Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis

The aim of this study was to evaluate the safety and effect on clinical outcomes and biomarkers of inflammation and tissue damage of the neutrophil elastase inhibitor AZD9668 (60 mg twice daily orally for 4 weeks) in cystic fibrosis. This was a randomised, double-blind, placebo-controlled study. Primary outcome measures were sputum neutrophil count, lung function, 24-h sputum weight, BronkoTest® diary card data and health-related quality-of-life (revised cystic fibrosis quality-of-life questionnaire). Secondary end-points included sputum neutrophil elastase activity, inflammatory biomarkers in sputum and blood, urine and plasma desmosine (an elastin degradation marker), AZD9668 levels and safety parameters (adverse events, routine haematology, biochemistry, electrocardiogram and sputum bacteriology). 56 patients were randomised, of which 27 received AZD9668. There was no effect for AZD9668 on sputum neutrophil counts, neutrophil elastase activity, lung function or clinical outcomes, including quality of life. In the AZD9668 group, there was a trend towards reduction in sputum inflammatory biomarkers with statistically significant changes in interleukin-6, RANTES and urinary desmosine. The pattern of adverse events was similar between groups. Consistent reductions in sputum inflammatory biomarkers were seen in the AZD9668 group, and reduction in urinary desmosine suggests that AZD9668 impacts elastin cleavage by neutrophil elastase.

Elderly patients with hypercholesterolaemia:a double-blind study of the efficacy, safety and tolerability of fluvastatin

Coronary heart disease is a major cause of morbidity and mortality in the elderly, a rapidly growing section of the population. Elderly patients have been excluded from most preventative risk factor trials.

Levels of cadmium and zinc in soil and plants following the toxic spill from a pyrite mine, Aznalcollar, Spain

On 25 April 1998, a breach of the tailings dam of the Los Frailes pyrite mine in southwestern Spain resulted in the release of 6 million m(3) of acidic water and toxic sludge high in heavy metals. Contaminated material extended 40 km downstream, affecting agricultural land and parts of the wildlife-rich Donana Natural and National Parks, including the Entremuros, a very important area for birds. We report on the concentrations, distributions and bioavailability of zinc and cadmium in soil and vegetation from the Entremuros in November 1998 and October 1999, following 2 'cleanup' operations. Levels of Zn and Cd in soil increased significantly over this period, although this was not reflected consistently in metal concentrations in emergent macrophytes. We recommend monitoring of further cleanup attempts in order to develop means of minimizing potential impacts to wildlife in the area.

Arsenic and selenium mobilisation from organic matter treated mine spoil with and without inorganic fertilisation

Organic matter amendments are applied to contaminated soil to provide a better habitat for revegetation and remediation, and olive mill waste compost (OMWC) has been described as a promising material for this aim. We report here the results of an incubation experiment carried out in flooded conditions to study its influence in As and metal solubility in a trace elements contaminated soil. NPK fertilisation and especially organic amendment application resulted in increased As, Se and Cu concentrations in pore water. Independent of the amendment, dimethylarsenic acid (DMA) was the most abundant As species in solution. The application of OMWC increased pore water dissolved organic-carbon (DOC) concentrations, which may explain the observed mobilisation of As, Cu and Se; phosphate added in NPK could also be in part responsible of the mobilisation caused in As. Therefore, the application of soil amendments in mine soils may be particularly problematic in flooded systems. (C) 2012 Elsevier Ltd. All rights reserved.

