Effects on the maternofetal unit of the rabbit model after substitution of the amniotic fluid with perfluorocarbons

Objectives: Exchanging amniotic fluid (AF) with perfluorocarbon (PFC) may serve as a medium for fetoscopic surgery. This study evaluates the distribution and physiologic effects of intraamniotic PFC as a medium for fetoscopy. Methods: Fetuses of 17 pregnant rabbits underwent either exchange of the AF with PFC, electrolyte solution (ES), or control. The quality of vision during fetoscopy was assessed in AF and PFC. After 6 h, we determined the distribution of PFC in the maternofetal unit. Results: Quality of vision during fetoscopy was better in PFC than with AF. There was no difference in fetal survival between the study groups. PFC was demonstrated on X-ray in the pharynx of 4 fetuses, and the esophagus in 1. Conclusions: PFC provided an ideal medium for fetoscopy without fetal compromise. Copyright (c) 2005 S. Karger AG, Basel

Tautomerism in large databases

We have used the Chemical Structure DataBase (CSDB) of the NCI CADD Group, an aggregated collection of over 150 small-molecule databases totaling 103.5 million structure records, to conduct tautomerism analyses on one of the largest currently existing sets of real (i.e. not computer-generated) compounds. This analysis was carried out using calculable chemical structure identifiers developed by the NCI CADD Group, based on hash codes available in the chemoinformatics toolkit CACTVS and a newly developed scoring scheme to define a canonical tautomer for any encountered structure. CACTVS’s tautomerism definition, a set of 21 transform rules expressed in SMIRKS line notation, was used, which takes a comprehensive stance as to the possible types of tautomeric interconversion included. Tautomerism was found to be possible for more than 2/3 of the unique structures in the CSDB. A total of 680 million tautomers were calculated from, and including, the original structure records. Tautomerism overlap within the same individual database (i.e. at least one other entry was present that was really only a different tautomeric representation of the same compound) was found at an average rate of 0.3% of the original structure records, with values as high as nearly 2% for some of the databases in CSDB. Projected onto the set of unique structures (by FICuS identifier), this still occurred in about 1.5% of the cases. Tautomeric overlap across all constituent databases in CSDB was found for nearly 10% of the records in the collection

Submucosal diclofenac for acute postoperative pain in third molar surgery: A randomized, controlled clinical trial

Diclofenac sodium is a widely used nonsteroidal anti-inflammatory drug (NSAID) for relief of inflammatory pain. A recent formulation combines this drug with hydroxypropyl-β-cyclodextrin (HPβCD) to improve its solubility and to enable subcutaneous administration. Previous studies confirmed the efficacy of this combination. This study’s aim was to evaluate the efficacy, safety, and local tolerability of diclofenac HPβCD administered as a local submucosal injection prior to lower third molar surgery. We conducted a prospective, randomized, double-blind, placebo-controlled, parallel-group phase II single-center study. Seventy-five patients requiring mandibular third molar surgery were randomized into 1 of 5 groups: 5 mg/1 mL diclofenac HPβCD, 12.5 mg/1 mL diclofenac HPβCD, 25 mg/1 mL diclofenac HPβCD, 50 mg/1 mL diclofenac HPβCD, or 1 mL placebo. The respective study drug was injected into the mucosal tissue surrounding the surgical site prior to surgery following achievement of local anesthesia. The primary outcome measure was the area under the curve (AUC) of cumulative pain scores from end of surgery to 6 h postsurgery. This demonstrated a global treatment effect between the active groups and placebo, hence confirming the study drug’s efficacy (P = 0.0126). Secondary outcome measures included the time until onset of pain and the time until patients required rescue medication, both showing statistical significance of the study drug compared to placebo (P < 0.0161 and P < 0.0001, respectively). The time until rescue medication ranged between 7.8 h (for 25 mg/1 mL diclofenac HPβCD) and 16 h (for 50 mg/1 mL diclofenac HPβCD). Interestingly, the 5-mg/1-mL solution appeared superior to the 12.5-mg/1-mL and 25-mg/1-mL solutions (time until rescue medication = 12.44 h). A total of 14% of patients experienced minor adverse drug reactions (ADRs), of which 2 cases demonstrated flap necrosis. These resolved without further intervention. The study results overall indicate efficacy, safety, and relative tolerability of diclofenac HPβCD used locally as a submucosal injection prior to third molar surgery (ClinicalTrials.gov NCT01706588)

Acute Ethanol Effects on Focal Cerebral Ischemia in Nonfasted Rats

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66417/1/j.1530-0277.1997.tb03832.x.pd

Global Analysis of the Higgs Candidate with Mass ~ 125 GeV

We analyze the properties of the Higgs candidate with mass ~ 125 GeV discovered by the CMS and ATLAS Collaborations, constraining the possible deviations of its couplings from those of a Standard Model Higgs boson. The CMS, ATLAS and Tevatron data are compatible with Standard Model couplings to massive gauge bosons and fermions, and disfavour several types of composite Higgs models unless their couplings resemble those in the Standard Model. We show that the couplings of the Higgs candidate are consistent with a linear dependence on particle masses, scaled by the electroweak scale ~ 246 GeV, the power law and the mass scale both having uncertainties ~ 20%.Comment: 22 pages, 9 figures, v2 incorporates experimental data released during July 2012 and corrected (and improved) treatment of mass dependence of coupling

Towards multi-scale dynamics on the baryonic branch of Klebanov-Strassler

We construct explicitly a new class of backgrounds in type-IIB supergravity which generalize the baryonic branch of Klebanov-Strassler. We apply a solution-generating technique that, starting from a large class of solutions of the wrapped-D5 system, yields the new solutions, and then proceed to study in detail their properties, both in the IR and in the UV. We propose a simple intuitive field theory interpretation of the rotation procedure and of the meaning of our new solutions within the Papadopoulos-Tseytlin ansatz, in particular in relation to the duality cascade in the Klebanov-Strassler solution. The presence in the field theory of different VEVs for operators of dimensions 2, 3 and 6 suggests that this is an important step towards the construction of the string dual of a genuinely multi-scale (strongly coupled) dynamical model.Comment: 37 pages, 7 figures. References added, version to appear in JHE

Phenomenology and Cosmology of an Electroweak Pseudo-Dilaton and Electroweak Baryons

In many strongly-interacting models of electroweak symmetry breaking the lowest-lying observable particle is a pseudo-Goldstone boson of approximate scale symmetry, the pseudo-dilaton. Its interactions with Standard Model particles can be described using a low-energy effective nonlinear chiral Lagrangian supplemented by terms that restore approximate scale symmetry, yielding couplings of the pseudo-dilaton that differ from those of a Standard Model Higgs boson by fixed factors. We review the experimental constraints on such a pseudo-dilaton in light of new data from the LHC and elsewhere. The effective nonlinear chiral Lagrangian has Skyrmion solutions that may be identified with the `electroweak baryons' of the underlying strongly-interacting theory, whose nature may be revealed by the properties of the Skyrmions. We discuss the finite-temperature electroweak phase transition in the low-energy effective theory, finding that the possibility of a first-order electroweak phase transition is resurrected. We discuss the evolution of the Universe during this transition and derive an order-of-magnitude lower limit on the abundance of electroweak baryons in the absence of a cosmological asymmetry, which suggests that such an asymmetry would be necessary if the electroweak baryons are to provide the cosmological density of dark matter. We revisit estimates of the corresponding spin-independent dark matter scattering cross section, with a view to direct detection experiments.Comment: 34 pages, 4 figures, additional references adde

Widespread Regulation of miRNA Biogenesis at the Dicer Step by the Cold-Inducible RNA-Binding Protein, RBM3

MicroRNAs (miRNAs) play critical roles in diverse cellular events through their effects on translation. Emerging data suggest that modulation of miRNA biogenesis at post-transcriptional steps by RNA-binding proteins is a key point of regulatory control over the expression of some miRNAs and the cellular processes they influence. However, the extent and conditions under which the miRNA pathway is amenable to regulation at posttranscriptional steps are poorly understood. Here we show that RBM3, a cold-inducible, developmentally regulated RNA-binding protein and putative protooncogene, is an essential regulator of miRNA biogenesis. Utilizing miRNA array, Northern blot, and PCR methods, we observed that over 60% of miRNAs detectable in a neuronal cell line were significantly downregulated by knockdown of RBM3. Conversely, for select miRNAs assayed by Northern blot, induction of RBM3 by overexpression or mild hypothermia increased their levels. Changes in miRNA expression were accompanied by changes in the levels of their ∼70 nt precursors, whereas primary transcript levels were unaffected. Mechanistic studies revealed that knockdown of RBM3 does not reduce Dicer activity or impede transport of pre-miRNAs into the cytoplasm. Rather, we find that RBM3 binds directly to ∼70 nt pre-miRNA intermediates and promotes / de-represses their ability as larger ribonucleoproteins (pre-miRNPs) to associate with active Dicer complexes. Our findings suggest that the processing of a majority of pre-miRNPs by Dicer is subject to an intrinsic inhibitory influence that is overcome by RBM3 expression. RBM3 may thus orchestrate changes in miRNA expression during hypothermia and other cellular stresses, and in the euthermic contexts of early development, differentiation, and oncogenesis where RBM3 expression is highly elevated. Additionally, our data suggest that temperature-dependent changes in miRNA expression mediated by RBM3 may contribute to the therapeutic effects of hypothermia, and are an important variable to consider in in vitro studies of translation-dependent cellular events

Systematic review and meta-analysis of therapeutic hypothermia in animal models of spinal cord injury

Therapeutic hypothermia is a clinically useful neuroprotective therapy for cardiac arrest and neonatal hypoxic ischemic encephalopathy and may potentially be useful for the treatment of other neurological conditions including traumatic spinal cord injury (SCI). The pre-clinical studies evaluating the effectiveness of hypothermia in acute SCI broadly utilise either systemic hypothermia or cooling regional to the site of injury. The literature has not been uniformly positive with conflicting studies of varying quality, some performed decades previously.In this study, we systematically review and meta-analyse the literature to determine the efficacy of systemic and regional hypothermia in traumatic SCI, the experimental conditions influencing this efficacy, and the influence of study quality on outcome. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of the (i) reporting of efficacy of hypothermia on functional outcome (ii) number of animals and (iii) mean outcome and variance in each group.Systemic hypothermia improved behavioural outcomes by 24.5% (95% CI 10.2 to 38.8) and a similar magnitude of improvement was seen across a number of high quality studies. The overall behavioural improvement with regional hypothermia was 26.2%, but the variance was wide (95% CI -3.77 to 56.2). This result may reflect a preponderance of positive low quality data, although a preferential effect of hypothermia in ischaemic models of injury may explain some of the disparate data. Sufficient heterogeneity was present between studies of regional hypothermia to reveal a number of factors potentially influencing efficacy, including depth and duration of hypothermia, animal species, and neurobehavioural assessment. However, these factors could reflect the influence of earlier lower quality literature.Systemic hypothermia appears to be a promising potential method of treating acute SCI on the basis of meta-analysis of the pre-clinical literature and the results of high quality animal studies