981 research outputs found
Systemic Effects Induced by Hyperoxia in a Preclinical Model of Intra-abdominal Sepsis
Supplemental oxygen is a supportive treatment in patients with sepsis to balance tissue oxygen delivery and demand in the tissues. However, hyperoxia may induce some pathological effects. We sought to assess organ damage associated with hyperoxia and its correlation with the production of reactive oxygen species (ROS) in a preclinical model of intra-abdominal sepsis. For this purpose, sepsis was induced in male, Sprague-Dawley rats by cecal ligation and puncture (CLP). We randomly assigned experimental animals to three groups: control (healthy animals), septic (CLP), and sham-septic (surgical intervention without CLP). At 18 h after CLP, septic (n = 39), sham-septic (n = 16), and healthy (n = 24) animals were placed within a sealed Plexiglas cage and randomly distributed into four groups for continuous treatment with 21%, 40%, 60%, or 100% oxygen for 24 h. At the end of the experimental period, we evaluated serum levels of cytokines, organ damage biomarkers, histological examination of brain and lung tissue, and ROS production in each surviving animal. We found that high oxygen concentrations increased IL-6 and biomarkers of organ damage levels in septic animals, although no relevant histopathological lung or brain damage was observed. Healthy rats had an increase in IL-6 and aspartate aminotransferase at high oxygen concentration. IL-6 levels, but not ROS levels, are correlated with markers of organ damage. In our study, the use of high oxygen concentrations in a clinically relevant model of intra-abdominal sepsis was associated with enhanced inflammation and organ damage. These findings were unrelated to ROS release into circulation. Hyperoxia could exacerbate sepsis-induced inflammation, and it could be by itself detrimental. Our study highlights the need of developing safer thresholds for oxygen therapy
Quasi-Exact Solvability and the direct approach to invariant subspaces
We propose a more direct approach to constructing differential operators that
preserve polynomial subspaces than the one based on considering elements of the
enveloping algebra of sl(2). This approach is used here to construct new
exactly solvable and quasi-exactly solvable quantum Hamiltonians on the line
which are not Lie-algebraic. It is also applied to generate potentials with
multiple algebraic sectors. We discuss two illustrative examples of these two
applications: an interesting generalization of the Lam\'e potential which
posses four algebraic sectors, and a quasi-exactly solvable deformation of the
Morse potential which is not Lie-algebraic.Comment: 17 pages, 3 figure
Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial
AIMS: The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin-kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (>/=1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. METHODS AND RESULTS: Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77-0.99; P = 0.032) and Type 2 (0.77, 0.61-0.97; P = 0.025), but not Type 4 MI. CONCLUSION: After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types
Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL
The EARS2 nuclear gene encodes mitochondrial glutamyl-tRNA synthetase, a member of the class I family of aminoacyl-tRNA synthetases (aaRSs) that plays a crucial role in mitochondrial protein biosynthesis by catalyzing the charging of glutamate to mitochondrial tRNA(Glu). Pathogenic EARS2 variants have been associated with a rare mitochondrial disorder known as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The targeted sequencing of 150 nuclear genes encoding respiratory chain complex subunits and proteins implicated in the oxidative phosphorylation (OXPHOS) function was performed. The oxygen consumption rate (OCR), and the extracellular acidification rate (ECAR), were measured. The enzymatic activities of Complexes I-V were analyzed spectrophotometrically. We describe a patient carrying two heterozygous EARS2 variants, c.376C>T (p.Gln126*) and c.670G>A (p.Gly224Ser), with infantile-onset disease and a severe clinical presentation. We demonstrate a clear defect in mitochondrial function in the patient's fibroblasts, suggesting the molecular mechanism underlying the pathogenicity of these EARS2 variants. Experimental validation using patient-derived fibroblasts allowed an accurate characterization of the disease-causing variants, and by comparing our patient's clinical presentation with that of previously reported cases, new clinical and radiological features of LTBL were identified, expanding the clinical spectrum of this disease
Epigenetic Silencing of Tumor Suppressor miR-124 Directly Supports STAT3 Activation in Cutaneous T-Cell Lymphoma