Arsenic behaviour from groundwater and soil to crops:impacts on agriculture and food safety

High levels of As in groundwater commonly found in Bangladesh and other parts of Asia not only pose a risk via drinking water consumption but also a risk in agricultural sustainability and food safety. This review attempts to provide an overview of current knowledge and gaps related to the assessment and management of these risks, including the behaviour of As in the soil-plant system, uptake, phytotoxicity, As speciation in foods, dietary habits, and human health risks. Special emphasis has been given to the situation in Bangladesh, where groundwater via shallow tube wells is the most important source of irrigation water in the dry season. Within the soil-plant system, there is a distinct difference in behaviour of As under flooded conditions, where arsenite (AsIII) predominates, and under nonflooded conditions, where arsenate (AsV) predominates. The former is regarded as most toxic to humans and plants. Limited data indicate that As-contaminated irrigation water can result in a slow buildup of As in the topsoil. In some cases the buildup is reflected by the As levels in crops, in others not. It is not yet possible to predict As uptake and toxicity in plants based on soil parameters. It is unknown under what conditions and in what time frame As is building up in the soil. Representative phytotoxicity data necessary to evaluate current and future soil concentrations are not yet available. Although there are no indications that crop production is currently inhibited by As, long-term risks are clearly present. Therefore, with concurrent assessments of the risks, management options to further prevent As accumulation in the topsoil should already have been explored. With regard to human health, data on As speciation in foods in combination with food consumption data are needed to assess dietary exposure, and these data should include spatial and seasonal variability. It is important to control confounding factors in assessing the risks. In a country where malnutrition is prevalent, levels of inorganic As in foods should be balanced against the nutritional value of the foods. Regarding agriculture, As is only one of the many factors that may pose a risk to the sustainability of crop production. Other risk factors such as nutrient depletion and loss of organic matter also must be taken into account to set priorities in terms of research, management, and overall strategy.

After the Aznalcóllar mine spill:arsenic, zinc, selenium, lead and copper levels in the livers and bones of five waterfowl species

In April 1998, a holding lagoon containing pyrite ore processing waste, failed and released 5-6 million m3 of highly polluting sludge and acidic water. Over 2650 ha of the internationally important Doñana Natural Park became contaminated, along with <100 ha of the more pristine Doñana National Park. In order to assess the affect of the spill on waterfowl from Doñana, bone and liver samples from 124 individuals have been analysed for As, Pb, Cu, Zn and Se. Five species have been studied, from the Rallidae (rails), Anatini (dabbling ducks) and Aythyini (pochards) families. Geometric mean bone concentrations 2-3 months after the spill were in the order of Zn > Cu > Pb > Se > As, while liver concentrations were in the order of Zn > Cu > Se > Pb > As. Dry weight bone concentrations ranged from n.d-1.76 mg kg(-1) As, 109.4-247.6 mg kg(-1) Zn, 0.06-1.27 mg kg(-1) Se, n.d-134.11 mg kg(-1) Pb, and 2.18-8.92 mg kg(-1) Cu. Wet weight liver concentrations ranged from n.d-0.34 mg kg(-1) As, 29.8-220.1 mg kg(-1) Zn, 0.15-0.85 mg kg(-1) Se, n.d-3.80 mg kg(-1) Pb, and 7.30-742.96 mg kg(-1) Cu. The most important factor related to the accumulation of these metals was commonly species; however, location and sex also had important effects on liver As levels, location and age affected Cu levels, while Zn and Pb were affected by age, sex and location. Birds from Natural Park areas were found to have significantly higher levels of bone Zn, Pb and Cu, and liver As and Cu than birds from National Park areas. Female birds had higher liver As, Zn and Pb than males; whilst adults appeared to have lower bone As and Zn but higher liver Pb than chicks/juveniles. Although metal concentrations were elevated in certain individuals, in the majority of birds studied, they did not reach levels widely considered to be toxic. However, it would appear that As and Cu liver levels (which may be indicative of short-medium term pollutant exposure) were elevated in waterbirds which died in the spill contaminated Natural Park, 2-3 months after the disaster.

