Simvastatin in the acute respiratory distress syndrome McAuley, Daniel F; Laffey, John G; O'Kane, Cecilia M ...
New England journal of medicine/The New England journal of medicine,
10/2014, Letnik:
371, Številka:
18
Journal Article
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Studies in animals and in vitro and phase 2 studies in humans suggest that statins may be beneficial in the treatment of the acute respiratory distress syndrome (ARDS). This study tested the ...hypothesis that treatment with simvastatin would improve clinical outcomes in patients with ARDS.
In this multicenter, double-blind clinical trial, we randomly assigned (in a 1:1 ratio) patients with an onset of ARDS within the previous 48 hours to receive enteral simvastatin at a dose of 80 mg or placebo once daily for a maximum of 28 days. The primary outcome was the number of ventilator-free days to day 28. Secondary outcomes included the number of days free of nonpulmonary organ failure to day 28, mortality at 28 days, and safety.
The study recruited 540 patients, with 259 patients assigned to simvastatin and 281 to placebo. The groups were well matched with respect to demographic and baseline physiological variables. There was no significant difference between the study groups in the mean (±SD) number of ventilator-free days (12.6±9.9 with simvastatin and 11.5±10.4 with placebo, P=0.21) or days free of nonpulmonary organ failure (19.4±11.1 and 17.8±11.7, respectively; P=0.11) or in mortality at 28 days (22.0% and 26.8%, respectively; P=0.23). There was no significant difference between the two groups in the incidence of serious adverse events related to the study drug.
Simvastatin therapy, although safe and associated with minimal adverse effects, did not improve clinical outcomes in patients with ARDS. (Funded by the U.K. National Institute for Health Research Efficacy and Mechanism Evaluation Programme and others; HARP-2 Current Controlled Trials number, ISRCTN88244364.).
Stochastic cell fate specification, in which a cell chooses between two or more fates with a set probability, diversifies cell subtypes in development. Although this is a vital process across ...species, a common mechanism for these cell fate decisions remains elusive. This review examines two well-characterized stochastic cell fate decisions to identify commonalities between their developmental programmes. In the fly eye, two subtypes of R7 photoreceptors are specified by the stochastic ON/OFF expression of a transcription factor,
. In the mouse olfactory system, olfactory sensory neurons (OSNs) randomly select to express one copy of an olfactory receptor (OR) gene out of a pool of 2800 alleles. Despite the differences in these sensory systems, both stochastic fate choices rely on the dynamic interplay between transcriptional priming, chromatin regulation and terminal gene expression. The coupling of transcription and chromatin modifications primes gene loci in undifferentiated neurons, enabling later expression during terminal differentiation. Here, we compare these mechanisms, examine broader implications for gene regulation during development and posit key challenges moving forward. This article is part of a discussion meeting issue 'Causes and consequences of stochastic processes in development and disease'.
Natural selection can drive the repeated evolution of reproductive isolation, but the genomic basis of parallel speciation remains poorly understood. We analyzed whole-genome divergence between ...replicate pairs of stick insect populations that are adapted to different host plants and undergoing parallel speciation. We found thousands of modest-sized genomic regions of accentuated divergence between populations, most of which are unique to individual population pairs. We also detected parallel genomic divergence across population pairs involving an excess of coding genes with specific molecular functions. Regions of parallel genomic divergence in nature exhibited exceptional allele frequency changes between hosts in a field transplant experiment. The results advance understanding of biological diversification by providing convergent observational and experimental evidence for selection's role in driving repeatable genomic divergence.
Tumors constitute highly suppressive microenvironments in which infiltrating T cells are “exhausted” by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that ...critically limits antitumor and other CD8+ T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblockade of TIGIT and PD-L1 synergistically and specifically enhanced CD8+ T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT’s complementary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8+ T cell-dependent responses.
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•Human and murine tumor-infiltrating CD8+ T cells express high levels of TIGIT•Antibody coblockade of TIGIT and PDL1 elicits tumor rejection in preclinical models•TIGIT selectively limits the effector function of chronically stimulated CD8+ T cells•TIGIT interacts with CD226 in cis and disrupts CD226 homodimerization
Checkpoint blockade has demonstrated success as a cancer immunotherapy strategy, but the limits of CTLA-4- and PD-1-blocking agents suggest the need for additional targets. Johnston et al. identify TIGIT as a coinhibitory receptor that critically limits antitumor CD8+ T cell-dependent immune responses
Across the animal kingdom, visual systems have evolved to be uniquely suited to the environments and behavioral patterns of different species. Visual acuity and color perception depend on the ...distribution of photoreceptor (PR) subtypes within the retina. Retinal mosaics can be organized into three broad categories: stochastic/regionalized, regionalized, and ordered. We describe here the retinal mosaics of flies, zebrafish, chickens, mice, and humans, and the gene regulatory networks controlling proper PR specification in each. By drawing parallels in eye development between these divergent species, we identify a set of conserved organizing principles and transcriptional networks that govern PR subtype differentiation.
