Acetaminophen is a mild analgesic and antipyretic agent known to cause centrilobular hepatic necrosis at toxic doses. Although this may be due to a direct interaction of reactive acetaminophen ...metabolites with hepatocyte proteins, recent studies have suggested that cytotoxic mediators produced by parenchymal and nonparenchymal cells also contribute to the pathophysiological process. Nitric oxide is a highly reactive oxidant produced in the liver in response to inflammatory mediators. In the present studies we evaluated the role of nitric oxide in the pathophysiology of acetaminophen‐induced liver injury. Treatment of male Long Evans Hooded rats with acetaminophen (1 g/kg) resulted in damage to centrilobular regions of the liver and increases in serum transaminase levels, which were evident within 6 hours of treatment of the animals and reached a maximum at 24 hours. This was correlated with expression of inducible nitric oxide synthase (iNOS) protein in these regions. Hepatocytes isolated from both control and acetaminophen‐treated rats were found to readily synthesize nitric oxide in response to inflammatory stimuli. Cells isolated from acetaminophen‐treated rats produced more nitric oxide than cells from control animals. Production of nitric oxide by cells from both control and acetaminophen‐treated rats was blocked by aminoguanidine, a relatively specific inhibitor of iNOS. Arginine uptake and metabolism studies revealed that the inhibitory effects of aminoguanidine were due predominantly to inhibition of iNOS enzyme activity. Pretreatment of rats with aminoguanidine was found to prevent acetaminophen‐induced hepatic necrosis and increases in serum transaminase levels. This was associated with reduced nitric oxide production by hepatocytes. Inhibition of toxicity was not due to alterations in acetaminophen metabolism since aminoguanidine had no effect on hepatocyte cytochrome P4502E1 protein expression or N‐acetyl‐p‐benzoquinone‐imine formation. Taken together, these data demonstrate that nitric oxide is an important mediator of acetaminophen‐induced hepatotoxicity.
To accelerate the discovery of novel small molecule central nervous system (CNS) positron emission tomography (PET) ligands, we aimed to define a property space that would facilitate ligand design ...and prioritization, thereby providing a higher probability of success for novel PET ligand development. Toward this end, we built a database consisting of 62 PET ligands that have successfully reached the clinic and 15 radioligands that failed in late-stage development as negative controls. A systematic analysis of these ligands identified a set of preferred parameters for physicochemical properties, brain permeability, and nonspecific binding (NSB). These preferred parameters have subsequently been applied to several programs and have led to the successful development of novel PET ligands with reduced resources and timelines. This strategy is illustrated here by the discovery of the novel phosphodiesterase 2A (PDE2A) PET ligand 4-(3-18Ffluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-4-(trifluoromethyl)phenyl-1H-pyrazol-4-yl}imidazo5,1-f1,2,4triazine, 18FPF-05270430 (5).
The energy reconstruction at KASCADE-Grande is based on a combination of the shower size and the total muon number, which are both estimated for each individual air shower event. We present ...investigations where we employed a second method to reconstruct the primary energy using S(500), which are the charged particle densities inferred with the KASCADE-Grande detector at a distance of 500 m from the shower axis. We considered the attenuation of inclined showers by applying the “Constant Intensity Cut” method and we employed a simulation-derived calibration to convert the recorded S(500) into primary energy. We observed a systematic shift in the S(500)-derived energy compared with previously reported results obtained using the standard reconstruction technique. However, a comparison of the two methods based on simulated and measured data showed that this shift only appeared in the measured data. Our investigations showed that this shift was caused mainly by the inadequate description of the shape of the lateral density distribution in the simulations.
The toxicology of inhaled nitric oxide WEINBERGER, Barry; LASKIN, Debra L; HECK, Diane E ...
Toxicological sciences,
2001, 2001-Jan, 2001-1-1, 20010101, Letnik:
59, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Inhaled nitric oxide is a targeted pulmonary vasodilator that improves clinical outcomes for newborn patients with persistent pulmonary hypertension of the newborn, and may be effective in treating ...some premature patients with acute respiratory distress syndrome or lung disease of prematurity. Nitric oxide is now recognized as playing an important role in the regulation of diverse physiological processes. However, the pharmacological properties of inhaled nitric oxide are not easy to separate from its toxicological effects. For example, the intended effect of inhaled nitric oxide, vasodilation in the lung, is mediated, in part, by increased cellular cyclic GMP (cGMP). However, increased cGMP can also interfere with normal cellular proliferation. Nitric oxide has also been shown to cause DNA strand breaks and/or base alterations that are potentially mutagenic. Inhaled nitric oxide can rapidly react with oxygen in the lung to form nitrogen dioxide, which is a potent pulmonary irritant. Nitric oxide also reacts with superoxide anion to form peroxynitrite, a cytotoxic oxidant that can interfere with surfactant functioning. The overall effect of inhaled nitric oxide in potentiating or attenuating inflammation and oxidative damage in diseased lung is dependent on the dose administered. Furthermore, despite rapid inactivation by circulating hemoglobin, inhaled nitric oxide exerts effects outside the lung, including blocking platelet aggregation, causing methemoglobinemia, and possibly inducing extrapulmonary vasodilation. The toxicology of inhaled nitric oxide is not completely understood and must be considered in the design of protocols for its safe and effective clinical use.
Using data measured by the KASCADE-Grande air shower array, an upper limit to the flux of ultra-high energy gamma-rays in the primary cosmic-ray flux is determined. KASCADE-Grande measures the ...electromagnetic and muonic components for individual air showers in the energy range from 10 PeV up to 1 EeV. The analysis is performed by selecting air showers with low muon contents. A preliminary result on the 90% C.L. upper limit to the relative intensity of gamma-ray with respect to cosmic ray primaries is presented and compared with limits reported by other measurements.
Fluid licking in mice is an example of a rhythmic behavior thought to be under the control of a central pattern generator. Inbred strains of mice have been shown to differ in mean or modal interlick ...interval (ILI) duration, suggesting a genetic‐based variation. We investigated water licking in the commonly used inbred strains C57BL/6J (B6) and DBA/2J (D2), using a commercially available contact lickometer. Results from 20‐min test sessions indicated that D2 mice lick at a faster rate than B6 mice (10.6 licks/s vs. 8.5 licks/s), based on analysis of the distribution of short‐duration ILIs (50–160 ms). This strain difference was independent of sex, extent of water deprivation or total number of licks. D2 mice also displayed a faster lick rate when the strains were tested with a series of brief (5 s) trials. However, when ingestion over the entire 20‐min session was analyzed, it was evident that D2 mice had an overall slower rate of ingestion than B6 mice. This was because of the tendency for D2 mice to have more very long pauses (>30 s) between sequences of licking bursts. Overall, it appeared that D2 mice licked more efficiently, ingesting more rapidly during excursions to the spout that were fewer and farther between.
Air shower simulation programs are essential tools for the analysis of data from cosmic ray experiments and for planning the layout of new detectors. They are used to estimate the energy and mass of ...the primary particle. Unfortunately the model uncertainties translate directly into systematic errors in the energy and mass determination. Aiming at energies>10
19 eV, the models have to be extrapolated far beyond the energies available at accelerators. On the other hand, hybrid measurement of ground particle densities and calorimetric shower energy, as will be provided by the Pierre Auger Observatory, will strongly constrain shower models. While the main uncertainty of contemporary models comes from our poor knowledge of the (soft) hadronic interactions at high energies, also electromagnetic interactions, low-energy hadronic interactions and the particle transport influence details of the shower development. We review here the physics processes and some of the computational techniques of air shower models presently used for highest energies, and discuss the properties and limitations of the models.
Saccharomyces cerevisiae carries approximately 150 copies of rDNA in tandem repeats. It was found that the absence of an essential subunit of RNA polymerase I (Pol I) in rpa135 deletion mutants ...triggers a gradual decrease in rDNA repeat number to about one-half the normal level. Reintroduction of the missing RPA135 gene induced a gradual increase in repeat number back to the normal level. Gene FOB1 was shown to be essential for both the decrease and increase of rDNA repeats. FOB1 was shown previously to be required for replication fork blocking (RFB) activity at RFB site in rDNA and for recombination hot-spot (HOT1) activity. Thus, DNA replication fork blockage appears to stimulate recombination and play an essential role in rDNA expansion/contraction and sequence homogenization, and possibly, in the instability of repeated sequences in general. RNA Pol I, on the other hand, appears to control repeat numbers, perhaps by stabilizing rDNA with the normal repeat numbers as a stable nucleolar structure.
To summarize and classify the evidence for the use of endovascular techniques in the treatment of patients with acute ischemic stroke.
Recommendations previously published by the American Heart ...Association (AHA) (Guidelines for the early management of adults with ischemic stroke (Circulation 2007) and Scientific statement indications for the performance of intracranial endovascular neurointerventional procedures (Circulation 2009)) were vetted and used as a foundation for the current process. Building on this foundation, a critical review of the literature was performed to evaluate evidence supporting the endovascular treatment of acute ischemic stroke. The assessment was based on guidelines for evidence based medicine proposed by the Stroke Council of the AHA and the University of Oxford, Centre for Evidence Based Medicine (CEBM). Procedural safety, technical efficacy and impact on patient outcomes were specifically examined.
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