Arsenic levels in the soils and macrophytes of the 'Entremuros' after the Aznalcóllar mine spill

In April 1998, a holding lagoon containing pyrite ore processing waste rich in arsenic, failed and released 5-6 million m(3) of highly polluting sludge and acidic water. Over 2700 ha of the internationally important Doñana National and Natural Parks were contaminated. The area of Natural Park to sustain the greatest impact was known as the Entremuros. This paper presents 0-5 cm soil monitoring data from the Entremuros, from sampling campaigns 6 and 18 months after the disaster; as well as macrophyte root, rhizome and stem data from samples taken 18 months after the spill. Results show a clear, decreasing, north-south arsenic soil pollution trend, both 6 and 18 months after the spill, and suggest a small reduction in total soil arsenic levels occurred over time; although a significant increase in extractable arsenic is also noted. The two macrophytes (Typha dominguensis and Scirpus maritimus) studied herein are not accumulating arsenic in stem parts, however, accumulation of arsenic on iron plaque on the roots of these plants may be occurring. Further work is recommended in order to determine the ecotoxicological significance of this process in relation to the avian food-chains of Doñana, and elsewhere.

Arsenic contamination in wood mice (Apodemus sylvaticus) and bank voles (Clethrionomys glareolus) on abandoned mine sites in southwest Britain

Arsenic can be highly toxic to mammals but there is relatively little information on its transfer to and uptake by free-living small mammals. The aim of this study was to determine whether intake and accumulation of arsenic by wild rodents living in arsenic-contaminated habitats reflected environmental levels of contamination and varied between species, sexes and age classes. Arsenic concentrations were measured in soil, litter, wood mice (Apodemus sylvaticus) and bank voles (Clethrionomys glareolus) from six sites which varied in the extent to which they were contaminated. Arsenic residues on the most contaminated sites were three and two orders of magnitude above background in soil and litter, respectively. Arsenic concentrations in the stomach contents, liver, kidney and whole body of small mammals reflected inter-site differences in environmental contamination. Wood mice and bank voles on the same sites had similar concentrations of arsenic in their stomach contents and accumulated comparable residues in the liver, kidney and whole body. Female bank voles, but not wood mice, had significantly higher stomach content and liver arsenic concentrations than males. Arsenic concentration in the stomach contents and body tissues did not vary with age class. The bioaccumulation factor (ratio of arsenic concentration in whole body to that in the diet) in wood mice was not significantly different to that in bank voles and was 0.69 for the two species combined, indicating that arsenic was not bioconcentrated in these rodents. Overall, this study has demonstrated that adult and juvenile wood mice and bank voles are exposed to and accumulate similar amounts of arsenic on arsenic-contaminated mine sites and that the extent of accumulation depends upon the level of habitat contamination.

The distribution of arsenic in soils affected by the Aznalcóllar mine spill, SW Spain

In April 1998, a holding lagoon containing pyrite ore processing waste, failed and released an estimated 5-6 million m(3) of metal rich sludge and acidic waters into the Rio Guadiamar, SW Spain. Over 2700 ha of the internationally important Doñana National and Natural Parks were contaminated. The sludge component of the waste contained up to 0.6% arsenic. This paper presents an extensive set of 0-5 cm soil analyses results from samples taken 6-8 months after the spill. Data are presented on pseudo-total arsenic levels in these samples, and on arsenic removed by both single batch and sequential extraction techniques. Pseudo-total levels of arsenic in the sludge ranged from 1521 to 3510 mg kg(-1), and a mean 4.4% of this was found to be extractable using 2.5% acetic acid. Soils in the Guadiamar Valley and Entremuros areas (those worst affected by the spill) were found to contain 85.4-782 mg kg(-1) and 7.1-196 mg kg(-1) pseudo-total arsenic, respectively. The mean acetic acid extractable component in these areas was 2.5% and 4.9%, respectively. Background pseudo-total arsenic levels in the soils of the area have been found to be 4.2-13.6 mg kg(-1). Rapid input of acidic waters, and the acidic nature of the sludge itself, may have caused depletion of Mg, Na and K, and to a lesser extent Mn, Ca and PO(4) in the upper 5 cm of the worst affected soils. Sequential extraction results suggest clear As-Fe associations, and possible As-Mn associations within the more soluble phases.

