to formyl peptides, which are produced at the core of inflammation sites.
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► LTB4 specifically modulates neutrophil polarization in response to formyl peptides ► Formyl peptide-induced LTB4 secretion acts in an autocrine and paracrine fashion ► LTB4 secretion amplifies neutrophil migration toward formyl peptides ► Secreted LTB4 acts as a signal-relay molecule during neutrophil chemotaxis
Leukotriene B4 (LTB4) is a potent chemoattractant secreted by neutrophils in response to formyl peptides. We demonstrate that LTB4 significantly amplifies neutrophil recruitment to primary chemoattractants by selectively modulating signaling cascades involved in cell polarization and by serving as a potent secondary gradient.
Many chronic pulmonary diseases are associated with pulmonary hypertension (PH) and pulmonary vascular remodeling, which is a term that continues to be used to describe a wide spectrum of vascular ...abnormalities. Pulmonary vascular structural changes frequently increase pulmonary vascular resistance, causing PH and right heart failure. Although rat models had been standard models of PH research, in more recent years the availability of genetically engineered mice has made this species attractive for many investigators. Here we review a large amount of data derived from experimental PH reports published since 1996. These studies using wild-type and genetically designed mice illustrate the challenges and opportunities provided by these models. Hemodynamic measurements are difficult to obtain in mice, and right heart failure has not been investigated in mice. Anatomical, cellular, and genetic differences distinguish mice and rats, and pharmacogenomics may explain the degree of PH and the particular mode of pulmonary vascular adaptation and also the response of the right ventricle.
Prostacyclin and its analogues improve cardiac output and functional capacity in patients with pulmonary arterial hypertension (PAH); however, the underlying mechanism is not fully understood. We ...hypothesised that prostanoids have load-independent beneficial effects on the right ventricle (RV). Angio-obliterative PAH and RV failure were induced in rats with a single injection of SU5416 followed by 4 weeks of exposure to hypoxia. Upon confirmation of RV dysfunction and PAH, rats were randomised to 0.1 μg·kg(-1) nebulised iloprost or drug-free vehicle, three times daily for 2 weeks. RV function and treadmill running time were evaluated pre- and post-iloprost/vehicle treatment. Pulmonary artery banded rats were treated 8 weeks after surgery to allow for significant RV hypertrophy. Inhaled iloprost significantly improved tricuspid annulus plane systolic excursion and increased exercise capacity, while mean pulmonary artery pressure and the percentage of occluded pulmonary vessels remained unchanged. Rats treated with iloprost had a striking reduction in RV collagen deposition, procollagen mRNA levels and connective tissue growth factor expression in both SU5416/hypoxia and pulmonary artery banded rats. In vitro, cardiac fibroblasts treated with iloprost showed a reduction in transforming growth factor (TGF)-β1-induced connective tissue growth factor expression, in a protein kinase A-dependent manner. Iloprost decreased TGF-β1-induced procollagen mRNA expression as well as cardiac fibroblast activation and migration. Iloprost significantly induced metalloproteinase-9 gene expression and activity and increased the expression of autophagy genes associated with collagen degradation. Inhaled iloprost improves RV function and reverses established RV fibrosis partially by preventing collagen synthesis and by increasing collagen turnover.
New and interesting properties can be obtained from macromolecular architectures functionalized with supramolecular moieties, particularly metal–ligand complexes. Self‐assembly, based on the ...selective control of noncovalent interactions, guides the creation of hierarchically ordered materials providing access to novel structures and new properties. This field has expanded significantly in the last two decades, and one of the most ubiquitous functionalities is terpyridine. Despite its wide‐spread use, much basic knowledge regarding the binding of terpyridine with metal ions remains unknown. Here, the binding constants of PEG‐substituted terpyridine in relation to other literature reports are studied and a few examples of supramolecular materials from our laboratory are summarized.
Terpyridine‐complex containing homopolymers (left) and block copolymers (right) behaved as rigid‐rod‐like molecules due to the increase in persistence length generated by the metal complex. This leads to interesting self‐assembling including hierarchical length scales in the block copolymer.
Raman microspectroscopy can provide the chemical contrast needed to characterize the complex intracellular environment and macromolecular organization in cells without exogenous labels. It has shown ...a remarkable ability to detect chemical changes underlying cell differentiation and pathology-related chemical changes in tissues but has not been widely adopted for imaging, largely due to low signal levels. Broadband coherent anti-Stokes Raman scattering (B-CARS) offers the same inherent chemical contrast as spontaneous Raman but with increased acquisition rates. To date, however, only spectrally resolved signals from the strong CH-related vibrations have been used for CARS imaging. Here, we obtain Raman spectral images of single cells with a spectral range of 600–3200 cm
−1, including signatures from weakly scattering modes as well as CH vibrations. We also show that B-CARS imaging can be used to measure spectral signatures of individual cells at least fivefold faster than spontaneous Raman microspectroscopy and can be used to generate maps of biochemical species in cells. This improved spectral range and signal intensity opens the door for more widespread use of vibrational spectroscopic imaging in biology and clinical diagnostics.
Few studies have assessed the presentation, management, and outcomes of sepsis in low-income countries (LICs). We sought to characterize these aspects of sepsis and to assess mortality predictors in ...sepsis in two referral hospitals in Rwanda. This was a retrospective cohort study in two public academic referral hospitals in Rwanda. Data was abstracted from paper medical records of adult patients who met our criteria for sepsis. Of the 181 subjects who met eligibility criteria, 111 (61.3%) met our criteria for sepsis without shock and 70 (38.7%) met our criteria for septic shock. Thirty-five subjects (19.3%) were known to be HIV positive. The vast majority of septic patients (92.7%) received intravenous fluid therapy (median = 1.0 L within 8 hours), and 94.0% received antimicrobials. Vasopressors were administered to 32.0% of the cohort and 46.4% received mechanical ventilation. In-hospital mortality for all patients with sepsis was 51.4%, and it was 82.9% for those with septic shock. Baseline characteristic mortality predictors were respiratory rate, Glasgow Coma Scale score, and known HIV seropositivity. Septic patients in two public tertiary referral hospitals in Rwanda are young (median age = 40, IQR = 29, 59) and experience high rates of mortality. Predictors of mortality included baseline clinical characteristics and HIV seropositivity status. The majority of subjects were treated with intravenous fluids and antimicrobials. Further work is needed to understand clinical and management factors that may help improve mortality in septic patients in LICs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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