Microbial biomass and activity dynamics in restored lands in a metal contaminated region.

Soil microbial communities are important for biogeochemical processes, along with the cycling of nutrients in an ecosystem. Their enzymatic activities are key indicators of their responses to stress. The objective of this research was to assess the effect of land reclamation on microbial biomass and activities in soils impacted by metal contamination. Phospholipid fatty acid analysis (PLFA) (PLFA) results revealed a significant increase in total microbial biomass, fungi, actinomycetes, and bacteria when limed soils were compared to unlimed samples. This change in microbial biomass was associated with a significant increase of pH. The overall level of the ß-glucosidase (BG), cellobiohydrolase (CBH), and aryl sulfatase (AS) activities was significantly higher in the dolomitic limestone treated soils than in the untreated samples. However, the activity of glycine aminopeptidase (GAP) was significantly lower in the limed soil than in unlimed samples used as reference. No significant differences (P ≥ 0.05) were observed between the two types of lands (limed vs unlimed) for other enzymes tested, which includes ß-N-acetylglucosaminidase (NAGase), acid phosphatase (AP), alkaline phosphatase (ALP), leucine aminopeptidase (LAP), and peroxidase (PER). The levels of enzymatic responses also varied among sites. Overall, this study revealed for the first time the effects of liming on soil microbial activities in recently reclaimed sites damaged by metals.

Variation in lung cancer resources and workload: results from the first national lung cancer organisational audit.

We report the findings of the first national lung cancer organisational audit. The results demonstrate marked variation in service provision and workload of some lung cancer specialists. For example, over half of the clinical nurse specialists report case volumes over recommended numbers. Some trusts have no access to key treatments such as video assisted thoracoscopy (VAT) lobectomy and stereotactic radiotherapy. Multivariate regression analysis demonstrated an association between higher surgical resection rates and the on-site availability of advanced staging and therapeutic modalities, for example, PET scan and VAT lobectomy. We conclude by making a number of recommendations to address the variation in lung cancer care.

Exploring variations in lung cancer care across the UK--the 'story so far' for the National Lung Cancer Audit.

The National Lung Cancer Audit was developed to improve the quality and outcomes of services for patients with lung cancer, knowing that outcomes vary widely across the UK and are poor compared to other western countries. After five years the audit is capturing approximately 100% of the expected number of incident cases across hospitals in England, Wales, Scotland, Northern Ireland and Jersey. Measures of process and outcome have improved over the audit period, such as the histological confirmation rate (64-76%), the proportion of patients discussed in a multidisciplinary team meeting (78-94%), and the proportion of patients having anti-cancer treatment (43-59%), surgical resection (9-14%) and small cell lung cancer chemotherapy (58-66%). These national averages hide wide variations between hospitals providing lung cancer care which cannot be accounted for by differences in casemix. This paper describes the evolution of the audit, and describes the ways in which it may have improved clinical practice.

Comparative soil metal analyses in Sudbury (Ontario, Canada) and Lubumbashi (Katanga, DR-Congo).

DR-Congo is a main world producer of copper (Cu) and cobalt (Co). Several hydrometallurgical plants and smelters also produced zinc, arsenic, and cadmium as by-products. In Sudbury (Canada), the production of nickel, copper and other metals has been maintained at high levels while industrial SO(2) emissions have been reduced by approximately 90% through combination of industrial technological developments and legislated controls. Metal analysis in the present study revealed that the levels of copper and cobalt in soils from mining sites in the Lubumbashi (DR-Congo) were up to 200 fold higher compared to contaminated Sudbury sites and tailings. Zinc content in soil samples from some mining areas in Lubumbashi was at least 70 times higher compared to samples from the Sudbury area. Nickel content in soil samples from Lubumbashi were much lower compared to the Sudbury Region samples. Overall, this study confirms that the African Copper belt region is among the ten most polluted areas in the world.

A review on the use of lichens as a biomonitoring tool for environmental radioactivity.

