A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis

<p>Abstract</p> <p>Objective</p> <p>We conducted a single-centre, randomised, double-blinded, placebo-controlled phase II clinical study to test safety and efficacy of a 12-week therapy with low-dose (700 mg/daily) or high-dose (2800 mg/daily) of NAC.</p> <p>Methods</p> <p>Twenty-one patients (ΔF508 homo/heterozygous, FEV₁> 40% pred.) were included in the study. After a 3-weeks placebo run-in phase, 11 patients received low-dose NAC, and 10 patients received high-dose NAC. Outcomes included safety and clinical parameters, inflammatory (total leukocyte numbers, cell differentials, TNF-α, IL-8) measures in induced sputum, and concentrations of extracellular glutathione in induced sputum and blood.</p> <p>Results</p> <p>High-dose NAC was a well-tolerated and safe medication. High-dose NAC did not alter clinical or inflammatory parameters. However, extracellular glutathione in induced sputum tended to increase on high-dose NAC.</p> <p>Conclusions</p> <p>High-dose NAC is a well-tolerated and safe medication for a prolonged therapy of patients with CF with a potential to increase extracellular glutathione in CF airways.</p

The Proprioceptive Map of the Arm Is Systematic and Stable, but Idiosyncratic

Visual and somatosensory signals participate together in providing an estimate of the hand's spatial location. While the ability of subjects to identify the spatial location of their hand based on visual and proprioceptive signals has previously been characterized, relatively few studies have examined in detail the spatial structure of the proprioceptive map of the arm. Here, we reconstructed and analyzed the spatial structure of the estimation errors that resulted when subjects reported the location of their unseen hand across a 2D horizontal workspace. Hand position estimation was mapped under four conditions: with and without tactile feedback, and with the right and left hands. In the task, we moved each subject's hand to one of 100 targets in the workspace while their eyes were closed. Then, we either a) applied tactile stimulation to the fingertip by allowing the index finger to touch the target or b) as a control, hovered the fingertip 2 cm above the target. After returning the hand to a neutral position, subjects opened their eyes to verbally report where their fingertip had been. We measured and analyzed both the direction and magnitude of the resulting estimation errors. Tactile feedback reduced the magnitude of these estimation errors, but did not change their overall structure. In addition, the spatial structure of these errors was idiosyncratic: each subject had a unique pattern of errors that was stable between hands and over time. Finally, we found that at the population level the magnitude of the estimation errors had a characteristic distribution over the workspace: errors were smallest closer to the body. The stability of estimation errors across conditions and time suggests the brain constructs a proprioceptive map that is reliable, even if it is not necessarily accurate. The idiosyncrasy across subjects emphasizes that each individual constructs a map that is unique to their own experiences

The ROS Scavenger, NAC, Regulates Hepatic Vα14iNKT Cells Signaling during Fas mAb-Dependent Fulminant Liver Failure

Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Vα14iNKT cell activation, IFN-γ signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Vα14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jα18−/− mice that inhibited apoptosis, nitrotyrosine formation, IFN-γ signaling and effector functions. In summary, we propose a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating Th1 signaling in Vα14iNKT cells to promote the development of FLF. Therefore, our study provides critical new insights into how NAC, a ROS scavenger, regulates Th1 signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses

Carbon dioxide reduction in the building life cycle: a critical review

The construction industry is known to be a major contributor to environmental pressures due to its high energy consumption and carbon dioxide generation. The growing amount of carbon dioxide emissions over buildings’ life cycles has prompted academics and professionals to initiate various studies relating to this problem. Researchers have been exploring carbon dioxide reduction methods for each phase of the building life cycle – from planning and design, materials production, materials distribution and construction process, maintenance and renovation, deconstruction and disposal, to the material reuse and recycle phase. This paper aims to present the state of the art in carbon dioxide reduction studies relating to the construction industry. Studies of carbon dioxide reduction throughout the building life cycle are reviewed and discussed, including those relating to green building design, innovative low carbon dioxide materials, green construction methods, energy efficiency schemes, life cycle energy analysis, construction waste management, reuse and recycling of materials and the cradle-to-cradle concept. The review provides building practitioners and researchers with a better understanding of carbon dioxide reduction potential and approaches worldwide. Opportunities for carbon dioxide reduction can thereby be maximised over the building life cycle by creating environmentally benign designs and using low carbon dioxide materials

