Diverse functions of clusterin promote and protect against the development of pulmonary fibrosis.

Pulmonary fibrosis is a progressive scarring disorder of the lung with dismal prognosis and no curative therapy. Clusterin, an extracellular chaperone and regulator of cell functions, is reduced in bronchoalveolar lavage fluid of patients with pulmonary fibrosis. However, its distribution and role in normal and fibrotic human lung are incompletely characterized. Immunohistochemical localization of clusterin revealed strong staining associated with fibroblasts in control lung and morphologically normal areas of fibrotic lung but weak or undetectable staining in fibrotic regions and particularly fibroblastic foci. Clusterin also co-localized with elastin in vessel walls and additionally with amorphous elastin deposits in fibrotic lung. Analysis of primary lung fibroblast isolates in vitro confirmed the down-regulation of clusterin expression in fibrotic compared with control lung fibroblasts and further demonstrated that TGF-β1 is capable of down-regulating fibroblast clusterin expression. shRNA-mediated down-regulation of clusterin did not affect TGF-β1-induced fibroblast-myofibroblast differentiation but inhibited fibroblast proliferative responses and sensitized to apoptosis. Down-regulation of clusterin in fibrotic lung fibroblasts at least partly due to increased TGF-β1 may therefore represent an appropriate but insufficient response to limit fibroproliferation. Reduced expression of clusterin in the lung may also limit its extracellular chaperoning activity contributing to dysregulated deposition of extracellular matrix proteins

Predicting mortality after acute coronary syndromes in people with chronic obstructive pulmonary disease

Objective To assess the accuracy of Global Registry of Acute Coronary Events (GRACE) scores in predicting mortality at 6 months for people with chronic obstructive pulmonary disease (COPD) and to investigate how it might be improved. Methods Data were obtained on 481 849 patients with acute coronary syndrome admitted to UK hospitals between January 2003 and June 2013 from the Myocardial Ischaemia National Audit Project (MINAP) database. We compared risk of death between patients with COPD and those without COPD at 6 months, adjusting for predicted risk of death. We then assessed whether several modifications improved the accuracy of the GRACE score for people with COPD. Results The risk of death after adjusting for GRACE score predicted that risk of death was higher for patients with COPD than that for other patients (RR 1.29, 95% CI 1.28 to 1.33). Adding smoking into the GRACE score model did not improve accuracy for patients with COPD. Either adding COPD into the model (relative risk (RR) 1.00, 0.94 to 1.02) or multiplying the GRACE score by 1.3 resulted in better performance (RR 0.99, 0.96 to 1.01). Conclusions GRACE scores underestimate risk of death for people with COPD. A more accurate prediction of risk of death can be obtained by adding COPD into the GRACE score equation, or by multiplying the GRACE score predicted risk of death by 1.3 for people with COPD. This means that one third of patients with COPD currently classified as low risk should be classified as moderate risk, and could be considered for more aggressive early treatment after non-ST-segment elevation myocardial infarction or unstable angina

Quantitative lipoprotein subclass and low molecular weight metabolite analysis in human serum and plasma by 1H NMR spectroscopy in a multilaboratory trial

We report an extensive 600 MHz NMR trial of a quantitative lipoprotein and small molecule measurements in human blood serum and plasma. Five centers with eleven 600 MHz NMR spectrometers were used to analyze 98 samples including: 20 QCs, 37 commercially sourced, paired serum and plasma samples and 2 National Institute of Science and Technology, NIST, reference material 1951c replicates. Samples were analyzed using rigorous protocols for sample preparation and experimental acquisition. A commercial lipoprotein subclass analysis was used to quantify 105 lipoprotein subclasses and 24 low molecular weight metabolites from the nuclear magnetic resonance, NMR, spectra. For all spectrometers, the instrument specific variance in measuring internal quality controls, QCs, was lower than the percentage described by the National Cholesterol Education Program, NCEP, criteria for lipid testing (triglycerides<2.7%, cholesterol<2.8%; LDL-cholesterol<2.8%; HDL-cholesterol<2.3%), showing exceptional reproducibility for direct quantitation of lipoproteins in both matrices. The average RSD for the 105 lipoprotein parameters in the 11 instruments was 4.6% and 3.9% for the two NIST samples while it was 38% and 40% for the 37 commercially sourced plasmas and sera, respectively, showing negligible analytical compared to biological variation. The coefficient of variance, CV, obtained for the quantification of the small molecules across the 11 spectrometers was below 15% for 20 out of the 24 metabolites analyzed. This study provides further evidence of the suitability of NMR for high-throughput lipoprotein subcomponent analysis and small molecule quantitation with the exceptional reproducibility required for clinical and other regulatory settings