Lichens have been widely used as a biomonitoring tool to record the distribution and concentration of airborne radioactivity and pollutants such as metals. There are limitations, however: although pollutants can be preserved in lichen tissues for long periods of time, not all radioactive and inert elements behave similarly. The chemical species of elements at the source, once captured, and the mode of storage within lichens play a role in this biomonitoring tool. Lichens are a symbiotic association of an algal or cyanobacterial partner (photobiont) with a fungal host (mycobiont). Lichens grow independently of the host substrates, including rocks, soils, trees and human-made structures. Lacking a root system, lichen nutrient or contaminant uptake is mostly through direct atmospheric inputs, mainly as wet and dry deposition. As lichens grow in a large variety of environments and are resilient in harsh climates, they are adapted to capture and retain nutrients from airborne sources. The context of this review partially relates to future deployment of small modular reactors (SMRs) and mining in remote areas of Canada. SMRs have been identified as a future source of energy (electricity and heat) for remote off-grid mines, potentially replacing diesel fuel generation facilities. For licensing purposes, SMR deployment and mine development requires capabilities to monitor background contaminants (natural radioactivity and metals) before, during and after deployment, including for decommissioning and removal. Key aspects reviewed herein include: (1) how lichens have been used in the past to monitor radioactivity; (2) radiocontaminants capture and storage in lichens; (3) longevity of radiocontaminant storage in lichen tissues; and (4) limitations of lichens use for monitoring radiocontaminants and selected metals.

Distribution of metals and radionuclides in the lichens Cladonia rangiferina and C. mitis from the past uranium mining region of Elliot Lake, Ontario, Canada.

The present study was performed in the Elliot Lake area (Ontario, Canada), a site of uranium mining and milling for nearly 40 years between 1950's and 1990's. Although mining activities ceased in the mid-1990's, the site hosts several tailings management areas (TMAs) which are under ongoing rehabilitation and monitoring. Several surveys using lichens as a biomonitoring tool were completed in the 1980s and the 1990s to assess the levels of contaminants. The present survey aimed to re-visit the historical surveys, and to determine the current status of environmental recovery of the area. Our survey consisted of sampling two lichen species, Cladonia rangiferina and C. mitis, in an area covering up to 50 km from the former mining operation and the TMAs. The results reported in this work indicated that the levels of metals and radionuclides, diagnostic of mining operations, have decreased over time: particularly, the U, Th and Pb levels in both lichen species dropped by about two orders of magnitude by the 2020's compared to the 1980's. Likewise, the Cs-137 levels in both lichen species reflect present day global background. The study provides a new set of present-day regional baseline elemental concentrations for other metals that are associated with mining (Cd, As, Ti, Cs). Finally, there were weak but statistically significant differences in the levels of some elements (U, Th, Cd) between the two lichens, suggesting these two species might have different capture mechanisms or retention abilities.

Changes in ambient air quality and atmospheric composition and reactivity in the South East of the UK as a result of the COVID-19 lockdown.

The COVID-19 pandemic forced governments around the world to impose restrictions on daily life to prevent the spread of the virus. This resulted in unprecedented reductions in anthropogenic activity, and reduced emissions of certain air pollutants, namely oxides of nitrogen. The UK 'lockdown' was enforced on 23/03/2020, which led to restrictions on movement, social interaction, and 'non-essential' businesses and services. This study employed an ensemble of measurement and modelling techniques to investigate changes in air quality, atmospheric composition and boundary layer reactivity in the South East of the UK post-lockdown. The techniques employed included in-situ gas- and particle-phase monitoring within central and local authority air quality monitoring networks, remote sensing by long path Differential Optical Absorption Spectroscopy and Sentinel-5P's TROPOMI, and detailed 0-D chemical box modelling. Findings showed that de-trended NO2 concentrations decreased by an average of 14-38% when compared to the mean of the same period over the preceding 5-years. We found that de-trended particulate matter concentrations had been influenced by interregional pollution episodes, and de-trended ozone concentrations had increased across most sites, by up to 15%, such that total Ox levels were roughly preserved. 0-D chemical box model simulations showed the observed increases in ozone concentrations during lockdown under the hydrocarbon-limited ozone production regime, where total NOx decreased proportionally greater than total non-methane hydrocarbons, which led to an increase in total hydroxyl, peroxy and organic peroxy radicals. These findings suggest a more complex scenario in terms of changes in air quality owing to the COVID-19 lockdown than originally reported and provide a window into the future to illustrate potential outcomes of policy interventions seeking large-scale NOx emissions reductions without due consideration of other reactive trace species.

Stage III Non-small Cell Lung Cancer Management in England.

