Determining the relationship between nanoparticle characteristics and immunotoxicity: key challenges and approaches

The growing wealth of information regarding the influence that physicochemical characteristics play on nanoparticle biocompatibility and safety is allowing improved design and rationale for their development and preclinical assessment. Accurate and appropriate measurement of these characteristics accompanied by informed toxicological assessment is a necessity for the development of safe and effective nanomedicines. While particle type, formulation and mode of administration dictate the individual causes for concern through development, the benefits of nanoformulation for treatment of the diseased state are great. Here we have proposed certain considerations and suggestions, which could lead to better-informed preclinical assessment of nanomaterials for nanomedicine, as well as how this information can and should be extrapolated to the physiological state of the end user

Interactions of antiretroviral drugs with the SLC22A1 (OCT1) drug transporter

The SLC22A1 influx transporter is expressed on the basolateral membrane of hepatocytes and is involved in the excretion of numerous cations. Inhibition of SLC22A1 by several antiretrovirals, such as the protease inhibitor darunavir, has not previously been determined. In order to better understand and predict drug-SLC22A1 interactions, a range of antiretrovirals were screened for SLC22A1-associated inhibition and transport. Stable SLC22A1-expressing KCL22 cells were produced previously by nucleofection. Control KCL22 cells were transfected with the empty vector pcDNA3.1. Accumulation of tetraethylammonium (5.5 μM, 30 min) was determined in SLC22A1-expressing and mock-transfected cells with and without 50 μM of SLC22A1 inhibitor prazosin, or 50 μM of each antiretroviral drug. SLC22A1 IC50 values for efavirenz, darunavir, and prazosin were determined. Cellular accumulation of efavirenz and darunavir was also assessed in SLC22A1-expressing KCL22 cells and reversibility of this accumulation was assessed using prazosin. Tetraethylammonium accumulation was higher in SLC22A1-expressing cells compared to mock-transfected cells (10.6 ± 0.8 μM vs. 0.3 ± 0.004 μM, p = 0.009) and was significantly reduced in SLC22A1-expressing cells when co-incubated with all antiretrovirals tested except atazanavir, lamivudine, tenofovir, zidovudine, and raltegravir. Particularly noticeable was the predominance of SLC22A1 inhibitors in the protease inhibitor and non-nucleoside reverse transcriptase inhibitor classes. Absolute SLC22A1 IC50 values for efavirenz, darunavir, and prazosin were 21.8, 46.2, and 2.8 μM, respectively. Efavirenz accumulation was higher in SLC22A1-expressing cells compared to mock-transfected cells (17% higher, p = 0.009) which was reversed using prazosin, whereas no difference was observed for darunavir (p = 0.86). These data inform the mechanistic basis for disposition, drug-drug interactions and pharmacogenetic candidate gene selection for antiretroviral drugs

How well can a seasonal forecast system represent 3 hourly compound wind and precipitation extremes over Europe?

This is the author accepted manuscript. The final version is available on open access from IOP Publishing via the DOI in this recordExtreme precipitation and winds can have a severe impact on society, particularly when they occur at the same place and time. In this study the Met Office's Global Seasonal forecast system version 5 (GloSea5) model ensembles are evaluated against the reanalysis dataset ERA5, to find out how well they represent 3 hourly extreme precipitation, extreme wind and extreme co-occurring events over Europe. Although substantial differences in magnitude are found between precipitation and wind extremes between the datasets, the conditional probability of exceedance above the 99th percentile, which measures the co-occurrence between the two extremes, compares well spatially over Europe. However, significant differences in frequency are found around and over some areas of high topography. Generally GloSea5 underestimates this co-occurrence over sea. The model's co-occurring events at individual locations investigated occur with very similar synoptic patterns to ERA5, indicating that the compound extremes are produced for the correct reasons.University of Exeter College of Engineering, Mathematics and Physical SciencesMet Office Hadley Centre Climate Programm

Compound precipitation and wind extremes over Europe and their relationship to extratropical cyclones

This is the final version. Available on open access from Elsevier via the DOI in this recordWe acknowledge the data providers in the ECA&D project. Klein Tank, A.M.G. and Coauthors, 2002. Daily dataset of 20th-century surface air temperature and precipitation series for the European Climate Assessment. Int. J. of Climatol., 22, 1441–1453. Data and metadata available at https://www.ecad.euWe acknowledge the E-OBS dataset and the data providers in the ECA&D project (https://www.ecad.eu). Cornes, R., G. van der Schrier, E.J.M. van den Besselaar, and P.D. Jones. 2018: An Ensemble Version of the E-OBS Temperature and Precipitation Datasets, J. Geophys. Res. Atmos., 123. doi:10.1029/2017JD028200Extratropical cyclones and their associated extreme precipitation and winds can have a severe impact on society and the co-occurrence between the two extremes is important when assessing risk. In this study the extremal dependency measure, χ, is used to quantify the co-occurrence of extreme precipitation and wind gusts, and is investigated at individual grid points and spatially over Europe. Results using three observational datasets and a higher spatial and temporal resolution version of ERA5 than previously used confirm previous studies. Over Europe high co-occurrence is found over western coasts and low co-occurrence is found over eastern coasts. All datasets have qualitatively similar spatial patterns over most regions of Europe excluding some regions of high topography where ERA5 χ values are much larger. ERA5 represents the timings of daily extreme co-occurring events well, compared to observations. The differences in precipitation accumulation timescales are also accounted for by considering hourly, 6, 24 and 48 hourly co-occurrence. In a few regions co-occurrence changes with longer accumulations, indicating the different speeds and sizes of weather systems affecting these regions. χ in most regions has little increase by allowing a 24 h lag and lead between the precipitation and wind, with a few exceptions where χ is increased by up to 24%. Regions with the larger of these increases are on or around elevated topography. Using an objective feature tracking method, insight into the spatial pattern of extreme precipitation and wind within cyclones over Europe is given. As well as suggesting how many hours apart the extremes occur from one another in a particular location. Extreme co-occurring events are associated with cyclones far more of the time than non extreme events. Given an extreme co-occurring event the chance of a cyclone being within 1110 km is more than 70% for much of Europe. Regions with low co-occurrence have extremes caused by different weather systems and regions with large co-occurrence have both extremes caused by the same weather system. Cyclones linked to extreme events, particularly co-occurring and extreme wind, have larger intensity than those not and for most of Europe these cyclones also have faster mean speed.Natural Environment Research Council (NERC)Met Office Hadley Centre Climate Programm

Investigations on the Peach 4 Debrite, a Late Pleistocene Mass Movement on the Northwest British Continental Margin

The Peach 4 debrite is the most recent in a series of large scale Pleistocene MTDs within the Barra fan on the northwest British continental margin. Geophysical data indicate that Peach 4 was formed through a combination of blocky and muddy debris flows and affects an area of ~ 700 km2. BGS core sample 56 -10 36, located directly over the Peach 4 debrite, provides a minimum age of 14.68 ka cal BP for the last major failure. An upwards fining turbidite sequence in BGS core sample 56 -10 239 is associ-ated with increased As and S concentrations, indicators of diagenetic pyrite which forms under anoxic conditions. It is proposed that As and S concentrations may pro-vide a method of distinguishing between contourite and turbidite sedimentation, though further research is required

Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells

The anti-diabetic drug metformin regulates T-cell responses to immune activation and is proposed to function by regulating the energy-stress-sensing adenosine-monophosphate-activated protein kinase (AMPK). However, the molecular details of how metformin controls T cell immune responses have not been studied nor is there any direct evidence that metformin acts on T cells via AMPK. Here, we report that metformin regulates cell growth and proliferation of antigen-activated T cells by modulating the metabolic reprogramming that is required for effector T cell differentiation. Metformin thus inhibits the mammalian target of rapamycin complex I signalling pathway and prevents the expression of the transcription factors c-Myc and hypoxia-inducible factor 1 alpha. However, the inhibitory effects of metformin on T cells did not depend on the expression of AMPK in T cells. Accordingly, experiments with metformin inform about the importance of metabolic reprogramming for T cell immune responses but do not inform about the importance of AMPK

Using magnetoencephalography to investigate brain activity during high frequency deep brain stimulation in a cluster headache patient

PURPOSE: Treatment-resistant cluster headache can be successfully alleviated with deep brain stimulation (DBS) of the posterior hypothalamus [1]. Magnetoencephalography (MEG) is a non-invasive functional imaging technique with both high temporal and high spatial resolution. However, it is not known whether the inherent electromagnetic (EM) noise produced by high frequency DBS is compatible with MEG. MATERIALS AND METHODS: We used MEG to record brain activity in an asymptomatic cluster headache patient with a DBS implanted in the right posterior hypothalamus while he made small movements during periods of no stimulation, 7 Hz stimulation and 180 Hz stimulation. RESULTS: We were able to measure brain activity successfully both during low and high frequency stimulation. Analysis of the MEG recordings showed similar activation in motor areas in during the patient's movements as expected. We also observed similar activations in cortical and subcortical areas that have previously been reported to be associated with pain when the patient's stimulator was turned on or off [2,3]. CONCLUSION: These results show that MEG can be used to measure brain activity regardless of the presence of high frequency deep brain stimulation

Predictive significance of the six-minute walk distance for long-term survival in chronic hypercapnic respiratory failure

Background: The 6-min walk distance ( 6-MWD) is a global marker of functional capacity and prognosis in chronic obstructive pulmonary disease ( COPD), but less explored in other chronic respiratory diseases. Objective: To study the role of 6-MWD in chronic hypercapnic respiratory failure ( CHRF). Methods: In 424 stable patients with CHRF and non-invasive ventilation ( NIV) comprising COPD ( n = 197), restrictive diseases ( RD; n = 112) and obesity-hypoventilation- syndrome ( OHS; n = 115), the prognostic value of 6-MWD for long- term survival was assessed in relation to that of body mass index (BMI), lung function, respiratory muscle function and laboratory parameters. Results: 6-MWD was reduced in patients with COPD ( median 280 m; quartiles 204/350 m) and RD ( 290 m; 204/362 m) compared to OHS ( 360 m; 275/440 m; p <0.001 each). Overall mortality during 24.9 (13.1/40.5) months was 22.9%. In the 424 patients with CHRF, 6-MWD independently predicted mortality in addition to BMI, leukocytes and forced expiratory volume in 1 s ( p <0.05 each). In COPD, 6-MWD was strongly associated with mortality using the median {[} p <0.001, hazard ratio ( HR) = 3.75, 95% confidence interval (CI): 2.24-6.38] or quartiles as cutoff levels. In contrast, 6-MWD was only significantly associated with impaired survival in RD patients when it was reduced to 204 m or less (1st quartile; p = 0.003, HR = 3.31, 95% CI: 1.73-14.10), while in OHS 6-MWD had not any prognostic value. Conclusions: In patients with CHRF and NIV, 6-MWD was predictive for long- term survival particularly in COPD. In RD only severely reduced 6-MWD predicted mortality, while in OHS 6-MWD was relatively high and had no prognostic value. These results support a disease-specific use of 6-MWD in the routine assessment of patients with CHRF. Copyright (C) 2007 S. Karger AG, Basel

Analysis of factors influencing the ultrasonic fetal weight estimation

Objective: The aim of our study was the evaluation of sonographic fetal weight estimation taking into consideration 9 of the most important factors of influence on the precision of the estimation. Methods: We analyzed 820 singleton pregnancies from 22 to 42 weeks of gestational age. We evaluated 9 different factors that potentially influence the precision of sonographic weight estimation ( time interval between estimation and delivery, experts vs. less experienced investigator, fetal gender, gestational age, fetal weight, maternal BMI, amniotic fluid index, presentation of the fetus, location of the placenta). Finally, we compared the results of the fetal weight estimation of the fetuses with poor scanning conditions to those presenting good scanning conditions. Results: Of the 9 evaluated factors that may influence accuracy of fetal weight estimation, only a short interval between sonographic weight estimation and delivery (0-7 vs. 8-14 days) had a statistically significant impact. Conclusion: Of all known factors of influence, only a time interval of more than 7 days between estimation and delivery had a negative impact on the estimation