Development and Application of Ultra-Performance Liquid Chromatography-TOF MS for Precision Large Scale Urinary Metabolic Phenotyping

To better understand the molecular mechanisms underpinning physiological variation in human populations, metabolic phenotyping approaches are increasingly being applied to studies involving hundreds and thousands of biofluid samples. Hyphenated ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) has become a fundamental tool for this purpose. However, the seemingly inevitable need to analyze large studies in multiple analytical batches for UPLC-MS analysis poses a challenge to data quality which has been recognized in the field. Herein, we describe in detail a fit-for-purpose UPLC-MS platform, method set, and sample analysis workflow, capable of sustained analysis on an industrial scale and allowing batch-free operation for large studies. Using complementary reversed-phase chromatography (RPC) and hydrophilic interaction liquid chromatography (HILIC) together with high resolution orthogonal acceleration time-of-flight mass spectrometry (oaTOF-MS), exceptional measurement precision is exemplified with independent epidemiological sample sets of approximately 650 and 1000 participant samples. Evaluation of molecular reference targets in repeated injections of pooled quality control (QC) samples distributed throughout each experiment demonstrates a mean retention time relative standard deviation (RSD) of <0.3% across all assays in both studies and a mean peak area RSD of <15% in the raw data. To more globally assess the quality of the profiling data, untargeted feature extraction was performed followed by data filtration according to feature intensity response to QC sample dilution. Analysis of the remaining features within the repeated QC sample measurements demonstrated median peak area RSD values of <20% for the RPC assays and <25% for the HILIC assays. These values represent the quality of the raw data, as no normalization or feature-specific intensity correction was applied. While the data in each experiment was acquired in a single continuous batch, instances of minor time-dependent intensity drift were observed, highlighting the utility of data correction techniques despite reducing the dependency on them for generating high quality data. These results demonstrate that the platform and methodology presented herein is fit-for-use in large scale metabolic phenotyping studies, challenging the assertion that such screening is inherently limited by batch effects. Details of the pipeline used to generate high quality raw data and mitigate the need for batch correction are provided

Roadmap of optical communications

© 2016 IOP Publishing Ltd. Lightwave communications is a necessity for the information age. Optical links provide enormous bandwidth, and the optical fiber is the only medium that can meet the modern society's needs for transporting massive amounts of data over long distances. Applications range from global high-capacity networks, which constitute the backbone of the internet, to the massively parallel interconnects that provide data connectivity inside datacenters and supercomputers. Optical communications is a diverse and rapidly changing field, where experts in photonics, communications, electronics, and signal processing work side by side to meet the ever-increasing demands for higher capacity, lower cost, and lower energy consumption, while adapting the system design to novel services and technologies. Due to the interdisciplinary nature of this rich research field, Journal of Optics has invited 16 researchers, each a world-leading expert in their respective subfields, to contribute a section to this invited review article, summarizing their views on state-of-the-art and future developments in optical communications

Bus accident severity and passenger injury: evidence from Denmark

Purpose Bus safety is a concern not only in developing countries, but also in the U.S. and Europe. In Denmark, disentangling risk factors that are positively or negatively related to bus accident severity and injury occurrence to bus passengers can contribute to promote safety as an essential principle of sustainable transit and advance the vision “every accident is one too many”. Methods Bus accident data were retrieved from the national accident database for the period 2002–2011. A generalized ordered logit model allows analyzing bus accident severity and a logistic regression enables examining occurrence of injury to bus passengers. Results Bus accident severity is positively related to (i) the involvement of vulnerable road users, (ii) high speed limits, (iii) night hours, (iv) elderly drivers of the third party involved, and (v) bus drivers and other drivers crossing in yellow or red light. Occurrence of injury to bus passengers is positively related to (i) the involvement of heavy vehicles, (ii) crossing intersections in yellow or red light, (iii) open areas, (iv) high speed limits, and (v) slippery road surface. Conclusions The findings of the current study provide a comprehensive picture of the bus safety situation in Denmark and suggest the necessity of further research into bus drivers’ attitudes and perceptions of risks and road users’ perceptions of bus operations. Moreover, these findings suggest the need for further training into bus drivers’ hazard recognition skills and infrastructural solutions to forgive possible driving errors

Drug coverage in treatment of malaria and the consequences for resistance evolution - evidence from the use of sulphadoxine/pyrimethamine

BACKGROUND\ud \ud It is argued that, the efficacy of anti-malarials could be prolonged through policy-mediated reductions in drug pressure, but gathering evidence of the relationship between policy, treatment practice, drug pressure and the evolution of resistance in the field is challenging. Mathematical models indicate that drug coverage is the primary determinant of drug pressure and the driving force behind the evolution of drug resistance. These models show that where the basis of resistance is multigenic, the effects of selection can be moderated by high recombination rates, which disrupt the associations between co-selected resistance genes.\ud \ud METHODS\ud \ud To test these predictions, dhfr and dhps frequency changes were measured during 2000-2001 while SP was the second-line treatment and contrasted these with changes during 2001-2002 when SP was used for first-line therapy. Annual cross sectional community surveys carried out before, during and after the policy switch in 2001 were used to collect samples. Genetic analysis of SP resistance genes was carried out on 4,950 Plasmodium falciparum infections and the selection pressure under the two policies compared.\ud \ud RESULTS\ud \ud The influence of policy on the parasite reservoir was profound. The frequency of dhfr and dhps resistance alleles did not change significantly while SP was the recommended second-line treatment, but highly significant changes occurred during the subsequent year after the switch to first line SP. The frequency of the triple mutant dhfr (N51I,C59R,S108N) allele (conferring pyrimethamine resistance) increased by 37% - 63% and the frequency of the double A437G, K540E mutant dhps allele (conferring sulphadoxine resistance) increased 200%-300%. A strong association between these unlinked alleles also emerged, confirming that they are co-selected by SP.\ud \ud CONCLUSION\ud \ud The national policy change brought about a shift in treatment practice and the resulting increase in coverage had a substantial impact on drug pressure. The selection applied by first-line use is strong enough to overcome recombination pressure and create significant linkage disequilibrium between the unlinked genetic determinants of pyrimethamine and sulphadoxine resistance, showing that recombination is no barrier to the emergence of resistance to combination treatments when they are used as the first-line malaria therapy

Prevalence of Disorders Recorded in Dogs Attending Primary-Care Veterinary Practices in England

Purebred dog health is thought to be compromised by an increasing occurence of inherited diseases but inadequate prevalence data on common disorders have hampered efforts to prioritise health reforms. Analysis of primary veterinary practice clinical data has been proposed for reliable estimation of disorder prevalence in dogs. Electronic patient record (EPR) data were collected on 148,741 dogs attending 93 clinics across central and south-eastern England. Analysis in detail of a random sample of EPRs relating to 3,884 dogs from 89 clinics identified the most frequently recorded disorders as otitis externa (prevalence 10.2%, 95% CI: 9.1-11.3), periodontal disease (9.3%, 95% CI: 8.3-10.3) and anal sac impaction (7.1%, 95% CI: 6.1-8.1). Using syndromic classification, the most prevalent body location affected was the head-and-neck (32.8%, 95% CI: 30.7-34.9), the most prevalent organ system affected was the integument (36.3%, 95% CI: 33.9-38.6) and the most prevalent pathophysiologic process diagnosed was inflammation (32.1%, 95% CI: 29.8-34.3). Among the twenty most-frequently recorded disorders, purebred dogs had a significantly higher prevalence compared with crossbreds for three: otitis externa (P = 0.001), obesity (P = 0.006) and skin mass lesion (P = 0.033), and popular breeds differed significantly from each other in their prevalence for five: periodontal disease (P = 0.002), overgrown nails (P = 0.004), degenerative joint disease (P = 0.005), obesity (P = 0.001) and lipoma (P = 0.003). These results fill a crucial data gap in disorder prevalence information and assist with disorder prioritisation. The results suggest that, for maximal impact, breeding reforms should target commonly-diagnosed complex disorders that are amenable to genetic improvement and should place special focus on at-risk breeds. Future studies evaluating disorder severity and duration will augment the usefulness of the disorder prevalence information reported herein