AIMS: We present the first analysis of the management and outcomes of stage III non-small cell lung cancer (NSCLC) conducted in England using National Lung Cancer Audit data. MATERIALS AND METHODS: Patients diagnosed with stage III NSCLC in 2016 were identified. Linked datasets (including Hospital Episode Statistics, the National Radiotherapy Dataset, the Systemic Anti-Cancer Dataset, pathology reports and death certificate data) were used to categorise the treatment received. Kaplan-Meier survival curves were obtained, with survival defined from the date of diagnosis to the date of death. RESULTS: In total, 6276 cases of stage III NSCLC were analysed: 3827 stage IIIA and 2449 stage IIIB; 1047 (17%) patients were treated with radical radiotherapy with 676 (11%) of these also receiving chemotherapy. Twenty per cent of patients with stage IIIA disease underwent surgery, with half of these also receiving chemotherapy, predominantly delivered in the adjuvant setting. Of note, 2148 (34%) patients received palliative-intent treatment and 2265 (36%) received no active anti-cancer treatment. The 1-year survival was 32.9% (37.4% for stage IIIA), with the highest survival seen for those patients receiving chemotherapy and surgery. CONCLUSIONS: We highlight important gaps in the optimal care of patients with stage III NSCLC in England. Multimodality treatment with either surgery or radical radiotherapy combined with chemotherapy was delivered to less than one-fifth of patients, even though these regimens are considered optimal. Timely access to specialist resources and staff, the practice of effective shared decision making and challenging preconceptions have the potential to optimise management.

From laboratory to Phase I/II cancer trials with recombinant biotherapeutics.

Many promising recombinant cancer medicines are generated by academic research and increasing the number of these products that are translated into the clinic will increase the pipeline of new therapies. Recombinant proteins for use in Phase I/II cancer trials must be produced to standards of Good Manufacturing Practice (GMP) in compliance with EU law. This can be a major obstacle for translating experimental products to clinical reality especially when there is no established process or prior experience with GMP. Here, we illustrate the principals of GMP with a step-by-step guide and we show that GMP can be achieved on a relatively small scale in the researchers own institution. The process is exemplified with an antibody-based therapeutic expressed in the yeast Pichia pastoris. The purified product has been used safely in patients and the principles are applicable to any recombinant protein required for Phase I/II cancer trials.

Matrix metalloproteinases and processing of pro-TNF-alpha.

Tumor necrosis factor-alpha (TNF-alpha) is released from a cell membrane-anchored precursor by proteolytic cleavage. We have shown that broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs) prevent the processing of the TNF precursor but do not inhibit the release of other cytokines. Purified MMPs, stromelysin, matrilysin, collagenase, and the gelatinases can all cleave a recombinant pro-TNF substrate to yield mature TNF. MMP inhibitors prevent the rise in blood levels of TNF after endotoxin administration in rats and are effective in animal models of inflammatory disease such as adjuvant arthritis. Drugs that inhibit MMP action and TNF release show great promise for the treatment of autoimmune inflammatory diseases.

Demographics, management and survival of patients with malignant pleural mesothelioma in the National Lung Cancer Audit in England and Wales.

INTRODUCTION AND METHODS: Malignant pleural mesothelioma (MPM) is an uncommon cancer with poor survival. We have used data collected for the UK National Lung Cancer Audit to assess current practice and to highlight regional variation in the management of mesothelioma patients, as well as to describe survival patterns in subgroups. RESULTS: Our data on 8740 cases seen in hospitals in England and Wales is the largest cohort of MPM in the literature and represents approximately 80% of the total incident cases. 83% are male and median age is 73 years. Performance status is recorded in 81% and of these approximately 70% are PS 0-2. Stage is poorly recorded and unreliable in this dataset. The patient pathway is similar to lung cancer with approximately one-fifth having a non-elective referral to secondary care. A histo-cytological diagnosis is made in 87% and varies across organisations. Only 67% have anti-cancer treatment, and this also varies across organisations, but there has been an annual increase in the proportion receiving chemotherapy. Overall median survival was 9.5 months, with a 1YS of 41.4% and 3YS of 12.0%, but was strongly linked to performance status and histological subtype. Median survival also varied by cancer network from 209 days to 349 days, but appeared to increase from of 9.2 months in 2008 to 10.5 months in 2012. CONCLUSION: Our data provide a large scale, detailed assessment of MPM epidemiology, treatment choices and outcomes. Incidence is increasing in line with predictions and uptake of treatments has generally mirrored publication of key MPM treatment trials, in particular increasing use of chemotherapy but low uptake of radical surgery. However, there is significant variation in care patterns and outcomes that may reflect limited expertise in area with low incidence. Initiatives to improve outcomes should include improved recording of clinical stage.

The efficiency of dietary protein utilization is increased during puberty.