Increasing evidence supports a potential role for STAT3 as a tumor driver in cutaneous T-cell lymphomas (CTCL). The mechanisms leading to STAT3 activation are not fully understood; however, we recently found that miR-124, a known STAT3 regulator, is robustly silenced in MF tumor-stage and CTCL cells. OBJECTIVE: We studied here whether deregulation of miR-124 contributes to STAT3 pathway activation in CTCL. METHODS: We measured the effect of ectopic mir-124 expression in active phosphorylated STAT3 (p-STAT3) levels and evaluated the transcriptional impact of miR-124-dependent STAT3 pathway regulation by expression microarray analysis. RESULTS: We found that ectopic expression of miR-124 results in massive downregulation of activated STAT3 in different CTCL lines, which resulted in a significant alteration of genetic signatures related with gene transcription and proliferation such as MYC and E2F. CONCLUSIONS: Our study highlights the importance of the miR-124/STAT3 axis in CTCL and demonstrates that the STAT3 pathway is regulated through epigenetic mechanisms in these cells. Since deregulated STAT3 signaling has a major impact on CTCL initiation and progression, a better understanding of the molecular basis of the miR-124/STAT3 axis may provide useful information for future personalized therapies
Molecular dynamics simulation for modeling plasma spectroscopy
The ion-electron coupling properties for a ion impurity in an electron gas
and for a two component plasma are carried out on the basis of a regularized
electron-ion potential removing the short-range Coulomb divergence. This work
is largely motivated by the study of radiator dipole relaxation in plasmas
which makes a real link between models and experiments. Current radiative
property models for plasmas include single electron collisions neglecting
charge-charge correlations within the classical quasi-particle approach
commonly used in this field. The dipole relaxation simulation based on
electron-ion molecular dynamics proposed here will provide means to benchmark
and improve model developments. Benefiting from a detailed study of a single
ion imbedded in an electron plasma, the challenging two-component ion-electron
molecular dynamics simulations are proven accurate. They open new possibilities
to obtain reference lineshape data.Comment: submitted for publication in the proceedings of the International
Conference on Strongly Coupled Coulomb Systems, Journal of Physics
On new gravitational instantons describing creation of brane-worlds
By considering 5--dimensional cosmological models with a bulk filled with a
pressureless scalar field; equivalently dust matter, and a negative
cosmological constant, we have found a regular instantonic solution which is
free from any singularity at the origin of the extra--coordinate. This
instanton describes 5--dimensional asymptotically anti de Sitter wormhole, when
the bulk has a topology R times S^4. Compactified brane-world instantons which
are built up from such instantonic solution describe either a single brane or a
string of branes. Their analytical continuation to the pseudo--Riemannian
metric can give rise to either 4-dimensional inflating branes or solutions with
the same dynamical behaviour for extra--dimension and branes, in addition to
multitemporal solutions. Dust brane-world models with arbitrary dimensions (D
>= 5) as well as other spatial topologies are also briefly discussed.Comment: 11 pages, 3 figures, LaTeX2e, accepted for publication in Classical
and Quantum Gravit
A hyperbolic slicing condition adapted to Killing fields and densitized lapses
We study the properties of a modified version of the Bona-Masso family of
hyperbolic slicing conditions. This modified slicing condition has two very
important features: In the first place, it guarantees that if a spacetime is
static or stationary, and one starts the evolution in a coordinate system in
which the metric coefficients are already time independent, then they will
remain time independent during the subsequent evolution, {\em i.e.} the lapse
will not evolve and will therefore not drive the time lines away from the
Killing direction. Second, the modified condition is naturally adapted to the
use of a densitized lapse as a fundamental variable, which in turn makes it a
good candidate for a dynamic slicing condition that can be used in conjunction
with some recently proposed hyperbolic reformulations of the Einstein evolution
equations.Comment: 11 page
Quantum Mechanics on the cylinder
A new approach to deformation quantization on the cylinder considered as
phase space is presented. The method is based on the standard Moyal formalism
for R^2 adapted to (S^1 x R) by the Weil--Brezin--Zak transformation. The
results are compared with other solutions of this problem presented by
Kasperkovitz and Peev (Ann. Phys. vol. 230, 21 (1994)0 and by Plebanski and
collaborators (Acta Phys. Pol. vol. B 31}, 561 (2000)). The equivalence of
these three methods is proved.Comment: 21 pages, LaTe
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