In a complex, diverse intestinal environment, commensal microbiota metabolizes excessive dietary tryptophan to produce more bioactive metabolites connecting with kinds of diverse process, such as ...host physiological defense, homeostasis, excessive immune activation and the progression and outcome of different diseases, such as inflammatory bowel disease, irritable bowel syndrome and others. Although commensal microbiota includes bacteria, fungi, and protozoa and all that, they often have the similar metabolites in tryptophan metabolism process via same or different pathways. These metabolites can work as signal to activate the innate immunity of intestinal mucosa and induce the rapid inflammation response. They are critical in reconstruction of lumen homeostasis as well. This review aims to seek the potential function and mechanism of microbiota‐derived tryptophan metabolites as targets to regulate and shape intestinal immune function, which mainly focused on two aspects. First, analyze the character of tryptophan metabolism in bacteria, fungi, and protozoa, and assess the functions of their metabolites (including indole and eight other derivatives, serotonin (5‐HT) and d‐tryptophan) on regulating the integrity of intestinal epithelium and the immunity of the intestinal mucosa. Second, focus on the mediator and pathway for their recognition, transfer and crosstalk between microbiota‐derived tryptophan metabolites and intestinal mucosal immunity. Disruption of intestinal homeostasis has been described in different intestinal inflammatory diseases, available data suggest the remarkable potential of tryptophan‐derived aryl hydrocarbon receptor agonists, indole derivatives on lumen equilibrium. These metabolites as preventive and therapeutic interventions have potential to promote proinflammatory or anti‐inflammatory responses of the gut.
Many patients show no or incomplete responses to current pharmacological or psychological therapies for depression. Here we explored the feasibility of a new brain self-regulation technique that ...integrates psychological and neurobiological approaches through neurofeedback with functional magnetic resonance imaging (fMRI). In a proof-of-concept study, eight patients with depression learned to upregulate brain areas involved in the generation of positive emotions (such as the ventrolateral prefrontal cortex (VLPFC) and insula) during four neurofeedback sessions. Their clinical symptoms, as assessed with the 17-item Hamilton Rating Scale for Depression (HDRS), improved significantly. A control group that underwent a training procedure with the same cognitive strategies but without neurofeedback did not improve clinically. Randomised blinded clinical trials are now needed to exclude possible placebo effects and to determine whether fMRI-based neurofeedback might become a useful adjunct to current therapies for depression.
The spectroscopic analysis of large biomolecules is important in applications such as biomedical diagnostics and pathogen detection, and spectroscopic techniques can detect such molecules at the ...nanogram level or lower. However, spectroscopic techniques have not been able to probe the structure of large biomolecules with similar levels of sensitivity. Here, we show that superchiral electromagnetic fields, generated by the optical excitation of plasmonic planar chiral metamaterials, are highly sensitive probes of chiral supramolecular structure. The differences in the effective refractive indices of chiral samples exposed to left- and right-handed superchiral fields are found to be up to 10(6) times greater than those observed in optical polarimetry measurements, thus allowing picogram quantities of adsorbed molecules to be characterized. The largest differences are observed for biomolecules that have chiral planar sheets, such as proteins with high β-sheet content, which suggests that this approach could form the basis for assaying technologies capable of detecting amyloid diseases and certain types of viruses.
The purpose of this study was to assess the validity and interunit reliability of 10 Hz (Catapult) and 15 Hz (GPSports) Global Positioning System (GPS) units and investigate the differences between ...these units as measures of team sport athlete movement demands. A team sport simulation circuit was completed by 8 trained male participants. The movement demands examined included: total distance covered (TD), average peak speed, and the distance covered, time spent, and the number of efforts performed low-speed running (0.00-13.99 km · h(-1)), high-speed running (14.00-19.99 km · h(-1)), and very high-speed running (>20.00 km · h(-1)). The degree of difference between the 10 Hz and the 15 Hz GPS units and validity was assessed using a paired samples t-test. Pearson's correlations were also used for validity assessment. Interunit reliability was established using percentage typical error of measurement (%TEM) and intraclass correlations. The findings revealed that 10 Hz GPS units were a valid (p > 0.05) and reliable (%TEM = 1.3%) measure of TD. In contrast, the 15 Hz GPS units exhibited lower validity for TD and average peak speed. Further, as the speed of movement increased the level of error for the 10 Hz and 15 Hz GPS units increased (%TEM = 0.8-19.9). The findings from this study suggest that comparisons should not be undertaken between 10 Hz and 15 Hz GPS units. In general, the 10 Hz GPS units measured movement demands with greater validity and interunit reliability than the 15 Hz units, however, both 10 Hz and 15 Hz units provided the improved measures of movement demands in comparison to 1 Hz and 5 Hz GPS units.
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