Comparing the sensitivity of chlorophytes, cyanobacteria and diatoms to major-use antibiotics

The occurrence of antibiotic residues in the aquatic environment is an emerging concern. In contrast to daphnia and fish, algae are known to be particularly sensitive to antibiotic exposure. However, to date, a systematic evaluation of the sensitivity of different algal species to antibiotics has not been performed. The aim of the present study was therefore to explore the sensitivity of a battery of algal species towards antibiotic exposures. The present study investigated the growth inhibition effects of three major-use antibiotics, tylosin, lincomycin and trimethoprim, on seven algal species from the chlorophyte, cyanobacteria and diatom groups. Based on EC50 values, cyanobacteria (EC50 = 0.095-0.13 µmol/L) were found to be the most sensitive group to lincomycin followed by chlorophytes (EC50 = 7.36-225.73 µmol/L) and diatoms (EC50 >225.73 µmol/L). Cyanobacteria were also the most sensitive group to tylosin (EC50 = 0.09-0.092 µmol/L) but, for this compound, diatoms (EC50 = 1.33-5.7 µmol/L) were more sensitive than chlorophytes (EC50 = 4.14-81.2 µmol/L). Diatoms were most sensitive to trimethoprim (EC50 = 7.36-74.61 µmol/L) followed by cyanobacteria (EC50 = 315.78-344.45 µmol/L) and chlorophytes (EC50 >344.45 µmol/L) for trimethoprim. While the results of our study partly support the current approach to regulatory environmental risk assessment where cyanobacterial species are recommended for use on antibiotic compounds, they indicate that for some antibiotics this group might not be the most appropriate test organism. We would therefore advocate that environmental risk assessments consider data on three algal groups (chlorophytes, cyanobacteria and diatoms) and use test species from these groups that are consistently found to be the most sensitive (Pseudokirchneriella subcapitata, Anabaena flos-aquae and Navicula pelliculosa). This article is protected by copyright. All rights reserved

A systematic review and economic evaluation of exercise referral schemes in primary care: a short report

Background - It is estimated that only 39% of men and 29% of women in England achieve the levels of physical activity that are recommended to protect health and prevent disease. One approach to addressing this problem has been the development of exercise referral schemes (ERSs), in which health professionals refer patients to external exercise providers. These schemes have been widely rolled out across the UK despite concerns that they may not produce sustained changes in levels of physical activity and, therefore, may not be cost-effective interventions. The evidence to determine clinical effectiveness and cost-effectiveness was evaluated in 2009. This review seeks to update this earlier work by incorporating new evidence and re-examining the cost-effectiveness. Objectives- To assess the clinical effectiveness and cost-effectiveness of ERSs compared with usual care. Design- Exhaustive searches of relevant electronic databases and journals were undertaken to identify new studies evaluating ERSs using a randomised controlled trial (RCT) design. RCTs that incorporated a qualitative evaluation of the intervention were identified in order to explore the barriers and facilitators to the uptake of and adherence to ERSs. Data were extracted using a previously designed tool and study quality assessed for potential bias. Where data could be pooled, meta-analyses were carried out. Qualitative analysis was also undertaken using a thematic approach. The cost-effectiveness was evaluated using a Markov structure which estimated the likelihood of becoming physically active and the subsequent risk reduction on coronary heart disease (CHD), stroke and type 2 diabetes mellitus. The model adopts a lifetime horizon, and a NHS and Personal Social Services perspective was taken with discounting at 1.5% for both costs and benefits. Results - The search identified one new RCT and one new qualitative study. The new data were pooled with existing data from the 2011 review by Pavey et al. [Pavey TG, Anokye N, Taylor AH, Trueman P, Moxham T, Fox KR, et al. The clinical effectiveness and cost-effectiveness of exercise referral schemes: a systematic review and economic evaluation. Health Technol Assess 2011;15(44)] to give a total of eight studies with 5190 participants. The proportion of individuals achieving 90–150 minutes of at least moderate-intensity activity per week at 6–12 months’ follow-up was greater for ERSs than usual care (relative risk 1.12; 95% confidence interval 1.04 to 1.20). Older patients and those referred for CHD risk factors appeared to be more likely than others to increase their levels of physical activity. Qualitative evidence suggests that interventions enabling the development of social support networks are beneficial in promoting uptake and adherence. Exercise referral gained 0.003 quality-adjusted life-years (QALYs) at an additional cost of £225 per person. The estimated mean incremental cost-effectiveness ratio (ICER) in the probabilistic sensitivity analysis was £76,276. In the univariate sensitivity analysis the results were very sensitive (ICERs ranged from  £100,000) to changes in the effect of ERSs on physical activity uptake and the duration of the protective effects and the direct health-related quality-of-life gains attributable to physical activity. Conclusions - Exercise referral schemes result in a small improvement in the number of people who increase their levels of physical activity. The cost-effectiveness analysis indicates that the ICER for ERSs compared with usual care is around £76,000 per QALY, although the cost-effectiveness of ERSs is subject to considerable uncertainty.National Institute for Health Research Health Technology Assessment programme

Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with recurrent or metastatic head and neck cancer

BACKGROUND: Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum‐based chemotherapy is often a first‐line treatment. Pemetrexed has shown single‐agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed‐cisplatin for SCCHN. METHODS: In a double‐blind phase 3 trial, patients with recurrent or metastatic SCCHN and no prior systemic therapy for metastatic disease were randomized to pemetrexed (500 mg/m 2 ) plus cisplatin (75 mg/m 2 ; n = 398) or placebo plus cisplatin (75 mg/m 2 ; n = 397) to assess overall survival (OS) and secondary endpoints. RESULTS: Median OS was 7.3 months in the pemetrexed‐cisplatin arm and 6.3 months in the placebo‐cisplatin arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.75‐1.02; P = .082). Median progression‐free survival (PFS, months) was similar in both treatment arms (pemetrexed‐cisplatin, 3.6; placebo‐cisplatin, 2.8; HR, 0.88; 95% CI, 0.76‐1.03; P = .166). Among patients with performance status 0 or 1, pemetrexed‐cisplatin (n = 347) led to longer OS and PFS than placebo‐cisplatin (n = 343; 8.4 vs 6.7 months; HR, 0.83; P = .026; 4.0 vs 3.0 months; HR, 0.84; P = .044, respectively). Among patients with oropharyngeal cancers, pemetrexed‐cisplatin (n = 86) resulted in longer OS and PFS than placebo‐cisplatin (n = 106; 9.9 vs 6.1 months; HR, 0.59; P = .002; 4.0 vs 3.4 months; HR, 0.73; P = .047, respectively). Pemetrexed‐cisplatin toxicity was consistent with studies in other tumors. CONCLUSIONS: Pemetrexed‐cisplatin compared with placebo‐cisplatin did not significantly improve survival for the intent‐to‐treat population. However, in a prespecified subgroup analysis, pemetrexed‐cisplatin showed OS and PFS advantage for patients with performance status 0 or 1 or oropharyngeal cancers. Cancer 2012. © 2012 American Cancer Society. In a double‐blind, placebo‐controlled, phase 3 trial, patients with recurrent or metastatic squamous cell carcinoma of the head and neck are randomized to pemetrexed plus cisplatin or placebo plus cisplatin to assess overall survival and secondary endpoints. Pemetrexed‐cisplatin does not significantly improve survival for the intention‐to‐treat population. However, in a preplanned subgroup analysis, pemetrexed‐cisplatin leads to longer overall survival and progression‐free survival for patients with performance status 0 or 1 and patients with oropharyngeal cancers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93741/1/27449_ftp.pd

Qatar-1b: a hot Jupiter orbiting a metal-rich K dwarf star

We report the discovery and initial characterisation of Qatar-1b, a hot Jupiter orbiting a metal-rich K dwarf star, the first planet discovered by the Alsubai Project exoplanet transit survey. We describe the strategy used to select candidate transiting planets from photometry generated by the Alsubai Project instrument. We examine the rate of astrophysical and other false positives found during the spectroscopic reconnaissance of the initial batch of candidates. A simultaneous fit to the follow-up radial velocities and photometry of Qatar-1b yield a planetary mass of 1.09+/-0.08 Mjup and a radius of 1.16+/-0.05 Rjup. The orbital period and separation are 1.420033 days and 0.0234 AU for an orbit assumed to be circular. The stellar density, effective temperature and rotation rate indicate an age greater than 4 Gyr for the system.Comment: 8 pages, 5 figures, submitted to Monthly Notices of the Royal Astronomical Societ

The spin-orbit angles of the transiting exoplanets WASP-1b, WASP-24b, WASP-38b and HAT-P-8b from Rossiter-McLaughlin observations

