Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. ...Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension. It is an attractive therapeutic, due to its dual action on receptors alpha and beta and its possible peripheral intravenous infusion. There are few data in the literature on the use of ephedrine in the context of pediatric anesthesia. The actual recommended dose of ephedrine (0.1 to 0.2 mg/Kg) frequently leads to a therapeutic failure in neonates and infants up to 6 months of age. The use of higher doses would probably lead to a better correction of hypotension in this population. The objective of our project is to determine the optimal dose of ephedrine for the treatment of hypotension after induction of general anesthesia with sevoflurane, in neonates and infants up to 6 months of age.
The ephedrine study is a prospective, randomized, open-label, controlled, dose-escalation trial. The dose escalation consists of 6 successive cohorts of 20 subjects. The doses studied are 0.6, 0.8, 1, 1.2, and 1.4 mg/kg. The dose chosen as the reference is 0.1 mg/kg, the actual recommended dose. Neonates and infants younger than 6 months, males and females, including preterm babies who undergo a surgery with general anesthesia inducted with sevoflurane were eligible. Parents of the subject were informed. Then, the subjects were randomized if presenting a decrease in mean blood pressure superior to 20% of their initial mean blood pressure (before induction of anesthesia), despite a vascular filling with sodium chloride 0.9%. The primary outcome is the success of the therapy defined as an mBP superior to 80% of the baseline mBP (prior to anesthesia) within 10 min post ephedrine administration. The subjects were followed-up for 3 days postanesthesia.
This study is the first randomized, controlled trial intending to determine the optimal dose of ephedrine to treat hypotension in neonates and infants below 6 months old.
ClinicalTrials.gov NCT02384876 . Registered on March 2015.
High-throughput sequencing of two trees with apple decline revealed the presence of three bunya-like viruses: apple rubbery wood-associated viruses 1 and 2 (ARWaV-1, ARWaV-2) and citrus concave ...gum-associated virus (CCGaV), which previously had only been observed in citrus trees. The apple and citrus CCGaV isolates shared over 97% sequence identity. A global collection of apple trees was screened by RT-PCR for these viruses. Twenty-seven of 30 trees were infected with one or more bunya-like virus. Sequence data revealed some diversity among isolates but no geographic grouping. Additional work will be needed to determine if any of these viruses contribute to apple decline.
Activation of the p53 pathway mediates cellular responses to diverse forms of stress. Here we report that the p53 target gene p21(CIP1) is regulated by stress at post-initiation steps through ...conversion of paused RNA polymerase II (RNAP II) into an elongating form. High-resolution chromatin immunoprecipitation assays (ChIP) demonstrate that p53-dependent activation of p21(CIP1) transcription after DNA damage occurs concomitantly with changes in RNAP II phosphorylation status and recruitment of the elongation factors DSIF (DRB Sensitivity-Inducing Factor), P-TEFb (Positive Transcription Elongation Factor b), TFIIH, TFIIF, and FACT (Facilitates Chromatin Transcription) to distinct regions of the p21(CIP1) locus. Paradoxically, pharmacological inhibition of P-TEFb leads to global inhibition of mRNA synthesis but activation of the p53 pathway through p53 accumulation, expression of specific p53 target genes, and p53-dependent apoptosis. ChIP analyses of p21(CIP1) activation in the absence of functional P-TEFb reveals the existence of two distinct kinases that phosphorylate Ser5 of the RNAP II C-terminal domain (CTD). Importantly, CTD phosphorylation at Ser2 is not required for p21(CIP1) transcription, mRNA cleavage, or polyadenylation. Furthermore, recruitment of FACT requires CTD kinases, yet FACT is dispensable for p21(CIP1) expression. Thus, select genes within the p53 pathway bypass the requirement for P-TEFb and RNAP II phosphorylation to trigger a cellular response to inhibition of global mRNA synthesis.
Abstract L-type calcium channels play an essential role in synaptic activity-dependent gene expression and are implicated in long-term alterations in synaptic efficacy underlying learning and memory ...in the hippocampus. The two principal pore-forming subunits of L-type Ca2+ channels expressed in neurons are the Cav 1.2 (α1C ) or Cav 1.3 (α1D ) subtypes. Experimental evidence suggests that calcium entry through Cav 1.2 and Cav 1.3 Ca2+ channels occurs in close proximity to key signalling molecules responsible for triggering signalling pathways leading to transcriptional responses. Determining the subcellular distribution of Cav 1.2 and Cav 1.3 L-type channels in neurons is clearly important for unravelling the molecular mechanisms underlying long-term alterations in neuronal function. In this study, we used immunogold-labelling techniques and electron-microscopy (EM) to analyse the subcellular distribution and density of both Cav 1.2 and Cav 1.3 Ca2+ channels in rat hippocampal CA1 pyramidal cells in vivo . We confirm that both Cav 1.2 and Cav 1.3 channel subtypes are predominantly but not exclusively located in postsynaptic dendritic processes and somata. Both Cav 1.2 and Cav 1.3 are distributed throughout the dendritic tree. However, the smallest (distal) dendritic processes and spines have proportionally more calcium channels inserted into their plasma membrane than located within cytoplasmic compartments indicating the potential targeting of calcium channels to microdomains within neurons. Cav 1.2 and Cav 1.3 Ca2+ channels are located at the postsynaptic density and also at extra-synaptic sites. The location of L-type Cav 1.2 and Cav 1.3 channels in distal dendrites and spines would thus place them at appropriate sites where they could initiate synapse to nucleus signalling.