We investigated whether the efficiency of dietary protein utilization for growth increases during the pubertal growth spurt in both nondiabetic and diabetic subjects. We measured leucine oxidation and retention (intake minus oxidation) in orally fed nondiabetic (n = 9) and diabetic (n = 9) human subjects, aged 7-17 yr. Eight subjects were Tanner stage I, and 10 were Tanner stages III-V; groups were not matched for gender. After 3 days of consuming a diet containing approximately 1 g/kg. day protein, subjects drank a commercial liquid nutrition formula, containing L-[1(-13)C]leucine, every 30 min for a total of 6 h to provide 1 g protein/kg. day. Isotopic enrichment of CO2 was used to calculate the fractional leucine oxidation rate and, together with alpha-ketoisocaproate isotopic enrichment, to calculate total leucine oxidation. Leucine oxidation rates decreased with puberty in both nondiabetic subjects (36.0 +/- 10.4 vs. 23.9 +/- 4.2 mumol/kg fat-free mass (FFM).h, prepubertal and pubertal, respectively; P < 0.05) and diabetic (33.6 +/- 4.9% vs. 27.3 +/- 3.4 mumol/kg FFM.h, prepubertal and pubertal, respectively; P < 0.1) subjects. Leucine retention increased with puberty in both nondiabetic (0.27 +/- 3.2 vs. 15.7 +/- 5.3 mumol/kg FFM.h, prepubertal and pubertal, respectively; P < 0.001) and diabetic (1.9 +/- 4.9 vs. 13.2 +/- 4.4 mumol/kg FFM.h, prepubertal and pubertal subjects, respectively; P < 0.05) subjects. The data suggest that the pubertal growth spurt is associated with a marked increase in the efficiency of dietary protein utilization for growth.

Insulin does not stimulate protein synthesis acutely in prepubertal children with insulin-dependent diabetes mellitus.

Insulin treatment in adult type I diabetic patients decreases protein loss primarily by inhibiting protein breakdown without stimulating protein synthesis. In young growing rodents, insulin treatment has been reported to stimulate protein synthesis. We examined whether insulin stimulates protein synthesis in normally growing prepubertal children with insulin-dependent diabetes mellitus. Five prepubertal children with insulin-dependent diabetes mellitus (aged 8.6-11.25 yr) were studied in the postabsorptive state on two occasions: once during insulin deprivation (I-; blood glucose, 325 +/- 67.8 mg/dL; mean +/- SD) and once during insulin administration for 4 h (I+; blood glucose, 96 +/- 23.6 mg/dL). Leucine kinetics were measured using a 4-h primed continuous infusion of L-[1-13C]leucine. Serum insulin concentrations were lower (I- vs. I+, 0.6 +/- 0.3 vs. 7.5 +/- 4.3 microU/mL; mean +/- SD; P = 0.02), whereas serum beta-hydroxy-butyrate (I- vs. I+, 3.4 +/- 0.5 vs. 0.9 +/- 0.5 mg/dL; P < 0.001) and free fatty acid concentrations (I- vs. I+, 2.9 +/- 0.4 vs. 0.9 +/- 0.4 mEq/L; P < 0.001) were higher in the insulin-deprived state than during insulin administration. Leucine Ra, an index of protein breakdown (I- vs. I+, 200.5 +/- 23.4 vs. 167 +/- 17 mumol/kg.h; P = 0.008), and leucine oxidation (I- vs. I+, 56.5 +/- 20.7 vs. 29.6 +/- 9.3 mumol/kg.h; P = 0.03) were reduced by insulin treatment. Nonoxidative leucine disposal, an index of protein synthesis, was not affected by insulin treatment (I- vs. I+, 144 +/- 20.8 vs. 137.5 +/- 13.5 mumol/kg.h; P = 0.4). We conclude that the acute decline in net protein loss during insulin treatment in growing prepubertal children, like that in adults, is due primarily to an inhibition of protein breakdown without stimulation of protein synthesis.

Preclinical and clinical studies of MMP inhibitors in cancer.

The role of matrix metalloproteinases in tumor angiogenesis and growth is now well recognized for models of both human and animal cancer. Clinical studies currently under way with the prototype matrix metalloproteinase inhibitor, marimastat, will establish whether inhibitors of these enzymes are of benefit in the treatment of different types of human cancer. On chronic therapy in humans, marimastat induces a reversible tendinitis that can also be detected in certain animal species. This paper compares the ability of broad-spectrum and various types of selective matrix metalloproteinase inhibitors to induce tendinitis and to exhibit anticancer effects in an animal cancer model. Under conditions in which both systemic exposure and inhibitor potency are controlled, selective inhibitors are less pro-tendinitic, but are weaker anticancer agents than broad-spectrum agents such as marimastat. The clinical relevance of these findings is discussed.

Developmental changes in the relationship between IGF-I and body composition during puberty.

To examine the hypothesis that anthropometric measures and physical fitness influence circulating insulin-like growth factor-I (IGF-I) during puberty, we measured IGF-I, free IGF-I, IGFBP-1, and IGFBP-3 concentrations in 156 healthy girls (9-16 years old) characterized by aerobic capacity (VO2max), fat-free mass (FFM), percent fat mass and pubertal development. IGF-I, free IGF-I and IGFBP-3 increased with pubertal development while IGFBP-1 declined. Percent fat mass correlated inversely with IGFBP-1 (r = -0.57) and directly with insulin (r = 0.50), while VO2max correlated inversely with percent fat mass (r = -0.63), body mass index (BMI, r = -0.57), and FFM (r = -0.40). When subdivided by Tanner stage, IGF-I correlated directly with weight, height, BMI, and FFM in pre-pubertal girls, but these relationships all diminished or disappeared completely by late puberty. Inverse correlations between IGF-I and percent fat mass, and direct correlations between IGF-I and VO2max as observed previously in adults, were not seen until late puberty. These data suggest that in pre-pubertal and early pubertal girls, IGF-I concentrations in blood reflect overall somatic size. This relationship between IGF-I and body size diminishes with sexual maturation, while correlations between IGF-I and both fitness and fatness emerge.

The alpha 1- and alpha 2-adrenoceptor involvement in the central cardiovascular action of clonidine in the conscious renal hypertensive cat.

An attempt has been made to characterise the alpha-adrenoceptor subtype (alpha 1 or alpha 2) mediating the hypotensive and bradycardic action of clonidine in conscious renal hypertensive cats. The relatively selective alpha 2-adrenoceptor agonists clonidine, UK-14,304, guanfacine and lofexidine caused significant hypotension and bradycardia when given intracerebroventricularly (i.c.v.). This suggests that alpha 2-adrenoceptors can mediate hypotension and bradycardia. However, both alpha 1- and alpha 2-adrenoceptor antagonists, prazosin, UK-33,274, corynanthine, yohimbine, rauwolscine and RS21361 blocked the hypotensive effect of clonidine. These results suggest an alpha 1-adrenoceptor may also mediate the central hypotensive action of clonidine, or possibly that the central alpha-adrenoceptors in which clonidine acts, may show pharmacological differences to peripheral alpha 1- and alpha 2-subtypes.

The action of barbiturates on contractile responses of canine and feline bronchial smooth muscle.

Pentobarbitone, thiopentone and phenobarbitone in concentrations ranging from 10(-4) M to 10(-3) M reduced the contractile responses of isolated canine and feline trachealis muscle to electrical field stimulation without affecting contractile responses to acetylcholine. The order of potency was thiopentone, pentobarbitone and phenobarbitone. Experiments using carbachol and neostigmine or physostigmine suggested that the barbiturates act by preventing the release of acetylcholine from nerve endings. In vivo, pentobarbitone (2.5-20 mg/kg i.v.) produced dose-related reductions in the increase in total lung resistance induced by vagal stimulation in chloralose-anaesthetised cats.

Development of the third component in prism adaptation: effects of active and passive movement.

Adaptation to prismatically displaced vision was assessed using a factorial design involving active or passive exposure movement, active or passive test movement, and target location. Tests of visual shift, ipsilateral and contralateral proprioceptive shift, and ipsilateral and contralateral target-pointing shift were made at the completion of 6, 12, 24, 48, and 96 exposure trials. During the early stages of adaptation (< 48 exposure trials), changes in ipsilateral target pointing were completely accounted for by the sum of the visual and ipsilateral proprioceptive changes. Following longer exposure durations, evidence of a third component was obtained, but only when exposure and test movements were the same (i.e., active-active and passive-passive conditions). The acquisition of such movement-specific response tendencies was interpreted as indicating that the third component represents a change in a central program or schema, which is responsible for guiding a limb to an externally specified location. Target location had no effect on the presence or magnitude of the third component, and there was no indication that the third component transferred intermanually.

The effect of long-acting beta2-agonists on airway inflammation in asthmatic patients.

Early observations suggested that the inhibition by long-acting beta2-agonists (LABAs) of non-specific bronchial hyperresponsiveness following allergen challenge was unrelated to bronchodilation or functional antagonism and might be a reflection of anti-inflammatory activity. Investigation of the effect of LABAs on airway inflammatory responses has demonstrated an inhibition of eosinophil recruitment in allergen challenge studies. Nevertheless, results from biopsy and other studies suggest that the chronic inflammatory process in asthma patients is unaffected by these drugs. There is no evidence from biopsy studies that LABAs are pro-inflammatory or that they mask existing inflammation. The beneficial effects of LABAs in allergen challenge are probably mediated through stabilization of mast cells. Recent evidence suggests that LABAs may reduce numbers of neutrophils and their associated markers; this observation needs to be confirmed in future studies and its relevance to the treatment of asthma determined.