Cyanobacterial lipopolysaccharides and human health – a review

Cyanobacterial lipopolysaccharide/s (LPS) are frequently cited in the cyanobacteria literature as toxins responsible for a variety of heath effects in humans, from skin rashes to gastrointestinal, respiratory and allergic reactions. The attribution of toxic properties to cyanobacterial LPS dates from the 1970s, when it was thought that lipid A, the toxic moiety of LPS, was structurally and functionally conserved across all Gram-negative bacteria. However, more recent research has shown that this is not the case, and lipid A structures are now known to be very different, expressing properties ranging from LPS agonists, through weak endotoxicity to LPS antagonists. Although cyanobacterial LPS is widely cited as a putative toxin, most of the small number of formal research reports describe cyanobacterial LPS as weakly toxic compared to LPS from the Enterobacteriaceae. We systematically reviewed the literature on cyanobacterial LPS, and also examined the much lager body of literature relating to heterotrophic bacterial LPS and the atypical lipid A structures of some photosynthetic bacteria. While the literature on the biological activity of heterotrophic bacterial LPS is overwhelmingly large and therefore difficult to review for the purposes of exclusion, we were unable to find a convincing body of evidence to suggest that heterotrophic bacterial LPS, in the absence of other virulence factors, is responsible for acute gastrointestinal, dermatological or allergic reactions via natural exposure routes in humans. There is a danger that initial speculation about cyanobacterial LPS may evolve into orthodoxy without basis in research findings. No cyanobacterial lipid A structures have been described and published to date, so a recommendation is made that cyanobacteriologists should not continue to attribute such a diverse range of clinical symptoms to cyanobacterial LPS without research confirmation

Optimal point of insertion of the needle in neuraxial blockade using a midline approach: study in a geometrical model

Mark Vogt,1 Dennis J van Gerwen,2 John J van den Dobbelsteen,2 Martin Hagenaars,3 1Department of Anesthesiology, Erasmus MC Sophia Children Hospital, Rotterdam, the Netherlands; 2Department of Biomechanical Engineering, Delft University of Technology, Delft, the Netherlands; 3Department of Anesthesiology, Canisius Wilhelmina Ziekenhuis, Nijmegen, the Netherlands Abstract: Performance of neuraxial blockade using a midline approach can be technically difficult. It is therefore important to optimize factors that are under the influence of the clinician performing the procedure. One of these factors might be the chosen point of insertion of the needle. Surprisingly few data exist on where between the tips of two adjacent spinous processes the needle should be introduced. A geometrical model was adopted to gain more insight into this issue. Spinous processes were represented by parallelograms. The length, the steepness relative to the skin, and the distance between the parallelograms were varied. The influence of the chosen point of insertion of the needle on the range of angles at which the epidural and subarachnoid space could be reached was studied. The optimal point of insertion was defined as the point where this range is the widest. The geometrical model clearly demonstrated, that the range of angles at which the epidural or subarachnoid space can be reached, is dependent on the point of insertion between the tips of the adjacent spinous processes. The steeper the spinous processes run, the more cranial the point of insertion should be. Assuming that the model is representative for patients, the performance of neuraxial blockade using a midline approach might be improved by choosing the optimal point of insertion. Keywords: neuraxial blockade, midline approach, optimal point of insertion, geometrical mode

Inhibition of Na+/K(+)-ATPase may be one mechanism contributing to potassium efflux and cell shrinkage in CD95-induced apoptosis.

To investigate the involvement of K+ efflux in apoptotic cell shrinkage, we monitored efflux of the K+ congener, 86Rb+, and cell volume during CD95-mediated apoptosis in Jurkat cells. An anti-CD95 antibody caused apoptosis associated with intracellular GSH depletion, a significant increase in 86Rb+ efflux, and a decrease in cell volume compared with control cells. Preincubating Jurkat cells with Val-Ala-Asp-chloromethylketone (VAD-cmk), an inhibitor of caspase proteases, prevented the observed 86Rb+ efflux and cell shrinkage induced by the anti-CD95 antibody. A wide range of inhibitors against most types of K+ channels could not inhibit CD95-mediated efflux of 86Rb+, however, the uptake of 86Rb+ by Jurkat cells was severely compromised when treated with anti-CD95 antibody. Uptake of 86Rb+ in Jurkat cells was sensitive to ouabain (a specific Na+/K(+)-ATPase inhibitor), demonstrating Na+/K(+)-ATPase dependent K+ uptake. Ouabain induced significant 86Rb+ efflux in untreated cells, as well as it seemed to compete with 86Rb+ efflux induced by the anti-CD95 antibody, supporting a role for Na+/K(+)-ATPase in the CD95-mediated 86Rb+ efflux. Ouabain treatment of Jurkat cells did not cause a reduction in cell volume, although together with the anti-CD95 antibody, ouabain potentiated CD95-mediated cell shrinkage. This suggests that the observed inhibition of Na+/K(+)-ATPase during apoptosis may also facilitate apoptotic cell shrinkage