Antimony bioavailability in mine soils

Five British former mining and smelting sites were investigated and found to have levels of total Sb of up to 700 mg kg(-1), indicating high levels of contamination which could be potentially harmful. However, this level of Sb was found to be biologically unavailable over a wide range of pH values, indicating that Sb is relatively unreactive and immobile in the surface layers of the soil, remaining where it is deposited rather than leaching into lower horizons and contaminating ground water. Sb, sparingly soluble in water, was unavailable to the bacterial biosensors tested. The bioluminescence responses were correlated to levels of co-contaminants such as arsenic and copper, rather than to Sb concentrations. This suggests that soil contamination by Sb due to mining and smelting operations is not a severe risk to the environment or human health provided that it is present as immobile species and contaminated sites are not used for purposes which increase the threat of exposure to identified receptors. Co-contaminants such as arsenic and copper are more bioavailable and may therefore be seen as a more significant risk.

Resistance to copper toxicity in populations of the earthworms Lumbricus rubellus and Dendrodrilus rubidus from contaminated mine wastes

Two arsenic and heavy metal-contaminated mine spoil sites, at Carrock Fell, Cumbria, United Kingdom, and Devon Great Consols Mine, Devon, United Kingdom, have been found to support populations of the earthworms Lumbricus rubellus Hoffmeister and Dendrodrilus rubidus (Savigny). Lumbricus rubellus and D. rubidus collected from the Devon site and an uncontaminated site were kept for 28 d in uncontaminated soil and in soil containing 750 mg/kg CuCl2, the state of the specimens being recorded using a semiquantitative assessment of earthworm health (condition index). The condition index remained high for all specimens except those of L. rubellus and D. rubidus from uncontaminated sites, which displayed 100% mortality. Bioavailability of Cu in the soils from one uncontaminated and two contaminated sites and in the uncontaminated soil treated with CuCl2 was determined using sequential extraction. Soils from Devon Great Consols had the greatest availability of Cu, Carrock Fell the lowest. Total tissue Cu for L. rubellus and D. rubidus from the contaminated sites did not change significantly for each species during the experiment. Total tissue concentrations of Cu for L. rubellus and D. rubidus from uncontaminated sites increased significantly during the first 7 d, after which mortality was 90%, making it impossible to continue the analysis.

The Doñana ecological disaster:contamination of a world heritage estuarine marsh ecosystem with acidified pyrite mine waste

One of the most important bird breeding and over wintering sites in the west of Europe, the Coto Doñana, was severely impacted by the release of 5 million cubic meters of acid waste from the processing of pyrite ore. The waste entered ecologically sensitive areas of the park (including breeding areas for internationally endangered bird species) causing sustained pH decreases from pH 8.5 to 4.5 and resulting in massive metal contamination of the impacted ecosystem. The contaminating sludge waste contained arsenic at 0.6%, lead at 1.2% and zinc at 0.8% on a dry weight basis. The acid conditions facilitated the solubilization of these metals, leading to water concentrations lethal for aquatic wildlife. The accident caused considerable fish and invertebrate kills and has severe consequences for the protected bird species dependent on the impacted habitats and adjacent areas.

Strategies for Effective Management of Health and Safety in Confined Site Construction

The overall aim of this research is to identify and catalogue the numerous managerial strategies for effective management of health and safety on a confined, urban, construction site. A mixed methods methodology was adopted using interviews and focus group discussions on three selected case studies of confined construction sites. In addition to these, a questionnaire survey was used based on the findings from the interviews and the focus group discussions. The top five key strategies include (1) Employ safe system of work plans to mitigate personnel health and safety issues; (2) Inform personnel, before starting on-site, of the potential issues using site inductions; (3) Effective communication among site personnel; (4) Draft and implement an effective design site layout prior to starting on-site; and (5) Use of banksman (traffic co-ordinator) to segregate personnel from vehicular traffic. The construction sector is one of the leading industries in accident causation and with the continued development and regeneration of our urban centres, confined site construction is quickly becoming the norm - an environment which only fuels accident creation within the construction sector. This research aids on-site management that requires direction and assistance in the identification and implementation of key strategies for the management of health and safety, particularly in confined construction site environments.

Learning curves, taking instructions, and patient safety:using a theoretical domains framework in an interview study to investigate prescribing errors among trainee doctors

ABSTRACT: