Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD

Objective We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy. Methods Three studies of ≥1-year duration met the inclusion criteria. Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%). At baseline, 57–75% of patients had ≥2% blood eosinophils. Changes in FEV1 and St George’s Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level. Results For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001). No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively). In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo). No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ. Discussion Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations

A 2-step synthesis of Combretastatin A-4 and derivatives as potent tubulin assembly inhibitors

A series of combretastatin derivatives were designed and synthesised by a two-step stereoselective synthesis by use of Wittig olefination followed by Suzuki cross-coupling. Interestingly, all new compounds (2a-2i) showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, 2a, 2b and 2e were the most active across three cancer cell lines. In addition, these compounds inhibited the polymerisation of tubulin in vitro more efficiently than CA-4. They caused cell cycle arrest in G2/M phase further confirming their ability to inhibit tubulin polymerisation

Syntheses of Combretastatin A‐4 and Related Stilbenes by Using Aqueous Conditions

Combretastatin A-4 (CA4) is a potent anti-mitotic and vascular disrupting agent. Organic chemists have been working to optimize the synthesis of CA4 for the past 3 decades, with methods requiring hazardous solvents and harsh reaction conditions. Here, we report the synthesis of CA4 and a variety of stilbenes in an aqueous Wittig system. Potassium carbonate or lithium hydroxide were used as base in this Wittig reaction to give excellent yields of mixtures of E- and Z-stilbenes. The synthesis of CA4 was achieved using tetrahydropyran (THP) or silyl protected phenolic aldehydes. The THP groups were removed using dilute acid whilst the silyl groups fortuitously fell off during work up

Chronic Obstructive Pulmonary Disease as a Predictor of Cardiovascular Risk: A Case-Control Study.

This is an Accepted Manuscript of an article published by Taylor & Francis in on 13 December 2019, available online: https://doi.org/10.1080/15412555.2019.1694501Chronic obstructive pulmonary disease (COPD) is a complex multi-morbid disorder with significant cardiac mortality. Current cardiovascular risk prediction models do not include COPD. We investigated whether COPD modifies future cardiovascular risk to determine if it should be considered in risk prediction models.Case-control study using baseline data from two randomized controlled trials performed between 2012 and 2015. Of the 90 eligible subjects, 26 COPD patients with lung hyperinflation were propensity matched for 10-year global cardiovascular risk score (QRISK2) with 26 controls having normal lung function. Patients underwent cardiac magnetic resonance imaging, arterial stiffness and lung function measurements. Differences in pulse wave velocity (PWV), total arterial compliance (TAC) and aortic distensibility were main outcome measures.PWV (mean difference 1.0 m/s, 95% CI 0.02-1.92; p = 0.033) and TAC (mean difference -0.27 mL/m2/mmHg, 95% CI 0.39-0.15; p < 0.001) were adversely affected in COPD compared to the control group. The PWV difference equates to an age, sex and risk-factor adjusted increase in relative risk of cardiovascular events and mortality of 14% and 15%, respectively.There were no differences in aortic distensibility. In the whole cohort (n = 90) QRISK2 (β = 0.045, p = 0.005) was associated with PWV in multivariate analysis. The relationship between QRISK2 and PWV were modified by COPD, where the interaction term reached significance (p = 0.014). FEV1 (β = 0.055 (0.027), p = 0.041) and pulse (B = -0.006 (0.002), p = 0.003) were associated with TAC in multivariate analysis.Markers of cardiovascular outcomes are adversely affected in COPD patients with lung hyperinflation compared to controls matched for global cardiovascular risk. Cardiovascular risk algorithms may benefit from the addition of a COPD variable to improve risk prediction and guide management.HAPPY London ClinicalTrials.gov: NCT01911910 and HZC116601; ClinicalTrials.gov: NCT01691885.The COPD trial was funded by GlaxoSmithKline (GSK), London, United Kingdom (HZC116601); SmithKline Beecham Pharma; The HAPPY London Study was funded by The Barts Charity (437/1412), London, United Kingdom

A platform for time-resolved scanning Kerr microscopy in the near-field

This is the author accepted manuscript. The final version is available from AIP Publishing via the DOI in this record.Time-resolved scanning Kerr microscopy (TRSKM) is a powerful technique for the investigation of picosecond magnetization dynamics at sub-micron length scales by means of the magneto-optical Kerr effect (MOKE). The spatial resolution of conventional (focused) Kerr microscopy using a microscope objective lens is determined by the optical diffraction limit so that the nanoscale character of the magnetization dynamics is lost. Here we present a platform to overcome this limitation by means of a near-field TRSKM that incorporates an atomic force microscope (AFM) with optical access to a metallic AFM probe with a nanoscale aperture at its tip. We demonstrate the near-field capability of the instrument through the comparison of time-resolved polar Kerr images of magnetization dynamics within a microscale NiFe rectangle acquired using both near-field and focused TRSKM techniques at a wavelength of 800 nm. The flux-closure domain state of the in-plane equilibrium magnetization provided the maximum possible dynamic polar Kerr contrast across the central domain wall and enabled an assessment of the magneto-optical spatial resolution of each technique. Line profiles extracted from the Kerr images demonstrate that the near-field spatial resolution was enhanced with respect to that of the focused Kerr images. Furthermore, the near-field polar Kerr signal (∼1 mdeg) was more than half that of the focused Kerr signal, despite the potential loss of probe light due to internal reflections within the AFM tip. We have confirmed the near-field operation by exploring the influence of the tip-sample separation and have determined the spatial resolution to be ∼550 nm for an aperture with a sub-wavelength diameter of 400 nm. The spatial resolution of the near-field TRSKM was in good agreement with finite element modeling of the aperture. Large amplitude electric field along regions of the modeled aperture that lie perpendicular to the incident polarization indicate that the aperture can support plasmonic excitations. The comparable near-field and focused polar Kerr signals suggest that such plasmonic excitations may lead to an enhanced near-field MOKE. This work demonstrates that near-field TRSKM can be performed without significant diminution of the polar Kerr signal in relatively large, sub-wavelength diameter apertures, while development of a near-field AFM probe utilizing plasmonic antennas specifically designed for measurements deeper into the nanoscale is discussed.The authors gratefully acknowledge the financial support of the UK Engineering and Physical Sciences Research Council under Grant No. EP/I038470/1 “A plasmonic antenna for magneto-optical imaging at the deep nanoscale.

Evolutionary history of the Nesophontidae, the last unplaced Recent mammal family

The mammalian evolutionary tree has lost several major clades through recent human-caused extinctions. This process of historical biodiversity loss has particularly affected tropical island regions such as the Caribbean, an area of great evolutionary diversification but poor molecular preservation. The most enigmatic of the recently extinct endemic Caribbean mammals are the Nesophontidae, a family of morphologically plesiomorphic lipotyphlan insectivores with no consensus on their evolutionary affinities, and which constitute the only major recent mammal clade to lack any molecular information on their phylogenetic placement. Here, we use a palaeogenomic approach to place Nesophontidae within the phylogeny of recent Lipotyphla. We recovered the near-complete mitochondrial genome and sequences for 17 nuclear genes from a ∼750-year-old Hispaniolan Nesophontes specimen, and identify a divergence from their closest living relatives, the Solenodontidae, more than 40 million years ago. Nesophontidae is thus an older distinct lineage than many extant mammalian orders, highlighting not only the role of island systems as “museums” of diversity that preserve ancient lineages, but also the major human-caused loss of evolutionary history

An analysis of interplanetary solar radio emissions associated with a coronal mass ejection

Coronal mass ejections (CMEs) are large-scale eruptions of magnetized plasma that may cause severe geomagnetic storms if Earth-directed. Here we report a rare instance with comprehensive in situ and remote sensing observa- tions of a CME combining white-light, radio, and plasma measurements from four different vantage points. For the first time, we have successfully applied a radio direction-finding technique to an interplanetary type II burst detected by two identical widely separated radio receivers. The derived locations of the type II and type III bursts are in general agreement with the white light CME recon- struction. We find that the radio emission arises from the flanks of the CME, and are most likely associated with the CME-driven shock. Our work demon- strates the complementarity between radio triangulation and 3D reconstruction techniques for space weather applications

The large-scale axisymmetric magnetic topology of avery-low-mass fully-convective star

Understanding how cool stars produce magnetic fields within their interiors is crucial for predicting the impact of such fields, such as the activity cycle of the Sun. In this respect, studying fully convective stars enables us to investigate the role of convective zones in magnetic field generation. We produced a magnetic map of a rapidly rotating, very-low-mass, fully convective dwarf through tomographic imaging from time series of spectropolarimetric data. Our results, which demonstrate that fully convective stars are able to trigger axisymmetric large-scale poloidal fields without differential rotation, challenge existing theoretical models of field generation in cool stars.Comment: 17 pages, 4 figures, supplementary online material (including 2 figures

Ultraluminous Infrared Galaxies

At luminosities above ~10^{11} L_sun, infrared galaxies become the dominant population of extragalactic objects in the local Universe (z < 0.5), being more numerous than optically selected starburst and Seyfert galaxies, and QSOs at comparable bolometric luminosity. At the highest luminosities, ultraluminous infrared galaxies (ULIGs: L_ir > 10^{12} L_sun), outnumber optically selected QSOs by a factor of ~1.5-2. All of the nearest ULIGs (z < 0.1) appear to be advanced mergers that are powered by both a circumnuclear starburst and AGN, both of which are fueled by an enormous concentration of molecular gas (~10^{10} M_sun) that has been funneled into the merger nucleus. ULIGs may represent a primary stage in the formation of massive black holes and elliptical galaxy cores. The intense circumnuclear starburst that accompanies the ULIG phase may also represent a primary stage in the formation of globular clusters, and the metal enrichment of the intergalactic medium by gas and dust expelled from the nucleus due to the combined forces of supernova explosions and powerful stellar winds.Comment: LaTex, 6 pages with 4 embedded .eps figures. Postscript version plus color plates available at http://www.ifa.hawaii.edu/users/sanders/astroph/s186/plates.html To appear in "Galaxy Interactions at Low and High Redshift" IAU Symposium 186, Kyoto, Japan, eds. J.E. Barnes and D.B. Sander

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret