Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency.

BACKGROUND: Cisplatin neuro-, oto-, and nephrotoxicity are major problems in children with malignant tumors, including medulloblastoma, negatively impacting educational achievement, socioemotional development, and overall quality of life. The blood-labyrinth barrier is somewhat permeable to cisplatin, and sensory hair cells and cochlear supporting cells are highly sensitive to this toxic drug. Several chemoprotective agents such as N-acetylcysteine (NAC) were utilized experimentally to avoid these potentially serious and life-long side effects, although no clinical phase I trial was performed before. The purpose of this study was to establish the maximum tolerated dose (MTD) and pharmacokinetics of both intravenous (IV) and intra-arterial (IA) NAC in adults with chronic kidney disease to be used in further trials on oto- and nephroprotection in pediatric patients receiving platinum therapy. METHODS: Due to ethical considerations in pediatric tumor patients, we used a clinical population of adults with non-neoplastic disease. Subjects with stage three or worse renal failure who had any endovascular procedure were enrolled in a prospective, non-randomized, single center trial to determine the MTD for NAC. We initially aimed to evaluate three patients each at 150, 300, 600, 900, and 1200 mg/kg NAC. The MTD was defined as one dose level below the dose producing grade 3 or 4 toxicity. Serum NAC levels were assessed before, 5 and 15 min post NAC. Twenty-eight subjects (15 men; mean age 72.2 +/- 6.8 years) received NAC IV (N = 13) or IA (N = 15). RESULTS: The first participant to experience grade 4 toxicity was at the 600 mg/kg IV dose, at which time the protocol was modified to add an additional dose level of 450 mg/kg NAC. Subsequently, no severe NAC-related toxicity arose and 450 mg/kg NAC was found to be the MTD in both IV and IA groups. Blood levels of NAC showed a linear dose response (p < 0.01). Five min after either IV or IA NAC MTD dose administration, serum NAC levels reached the 2-3 mM concentration which seemed to be nephroprotective in previous preclinical studies. CONCLUSIONS: In adults with kidney impairment, NAC can be safely given both IV and IA at a dose of 450 mg/kg. Additional studies are needed to confirm oto- and nephroprotective properties in the setting of cisplatin treatment. Clinical Trial Registration URL: https://eudract.ema.europa.eu . Unique identifier: 2011-000887-92

Species-speciWc defense strategies of vegetative versus reproductive blades of the PaciWc kelps Lessonia nigrescens and Macrocystis integrifolia

Chemical defense is assumed to be costly and therefore algae should allocate defense investments in a way to reduce costs and optimize their overall fitness. Thus, lifetime expectation of particular tissues and their contribution to the fitness of the alga may affect defense allocation. Two brown algae common to the SE Pacific coasts, Lessonia nigrescens Bory and Macrocystis integrifolia Bory, feature important ontogenetic differences in the development of reproductive structures; in L. nigrescens blade tissues pass from a vegetative stage to a reproductive stage, while in M. integrifolia reproductive and vegetative functions are spatially separated on different blades. We hypothesized that vegetative blades of L. nigrescens with important future functions are more (or equally) defended than reproductive blades, whereas in M. integrifolia defense should be mainly allocated to reproductive blades (sporophylls), which are considered to make a higher contribution to fitness. Herein, within-plant variation in susceptibility of reproductive and vegetative tissues to herbivory and in allocation of phlorotannins (phenolics) and N-compounds was compared. The results show that phlorotannin and N-concentrations were higher in reproductive blade tissues for both investigated algae. However, preferences by amphipod grazers (Parhyalella penai) for either tissue type differed between the two algal species. Fresh reproductive tissue of L. nigrescens was more consumed than vegetative tissue, while the reverse was found in M. integrifolia, thus confirming the original hypothesis. This suggests that future fitness function might indeed be a useful predictor of anti-herbivore defense in large, perennial kelps. Results from feeding assays with artificial pellets that were made with air-dried material and extract-treated Ulva powder indicated that defenses in live algae are probably not based on chemicals that can be extracted or remain intact after air-drying and grinding up algal tissues. Instead, anti-herbivore defense against amphipod mesograzers seems to depend on structural traits of living algae

Spatial and temporal dynamics of fucoid populations (Ascophyllum nodosum and Fucus serratus): A comparison between central and range edge populations

Persistence of populations at range edges relies on local population dynamics and fitness, in the case of geographically isolated populations of species with low dispersal potential. Focusing on spatial variations in demography helps to predict the long-term capability for persistence of populations across the geographical range of species' distribution. The demography of two ecological and phylogenetically close macroalgal species with different life history characteristics was investigated by using stochastic, stage-based matrix models. Populations of Ascophyllum nodosum and Fucus serratus were sampled for up to 4 years at central locations in France and at their southern range limits in Portugal. The stochastic population growth rate (lambda(s)) of A. nodosum was lower and more variable in central than in southern sites whilst for F. serratus this trend was reversed with lambda(s) much lower and more variable in southern than in central populations. Individuals were larger in central than in southern populations for both species, which was reflected in the lower transition probabilities of individuals to larger size classes and higher probability of shrinkage in the southern populations. In both central and southern populations elasticity analysis (proportional sensitivity) of population growth rate showed that fertility elements had a small contribution to lambda(s) that was more sensitive to changes in matrix transitions corresponding to survival. The highest elasticities were found for loop transitions in A. nodosum and for growth to larger size classes in F. serratus. Sensitivity analysis showed high selective pressure on individual growth for both species at both locations. The results of this study highlight the deterministic role of species-specific life-history traits in population demography across the geographical range of species. Additionally, this study demonstrates that individuals' life-transitions differ in vulnerability to environmental variability and shows the importance of vegetative compared to reproductive stages for the long-term persistence of populations.Portuguese Foundation for Science and Technology (FCT) [SFRH/BPD/75843/2011]; European Regional Development Fund (ERDF) through the COMPETE - Operational Competitiveness Programme; FCT [Pest-CIMAR LA 0015/2013, EXCL/AAG-GLO/0661/2012

Improving fleet solution – a case study

Transportation management is a logistical activity with a high impact on a company’s ability to compete in the market. Although the focus on cost reduction is the most usual concern with this activity, lead times and the quality of the service provided should also be considered depending on the market to be served. The goal of this research was to compare different fleet alternatives for a specific construction materials company and discuss which scenario is the most suited to fulfil the company’s customer service policy. A case study approach was developed, and four alternative scenarios were considered. These were compared both regarding the costs they involve, which was analysed using a vehicle routing problem heuristic, and the quality of the customer service they allow, which was assessed based on their ability to provide flexibility in the fleet occupancy rate to respond to unexpected orders. Evidence showed that the current fleet solution is not adequate and investment should be made only if the demand level increases, otherwise outsourcing should be considered along with a minimum level of the self-owned fleet.info:eu-repo/semantics/acceptedVersio

Water-Borne Cues of a Non-Indigenous Seaweed Mediate Grazer-Deterrent Responses in Native Seaweeds, but Not Vice Versa

Plants optimise their resistance to herbivores by regulating deterrent responses on demand. Induction of anti-herbivory defences can occur directly in grazed plants or from emission of risk cues to the environment, which modifies interactions of adjacent plants with, for instance, their consumers. This study confirmed the induction of anti-herbivory responses by water-borne risk cues between adjoining con-specific seaweeds and firstly examined whether plant-plant signalling also exists among adjacent hetero-specific seaweeds. Furthermore, differential abilities and geographic variation in plant-plant signalling by a non-indigenous seaweed as well as native seaweeds were assessed. Twelve-day induction experiments using the non-indigenous seaweed Sargassum muticum were conducted in the laboratory in Portugal and Germany with one local con-familiar (Portugal: Cystoseira humilis, Germany: Halidrys siliquosa) and hetero-familiar native species (Portugal: Fucus spiralis, Germany: F. vesiculosus). All seaweeds were grazed by a local isopod species (Portugal: Stenosoma nadejda, Germany: Idotea baltica) and were positioned upstream of con- and hetero-specific seaweeds. Grazing-induced modification in seaweed traits were tested in three-day feeding assays between cue-exposed and cue-free ( = control) pieces of both fresh and reconstituted seaweeds. Both Fucus species reduced their palatability when positioned downstream of isopod-grazed con-specifics. Yet, the palatability of non-indigenous S. muticum remained constant in the presence of upstream grazed con-specifics and native hetero-specifics. In contrast, both con-familiar (but neither hetero-familiar) native species reduced palatability when located downstream of grazed S. muticum. Similar patterns of grazer-deterrent responses to water-borne cues were observed on both European shores, and were almost identical between assays using fresh and reconstituted seaweeds. Hence, seaweeds may use plant-plant signalling to optimise chemical resistance to consumers, though this ability appeared to be species-specific. Furthermore, this study suggests that native species may benefit more than a non-indigenous species from water-borne cue mediated reduction in consumption as only natives responded to signals emitted by hetero-specifics

Hydrochemical system analysis of public supply well fields, to reveal water-quality patterns and define groundwater bodies:The Netherlands

Hydrochemical system analysis (HCSA) is used to better understand the individual state of and spatial patterns in groundwater quality, by addressing the spatial distribution of groundwater bodies with specific origins (hydrosomes) and characteristic hydrochemical zones within each hydrosome (facies). The origin is determined by environmental tracers or geomorphological and potentiometric maps, the facies by combining age, redox and alkalinity indices. The HCSA method is applied to all 206 active public supply well fields (PSWFs) in The Netherlands, resulting in the distinction of nine hydrosomes and eleven facies parameters-age (young, intermediate, old), redox ((sub)oxic, anoxic, deep anoxic, mixed) and alkalinity (very low, low, intermediate and high). The resulting classification of PSWFs provides a means to (1) predict their vulnerability; (2) optimize groundwater-quality monitoring programs; and (3) better delineate groundwater bodies, by considering groundwater origin and flow. The HCSA translates complex hydrochemical patterns into easily interpretable maps by showing PSWFs, groundwater bodies and hydrochemical facies. Such maps facilitate communication between researchers, water resources managers and policy makers and can help to solve complex groundwater resources management problems at different scales, ranging from a single well(field) or region to the national or European scale. © 2010 Springer-Verlag

Search for Charged Higgs Bosons in e+e- Collisions at \sqrt{s} = 189 GeV

A search for pair-produced charged Higgs bosons is performed with the L3 detector at LEP using data collected at a centre-of-mass energy of 188.6 GeV, corresponding to an integrated luminosity of 176.4 pb^-1. Higgs decays into a charm and a strange quark or into a tau lepton and its associated neutrino are considered. The observed events are consistent with the expectations from Standard Model background processes. A lower limit of 65.5 GeV on the charged Higgs mass is derived at 95 % confidence level, independent of the decay branching ratio Br(H^{+/-} -> tau nu)

Impact of nutraceuticals on markers of systemic inflammation: Potential relevance to cardiovascular diseases – A position paper from the International Lipid Expert Panel (ILEP)

Inflammation is a marker of arterial disease stemming from cholesterol-dependent to -independent molecular mechanisms. In recent years, the role of inflammation in atherogenesis has been underpinned by pharmacological approaches targeting systemic inflammation that have led to a significant reduction in cardiovascular disease (CVD) risk. Although the use of nutraceuticals to prevent CVD has largely focused on lipid-lowering (e.g, red-yeast rice and omega-3 fatty acids), there is growing interest and need, especially now in the time of coronavirus pandemic, in the use of nutraceuticals to reduce inflammatory markers, and potentially the inflammatory CVD burden, however, there is still not enough evidence to confirm this. Indeed, diet is an important lifestyle determinant of health and can influence both systemic and vascular inflammation, to varying extents, according to the individual nutraceutical constituents. Thus, the aim of this Position Paper is to provide the first attempt at recommendations on the use of nutraceuticals with effective anti-inflammatory properties

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns