The transferrin receptor CD71 delineates functionally distinct airway macrophage subsets during idiopathic pulmonary fibrosis

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease with limited therapeutic options. Airway macrophages (AMs) are key components of the defence of the airways and are implicated in the pathogenesis of IPF. Alterations in iron metabolism have been described during fibrotic lung disease and in murine models of lung fibrosis. However, the role of transferrin receptor-1 (CD71)-expressing AMs in IPF is not known. OBJECTIVES: To assess the role of CD71 expressing AMs in the IPF-lung. METHODS: We utilized multi-parameter flow cytometry, gene expression analysis and phagocytosis/transferrin uptake assays to delineate the role of AMs expressing, or lacking, CD71 in the BAL of patients with IPF or healthy controls. MEASUREMENTS AND MAIN RESULTS: There was a distinct increase in proportions of AMs lacking CD71 in IPF patients in comparison to healthy controls. Levels of BAL transferrin were enhanced in IPF-BAL and furthermore, CD71- AMs had an impaired ability to sequester transferrin. CD71+ and CD71- AMs were phenotypically, functionally and transcriptionally distinct, with CD71- AMs characterised by reduced expression of markers of macrophage maturity, impaired phagocytosis and enhanced expression of pro-fibrotic genes. Importantly, proportions of AMs lacking CD71 were independently associated with worse survival, underlining the importance of this population in IPF and as a potential therapeutic target. CONCLUSIONS: Taken together these data highlight how CD71 delineates AM subsets which play distinct roles in IPF and furthermore, CD71- AMs may be an important pathogenic component of fibrotic lung disease

First administration to man of Org 25435, an intravenous anaesthetic: A Phase 1 Clinical Trial

BACKGROUND: Org 25435 is a new water-soluble alpha-amino acid ester intravenous anaesthetic which proved satisfactory in animal studies. This study aimed to assess the safety, tolerability and efficacy of Org 25435 and to obtain preliminary pharmacodynamic and pharmacokinetic data. METHODS: In the Short Infusion study 8 healthy male volunteers received a 1 minute infusion of 0.25, 0.5, 1.0, or 2.0 mg/kg (n = 2 per group); a further 10 received 3.0 mg/kg (n = 5) or 4.0 mg/kg (n = 5). Following preliminary pharmacokinetic modelling 7 subjects received a titrated 30 minute Target Controlled Infusion (TCI), total dose 5.8-20 mg/kg. RESULTS: Within the Short Infusion study, all subjects were successfully anaesthetised at 3 and 4 mg/kg. Within the TCI study 5 subjects were anaesthetised and 2 showed signs of sedation. Org 25435 caused hypotension and tachycardia at doses over 2 mg/kg. Recovery from anaesthesia after a 30 min administration of Org 25435 was slow (13.7 min). Pharmacokinetic modelling suggests that the context sensitive half-time of Org 25435 is slightly shorter than that of propofol in infusions up to 20 minutes but progressively longer thereafter. CONCLUSIONS: Org 25435 is an effective intravenous anaesthetic in man at doses of 3 and 4 mg/kg given over 1 minute. Longer infusions can maintain anaesthesia but recovery is slow. Hypotension and tachycardia during anaesthesia and slow recovery of consciousness after cessation of drug administration suggest this compound has no advantages over currently available intravenous anaesthetics

How does export compliance influence the internationalization of firms:Is it a thread or an opportunity?

Internationalization is a complex process, in which firms face various challenges that may lead to opportunities or threads. One of these challenges is export compliance. The objective of this paper is to disentangle the nature of export compliance and its function in international entrepreneurship. This study outlines a perspective on the export control system, discusses the most relative legislation, reveals the consequences of non-compliance and provides a case study and finally explains the function of export compliance in the international activities of firms

More frequent, more costly? Health economic modelling aspects of monitoring glaucoma patients in England

BACKGROUND: Chronic open angle glaucoma (COAG) is an age-related eye disease causing irreversible loss of visual field (VF). Health service delivery for COAG is challenging given the large number of diagnosed patients requiring lifelong periodic monitoring by hospital eye services. Yet frequent examination better determines disease worsening and speed of VF loss under treatment. We examine the cost-effectiveness of increasing frequency of VF examinations during follow-up using a health economic model. METHODS: Two different VF monitoring schemes defined as current practice (annual VF testing) and proposed practice (three VF tests per year in the first 2 years after diagnosis) were examined. A purpose written health economic Markov model is used to test the hypothesis that cost effectiveness improves by implementing proposed practice on groups of patients stratified by age and severity of COAG. Further, a new component of the model, estimating costs of visual impairment, was added. Results were derived from a simulated cohort of 10000 patients with quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) used as main outcome measures. RESULTS: An ICER of £21,392 per QALY was derived for proposed practice improving to a value of £11,382 once savings for prevented visual impairment was added to the model. Proposed practice was more cost-effective in younger patients. Proposed practice for patients with advanced disease at diagnosis generated ICERs > £60,000 per QALY; these cases would likely be on the most intensive treatment pathway making clinical information on speed of VF loss redundant. Sensitivity analysis indicated results to be robust in relation to hypothetical willingness to pay threshold identified by national guidelines, although greatest uncertainty was allied to estimates of implementation and visual impairment costs. CONCLUSION: Increasing VF monitoring at the earliest stages of follow-up for COAG appears to be cost-effective depending on reasonable assumptions about implementation costs. Our health economic model highlights benefits of stratifying patients to more or less monitoring based on age and stage of disease at diagnosis; a prospective study is needed to prove these findings. Further, this works highlights gaps in knowledge about long term costs of visual impairment

Intertwined superfluid and density wave order in two-dimensional 4He

Superfluidity is a manifestation of the operation of the laws of quantum mechanics on a macroscopic scale. The conditions under which superfluidity becomes manifest have been extensively explored experimentally in both quantum liquids (liquid 4He being the canonical example) and ultracold atomic gases1, 2, including as a function of dimensionality3, 4. Of particular interest is the hitherto unresolved question of whether a solid can be superfluid5, 6. Here we report the identification of a new state of quantum matter with intertwined superfluid and density wave order in a system of two-dimensional bosons subject to a triangular lattice potential. Using a torsional oscillator we have measured the superfluid response of the second atomic layer of 4He adsorbed on the surface of graphite, over a wide temperature range down to 2 mK. Superfluidity is observed over a narrow range of film densities, emerging suddenly and subsequently collapsing towards a quantum critical point. The unusual temperature dependence of the superfluid density in the limit of zero temperature and the absence of a clear superfluid onset temperature are explained, self-consistently, by an ansatz for the excitation spectrum, reflecting density wave order, and a quasi-condensate wavefunction breaking both gauge and translational symmetry

Connexin 43 mediated gap junctional communication enhances breast tumor cell diapedesis in culture

INTRODUCTION: Metastasis involves the emigration of tumor cells through the vascular endothelium, a process also known as diapedesis. The molecular mechanisms regulating tumor cell diapedesis are poorly understood, but may involve heterocellular gap junctional intercellular communication (GJIC) between tumor cells and endothelial cells. METHOD: To test this hypothesis we expressed connexin 43 (Cx43) in GJIC-deficient mammary epithelial tumor cells (HBL100) and examined their ability to form gap junctions, establish heterocellular GJIC and migrate through monolayers of human microvascular endothelial cells (HMVEC) grown on matrigel-coated coverslips. RESULTS: HBL100 cells expressing Cx43 formed functional heterocellular gap junctions with HMVEC monolayers within 30 minutes. In addition, immunocytochemistry revealed Cx43 localized to contact sites between Cx43 expressing tumor cells and endothelial cells. Quantitative analysis of diapedesis revealed a two-fold increase in diapedesis of Cx43 expressing cells compared to empty vector control cells. The expression of a functionally inactive Cx43 chimeric protein in HBL100 cells failed to increase migration efficiency, suggesting that the observed up-regulation of diapedesis in Cx43 expressing cells required heterocellular GJIC. This finding is further supported by the observation that blocking homocellular and heterocellular GJIC with carbenoxolone in co-cultures also reduced diapedesis of Cx43 expressing HBL100 tumor cells. CONCLUSION: Collectively, our results suggest that heterocellular GJIC between breast tumor cells and endothelial cells may be an important regulatory step during metastasis

The impact of quality management systems on construction performance in the North West of England

As the total construction output in the North West of England (NWE) is forecast to rise by an average of 2.5% over the next five years. It is imperative for organizations in the region to improve their overall construction performance, particularly if they are to hit the targets presented by UK Government in the construction 2025 report. Despite the known benefits of quality management systems (QMS) its implementation in relation to construction performance is very limited, particularly in the UK. Therefore, the purpose of this paper is to examine whether QMS can affect construction performance in the NWE. A pragmatic mixed method approach of sequential explanatory strategy was adopted to conduct this research. This initially involved a quantitative approach of questionnaire surveys to gain opinions and views of a representative sample of industry professionals based in the NWE. The quantitative results were analyzed to discover relationships in the data and further formulate the questions for the qualitative interviews. Three interviews with leading industry professionals were then conducted and the data was analyzed using a thematic approach. The themes identified in the interviews were then cross-referenced with the data discovered in the questionnaire survey and literature review. The findings provide a clear indication that the implementation of a QMS has a positive effect on construction performance in the NWE. Immediate improvements in efficiency of a construction organization when implementing a QMS were discovered, including greater managerial control and the recording and reduction in defects. Long term effects of changing company attitude by setting out company requirements and responsibilities through highlighting the significance of quality, and furthermore encouraging a culture of co-operation and teamwork, were also proven to increase construction performance as time progresses. To further enhance this research the focus could be on the whole of the UK. However, a greater amount of time would be required to gain the required representative sample. Furthermore, although the questionnaire survey was distributed equally within the selected sample, a greater number of respondents working for contractors responded. Therefore, the respondents of the questionnaire survey were not equal in terms of organization (client, contractor, sub-contractor, project manager). According to the best knowledge of the authors and through searching many sources, there are no specific studies examining QMS and their effect on construction performance in the UK and particularly in the NWE. Therefore, it is believed the study is the first of its kind. The study discovered many findings that can be considered as a contribution to practice and theory. Moreover, it can be considered as a fundamental base for future studies in this research area. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group

Cloning, purification and characterisation of a recombinant purine nucleoside phosphorylase from Bacillus halodurans Alk36

A purine nucleoside phosphorylase from the alkaliphile Bacillus halodurans Alk36 was cloned and overexpressed in Escherichia coli. The enzyme was purified fivefold by membrane filtration and ion exchange. The purified enzyme had a Vmax of 2.03 × 10−9 s −1 and a Km of 206 μM on guanosine. The optimal pH range was between 5.7 and 8.4 with a maximum at pH 7.0. The optimal temperature for activity was 70°C and the enzyme had a half life at 60°C of 20.8 h

APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; A case control study from central Norway

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to analyze factors influencing the risk and timing of Alzheimer's disease (AD) in central Norway. The <it>APOE </it>ε4 allele is the only consistently identified risk factor for late onset Alzheimer's disease (LOAD). We have described the allele frequencies of the apolipoprotein E gene (<it>APOE</it>) in a large population of patients with AD compared to the frequencies in a cognitively-normal control group, and estimated the effect of the <it>APOE </it>ε4 allele on the risk and the age at onset of AD in this population.</p> <p>Methods</p> <p>376 patients diagnosed with AD and 561 cognitively-normal control individuals with no known first degree relatives with dementia were genotyped for the <it>APOE </it>alleles. Allele frequencies and genotypes in patients and control individuals were compared. Odds Ratio for developing AD in different genotypes was calculated.</p> <p>Results</p> <p>Odds Ratio (OR) for developing AD was significantly increased in carriers of the <it>APOE </it>ε4 allele compared to individuals with the <it>APOE </it>ε3/ε3 genotype. Individuals carrying <it>APOE </it>ε4/ε4 had OR of 12.9 for developing AD, while carriers of <it>APOE </it>ε2/ε4 and <it>APOE </it>ε3/ε4 had OR of 3.2 and 4.2 respectively. The effect of the <it>APOE </it>ε4 allele was weaker with increasing age. Carrying the <it>APOE </it>ε2 allele showed no significant protective effect against AD and did not influence age at onset of the disease. Onset in LOAD patients was significantly reduced in a dose dependent manner from 78.4 years in patients without the <it>APOE </it>ε4 allele, to 75.3 in carriers of one <it>APOE </it>ε4 allele and 72.9 in carriers of two <it>APOE </it>ε4 alleles. Age at onset in early onset AD (EOAD) was not influenced by <it>APOE </it>ε4 alleles.</p> <p>Conclusion</p> <p><it>APOE </it>ε4 is a very strong risk factor for AD in the population of central Norway, and lowers age at onset of LOAD significantly.</p

Polyandry Is a Common Event in Wild Populations of the Tsetse Fly Glossina fuscipes fuscipes and May Impact Population Reduction Measures

Glossina fuscipes fuscipes is the most common tsetse species in Uganda where it is responsible for transmitting Trypanosoma brucei rhodensiense and Trypanosoma brucei gambiense parasites causing sleeping sickness in humans in addition to related trypanosomes that cause Nagana in cattle. An understanding of the reproductive biology of this vector is essential for the application of sustainable control/eradication methods such as Sterile Insect Technique (SIT). We have analysed the number of times a female mates in the wild as this aspect of the reproductive behaviour may affect the stability and size of populations. We provide evidence that remating is a common event in the wild and females store sperm from multiple males, which may potentially be used for insemination. In vector eradication programmes, re-infestation of cleared areas and/or in cases of residual populations, the occurrence of remating may unfortunately enhance the reproductive potential of the re-invading propagules. We suggest that population age structure may influence remating frequency. Considering the seasonal demographic changes that this fly undergoes during the dry and wet seasons, control programmes based on SIT should release large numbers of sterile males, even in residual surviving target populations, in the dry season