We present time-resolved broadband observations of the quasar 3C 279 obtained from multi-wavelength campaigns conducted during the first two years of the Fermi Gamma-ray Space Telescope mission. ...While investigating the previously reported gamma -ray/optical flare accompanied by a change in optical polarization, we found that the optical emission appears to be delayed with respect to the gamma -ray emission by about 10 days. X-ray observations reveal a pair of "isolated" flares separated by ~90 days, with only weak gamma -ray/optical counterparts. The spectral structure measured by Spitzer reveals a synchrotron component peaking in the mid-infrared band with a sharp break at the far-infrared band during the gamma -ray flare, while the peak appears in the millimeter (mm)/submillimeter (sub-mm) band in the low state. Selected spectral energy distributions are fitted with leptonic models including Comptonization of external radiation produced in a dusty torus or the broad-line region. Adopting the interpretation of the polarization swing involving propagation of the emitting region along a curved trajectory, we can explain the evolution of the broadband spectra during the gamma -ray flaring event by a shift of its location from ~1 pc to ~4 pc from the central black hole. On the other hand, if the gamma -ray flare is generated instead at sub-pc distance from the central black hole, the far-infrared break can be explained by synchrotron self-absorption. We also model the low spectral state, dominated by the mm/sub-mm peaking synchrotron component, and suggest that the corresponding inverse-Compton component explains the steady X-ray emission.
Endometrosis is a degenerative chronic process, characterized by paramount fibrosis development in mare endometrium. This condition is one of the major causes of subfertility/infertility in mares. As ...in other organs, fibrosis might be a pathologic sequel of many chronic inflammatory diseases. However, aetiology and physiopathologic mechanisms involved in endometrial fibrosis are still controversial. This review presents new hypotheses based on our newest data. As the first line of innate immune defence, systemic neutrophils arrive in the uterus at mating or in the presence of pathogens. A novel paradigm is that neutrophils cast out their DNA in response to infectious stimuli and form neutrophil extracellular traps (NETs). We have shown that bacterial strains of Streptococcus zooepidemicus, Escherichia coli or Staphylococcus capitis, known to cause endometritis in mares were able to induce NETs release in vitro by equine PMN to different extents. An intriguing dilemma is the dual action of NETs. While NETs play a desirable role fighting micro‐organisms in mare uterus, they may also contribute to endometrial fibrosis. A long‐term in vitro exposure of mare endometrium explants to NETs components (myeloperoxidase, elastase and cathepsin G) up‐regulated fibrosis markers TGFβ and Tissue inhibitor of metalloproteinase (TIMP‐1). Also, pro‐fibrotic cytokines regulated collagen deposition and fibrosis. Changes in expression of connective tissue growth factor (CTGF), interleukins (IL)1‐α, IL‐1β, IL‐6 and receptors in endometrium with different degrees of fibrosis and/or inflammation were observed. A putative role of CTGF, IL and NETs components in endometrosis development should be considered. Additionally, we speculate that in sustained endometritis in mares, prostaglandins may not only cause early luteolysis or early pregnancy loss, but may also be related to endometrial fibrosis pathogenesis by stimulating collagen deposition.
With frequent flaring activity of its relativistic jets, Cygnus X-3 (Cyg X-3) is one of the most active microquasars and is the only Galactic black hole candidate with confirmed high-energy γ-ray ...emission, thanks to detections by Fermi Large Area Telescope (Fermi/LAT) and AGILE. In 2011, Cyg X-3 was observed to transit to a soft X-ray state, which is known to be associated with high-energy γ-ray emission. We present the results of a multiwavelength campaign covering a quenched state, when radio emission from Cyg X-3 is at its weakest and the X-ray spectrum is very soft. A giant (∼20 Jy) optically thin radio flare marks the end of the quenched state, accompanied by rising non-thermal hard X-rays. Fermi/LAT observations (E≥ 100 MeV) reveal renewed γ-ray activity associated with this giant radio flare, suggesting a common origin for all non-thermal components. In addition, current observations unambiguously show that the γ-ray emission is not exclusively related to the rare giant radio flares. A three-week period of γ-ray emission is also detected when Cyg X-3 was weakly flaring in radio, right before transition to the radio quenched state. No γ-rays are observed during the ∼1-month long quenched state, when the radio flux is weakest. Our results suggest transitions into and out of the ultrasoft X-ray (radio-quenched) state trigger γ-ray emission, implying a connection to the accretion process, and also that the γ-ray activity is related to the level of radio flux (and possibly shock formation), strengthening the connection to the relativistic jets.
Context. The microquasar Cygnus X-3 was detected at high energies by the gamma-ray space telescopes AGILE and Fermi. The gamma-ray emission is transient, modulated with the orbital period and seems ...related to major radio flares, i.e. to the relativistic jet. The GeV gamma-ray flux can be substantially attenuated by internal absorption with the ambient X-rays. Aims. We examine quantitatively the effect of pair production in Cygnus X-3 and put constraints on the location of the gamma-ray source. Methods. Cygnus X-3 exhibits complex temporal and spectral patterns in X-rays. During gamma-ray flares, the X-ray emission can be approximated by a bright disk black-body component and a non-thermal tail extending in hard X-rays, which is possibly related to a corona above the disk. We calculate numerically the exact optical depth for gamma rays above a standard accretion disk. Emission and absorption in the corona are also investigated. Results. GeV gamma rays are significantly absorbed by soft X-rays emitted from the inner parts of the accretion disk. The absorption pattern is complex and anisotropic. Isotropization of X-rays caused by Thomson scattering in the companion-star wind tends to increase the gamma-ray opacity. Gamma rays from the corona suffer from strong absorption by photons from the disk and cannot explain the observed high-energy emission, unless the corona is unrealistically extended. Conclusions. The lack of an absorption feature in the GeV emission indicates that high-energy gamma rays should be located at a minimum distance ~108−1010 cm from the compact object. The gamma-ray emission is unlikely to have a coronal origin.
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