We present observations of the Rossiter-McLaughlin effect for the transiting exoplanet systems WASP-1, WASP-24, WASP-38 and HAT-P-8, and deduce the orientations of the planetary orbits with respect to the host stars' rotation axes. The planets WASP-24b, WASP-38b and HAT-P-8b appear to move in prograde orbits and be well aligned, having sky-projected spin orbit angles consistent with zero: {\lambda} = -4.7 \pm 4.0{\deg}, {\lambda} = 15 + 33{\deg}/-43{\deg} and {\lambda} = -9.7 +9.0{\deg}/-7.7{\deg}, respectively. The host stars have Teff < 6250 K and conform with the trend of cooler stars having low obliquities. WASP-38b is a massive planet on a moderately long period, eccentric orbit so may be expected to have a misaligned orbit given the high obliquities measured in similar systems. However, we find no evidence for a large spin-orbit angle. By contrast, WASP-1b joins the growing number of misaligned systems and has an almost polar orbit, {\lambda} = -79 +4.5{\deg}/-4.3{\deg}. It is neither very massive, eccentric nor orbiting a hot host star, and therefore does not share the properties of many other misaligned systems.Comment: Submitted to MNRAS, 13 pages, 8 tables, 6 figures. Includes revised parameter values for WASP-38 and HAT-P-

A quantum spin transducer based on nano electro-mechancial resonator arrays

Implementation of quantum information processing faces the contradicting requirements of combining excellent isolation to avoid decoherence with the ability to control coherent interactions in a many-body quantum system. For example, spin degrees of freedom of electrons and nuclei provide a good quantum memory due to their weak magnetic interactions with the environment. However, for the same reason it is difficult to achieve controlled entanglement of spins over distances larger than tens of nanometers. Here we propose a universal realization of a quantum data bus for electronic spin qubits where spins are coupled to the motion of magnetized mechanical resonators via magnetic field gradients. Provided that the mechanical system is charged, the magnetic moments associated with spin qubits can be effectively amplified to enable a coherent spin-spin coupling over long distances via Coulomb forces. Our approach is applicable to a wide class of electronic spin qubits which can be localized near the magnetized tips and can be used for the implementation of hybrid quantum computing architectures

Discovery of Adamantyl Heterocyclic Ketones as Potent 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11β-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective with no activity against 11β-HSD2 and 17β-HSD1. Selected potent 11β-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes

Adamantyl Ethanone Pyridyl Derivatives: Potent and Selective Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1

Elevated levels of active glucocorticoids have been implicated in the development of several phenotypes of metabolic syndrome, such as type 2 diabetes and obesity. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the intracellular conversion of inactive cortisone to cortisol. Selective 11β-HSD1 inhibitors have shown beneficial effects in various conditions, including diabetes, dyslipidemia and obesity. A series of adamantyl ethanone pyridyl derivatives has been identified, providing potent and selective inhibitors of human 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective for this isoform, with no activity against 11β-HSD2 and 17β-HSD1. Structure–activity relationship studies reveal that an unsubstituted pyridine tethered to an adamantyl ethanone motif through an ether or sulfoxide linker provides a suitable pharmacophore for activity. The most potent inhibitors have IC50 values around 34–48 nm against human 11β-HSD1, display reasonable metabolic stability in human liver microsomes, and weak inhibition of key human CYP450 enzymes

Effects of Hypothalamic Neurodegeneration on Energy Balance

Normal aging in humans and rodents is accompanied by a progressive increase in adiposity. To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp) or proopiomelanocortin (Pomc), neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling. In previous studies, Pomc mutant mice became obese, but Agrp mutant mice were surprisingly normal, suggesting potential compensation by neuronal circuits or genetic redundancy. Here we find that Pomc-ablation mice develop obesity similar to that described for Pomc knockout mice, but also exhibit defects in compensatory hyperphagia similar to what occurs during normal aging. Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype. These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging

IgA in the horse: cloning of equine polymeric Ig receptor and J chain and characterization of recombinant forms of equine IgA

As in other mammals, immunoglobulin A (IgA) in the horse has a key role in immune defense. To better dissect equine IgA function, we isolated complementary DNA (cDNA) clones for equine J chain and polymeric Ig receptor (pIgR). When coexpressed with equine IgA, equine J chain promoted efficient IgA polymerization. A truncated version of equine pIgR, equivalent to secretory component, bound with nanomolar affinity to recombinant equine and human dimeric IgA but not with monomeric IgA from either species. Searches of the equine genome localized equine J chain and pIgR to chromosomes 3 and 5, respectively, with J chain and pIgR coding sequence distributed across 4 and 11 exons, respectively. Comparisons of transcriptional regulatory sequences suggest that horse and human pIgR expression is controlled through common regulatory mechanisms that are less conserved in rodents. These studies pave the way for full dissection of equine IgA function and open up possibilities for immune-based treatment of equine diseases