Activity of chitosan and its derivatives against Leishmania major and L. mexicana in vitro

There is an urgent need for safe, efficacious, affordable and field-adapted drugs for the treatment of cutaneous leishmaniasis which affects around 1.5 million new people worldwide annually. Chitosan, a biodegradable cationic polysaccharide, has previously been reported to have antimicrobial, anti-leishmanial and immunostimulatory activities. We investigated the in vitro activity of chitosan and several of its derivatives and showed that pH of the culture medium plays a critical role on anti-leishmanial activity of chitosan against both extracellular promastigotes and intracellular amastigotes of Leishmania major and Leishmania mexicana Chitosan and its derivatives were approximately 7-20 times more active at pH 6.5 than at pH 7.5 with high molecular weight chitosan being the most potent. High molecular weight chitosan stimulated the production of nitric oxide and reactive oxygen species by uninfected and Leishmania infected macrophages in a time and dose dependent manner at pH 6.5. Despite the in vitro activation of bone marrow macrophages by chitosan to produce nitric oxide and reactive oxygen species, we showed that the anti-leishmanial activity of chitosan was not mediated by these metabolites. Finally, we showed that rhodamine-labelled chitosan is taken up by pinocytosis and accumulates in the parasitophorous vacuole of Leishmania infected macrophages

Relation between Skin Pharmacokinetics and Efficacy in AmBisome Treatment of Murine Cutaneous Leishmaniasis

AmBisome® (LAmB), a liposomal formulation of amphotericin B (AmB), is a second-line treatment for the parasitic skin disease cutaneous leishmaniasis (CL). Little is known about its tissue distribution and pharmacodynamics to inform clinical use in CL. Here, we compared the skin pharmacokinetics of LAmB with Fungizone® (DAmB), the deoxycholate form of AmB, in murine models of Leishmania major CL. Drug levels at the target site (the localized lesion) 48 hours after single intravenous (IV) dosing of the individual AmB formulations (1 mg/kg of body weight) were similar, but were 3-fold higher for LAmB than for DAmB on day 10 after multiple administrations (1 mg/kg on days 0, 2, 4, 6 and 8). After single and multiple dosing, intralesional concentrations were respectively 5- and 20-fold higher compared to those in the healthy control skin of the same infected mice. We then evaluated how drug levels in the lesion after LAmB treatment relate to therapeutic outcomes. After five administrations of the drug at 0, 6.25 or 12.5 mg/kg (IV), there was a clear correlation between dose level, intralesional AmB concentration and relative reduction in parasite load and lesion size (R2 values > 0.9). This study confirms the improved efficacy of the liposomal over the deoxycholate AmB formulation in experimental CL, which is related to higher intralesional drug accumulation

A procedure for indirect and automatic measurement of prior austenite grain size in bainite/martensite microstructures

An alternative procedure for indirect and automatic measurement of the prior austenite grain size (PAGS) in bainite/martensite is proposed in this work. It consists in the determination of an effective grain size (EGS) by means of statistical post-processing of electron backscatter diffraction (EBSD) data. The algorithm developed for that purpose, which is available on-line, has been applied to simulated EBSD maps as well as to both a nanocrystalline bainitic steel and a commercial hot-rolled air-cooled steel with a granular bainitic microstructure. The new proposed method has been proven to be robust and results are in good agreement with conventional PAGS measurements. The added value of the procedure comes from its simplicity, as no parent reconstruction is involved during the process, and its suitability for low-magnification EBSD maps, thus allowing a large step-size and coverage of a substantially broader area of the sample than the previous methods reported.Spanish Ministry of Economy and Competitiveness for funding this research under the contract IPT-2012-0320-420000. L.M.-R. also acknowledges the Spanish Ministry of Economy and Competitiveness for financial support in the form of a PhD research grant (FPI-Ref. BES-2011-044186).Peer reviewe

Patients' perceptions of the potential of breathing training for asthma: a qualitative study.

Poor symptom control is common in asthma. Breathing training exercises may be an effective adjunct to medication; it is therefore important to understand facilitators and barriers to uptake of breathing training exercises

Visceral leishmaniasis patients display altered composition and maturity of neutrophils as well as impaired neutrophil effector functions

Immunologically, active visceral leishmaniasis (VL) is characterised by profound immunosuppression, severe systemic inflammatory responses and an impaired capacity to control parasite replication. Neutrophils are highly versatile cells, which play a crucial role in the induction as well as the resolution of inflammation, the control of pathogen replication and the regulation of immune responses. Neutrophil functions have been investigated in human cutaneous leishmaniasis, however, their role in human visceral leishmaniasis is poorly understood. In the present study we evaluated the activation status and effector functions of neutrophils in patients with active VL and after successful anti-leishmanial treatment. Our results show that neutrophils are highly activated and have degranulated; high levels of arginase, myeloperoxidase and elastase, all contained in neutrophils’ granules, were found in the plasma of VL patients. In addition, we show that a large proportion of these cells are immature. We also analysed effector functions of neutrophils that are essential for pathogen clearance and show that neutrophils have an impaired capacity to release neutrophil extracellular traps, produce reactive oxygen species and phagocytose bacterial particles, but not Leishmania parasites. Our results suggest that impaired effector functions, increased activation and immaturity of neutrophils play a key role in the pathogenesis of VL

Status Update of the Parkes Pulsar Timing Array

The Parkes Pulsar Timing Array project aims to make a direct detection of a gravitational-wave background through timing of millisecond pulsars. In this article, the main requirements for that endeavour are described and recent and ongoing progress is outlined. We demonstrate that the timing properties of millisecond pulsars are adequate and that technological progress is timely to expect a successful detection of gravitational waves within a decade, or alternatively to rule out all current predictions for gravitational wave backgrounds formed by supermassive black-hole mergers.Comment: 10 pages, 3 figures, Amaldi 8 conference proceedings, accepted by Classical & Quantum Gravit

Randomised controlled feasibility trial of a web-based weight management intervention with nurse support for obese patients in primary care

<b>Background</b><p></p> There is a need for cost-effective weight management interventions that primary care can deliver to reduce the morbidity caused by obesity. Automated web-based interventions might provide a solution, but evidence suggests that they may be ineffective without additional human support. The main aim of this study was to carry out a feasibility trial of a web-based weight management intervention in primary care, comparing different levels of nurse support, to determine the optimal combination of web-based and personal support to be tested in a full trial.<p></p> <b>Methods</b><p></p> This was an individually randomised four arm parallel non-blinded trial, recruiting obese patients in primary care. Following online registration, patients were randomly allocated by the automated intervention to either usual care, the web-based intervention only, or the web-based intervention with either basic nurse support (3 sessions in 3 months) or regular nurse support (7 sessions in 6 months). The main outcome measure (intended as the primary outcome for the main trial) was weight loss in kg at 12 months. As this was a feasibility trial no statistical analyses were carried out, but we present means, confidence intervals and effect sizes for weight loss in each group, uptake and retention, and completion of intervention components and outcome measures.<p></p> <b>Results</b><p></p> All randomised patients were included in the weight loss analyses (using Last Observation Carried Forward). At 12 months mean weight loss was: usual care group (n = 43) 2.44 kg; web-based only group (n = 45) 2.30 kg; basic nurse support group (n = 44) 4.31 kg; regular nurse support group (n = 47) 2.50 kg. Intervention effect sizes compared with usual care were: d = 0.01 web-based; d = 0.34 basic nurse support; d = 0.02 regular nurse support. Two practices deviated from protocol by providing considerable weight management support to their usual care patients.<p></p> <b>Conclusions</b><p></p> This study demonstrated the feasibility of delivering a web-based weight management intervention supported by practice nurses in primary care, and suggests that the combination of the web-based intervention with basic nurse support could provide an effective solution to weight management support in a primary care context

Gender perspectives on views and preferences of older people on exercise to prevent falls: a systematic mixed studies review

Background: To offer fall prevention exercise programs that attract older people of both sexes there is a need to understand both womens and mens views and preferences regarding these programs. This paper aims to systematically review the literature to explore any underlying gender perspectives or gender interpretations on older peoples views or preferences regarding uptake and adherence to exercise to prevent falls. Methods: A review of the literature was carried out using a convergent qualitative design based on systematic searches of seven electronic databases (PubMed, CINAHL, Amed, PsycINFO, Scopus, PEDro, and OTseeker). Two investigators identified eligible studies. Each included article was read by at least two authors independently to extract data into tables. Views and preferences reported were coded and summarized in themes of facilitators and barriers using a thematic analysis approach. Results: Nine hundred and nine unique studies were identified. Twenty five studies met the criteria for inclusion. Only five of these contained a gender analysis of mens and womens views on fall prevention exercises. The results suggests that both women and men see women as more receptive to and in more need of fall prevention messages. The synthesis from all 25 studies identified six themes illustrating facilitators and six themes describing barriers for older people either starting or adhering to fall prevention exercise. The facilitators were: support from professionals or family; social interaction; perceived benefits; a supportive exercise context; feelings of commitment; and having fun. Barriers were: practical issues; concerns about exercise; unawareness; reduced health status; lack of support; and lack of interest. Considerably more women than men were included in the studies. Conclusion: Although there is plenty of information on the facilitators and barriers to falls prevention exercise in older people, there is a distinct lack of studies investigating differences or similarities in older womens and mens views regarding fall prevention exercise. In order to ensure that fall prevention exercise is appealing to both sexes and that the inclusion of both men and women are encouraged, more research is needed to find out whether gender differences exists and whether practitioners need to offer a range of opportunities and support strategies to attract both women and men to falls prevention exercise.Funding Agencies|Swedish Research Council [2015-03481]; Strategic Research Programme in Care Sciences, Umea University; Karolinska Institute, Sweden; Umea University</p

Development of a pulsar-based timescale

Using observations of pulsars from the Parkes Pulsar Timing Array (PPTA) project we develop the first pulsar-based timescale that has a precision comparable to the uncertainties in international atomic timescales. Our ensemble of pulsars provides an Ensemble Pulsar Scale (EPS) analogous to the free atomic timescale Echelle Atomique Libre (EAL). The EPS can be used to detect fluctuations in atomic timescales and therefore can lead to a new realisation of Terrestrial Time, TT(PPTA11). We successfully follow features known to affect the frequency of the International Atomic Timescale (TAI) and we find marginally significant differences between TT(PPTA11) and TT(BIPM11). We discuss the various phenomena that lead to a correlated signal in the pulsar timing residuals and therefore limit the stability of the pulsar timescale.Comment: Accepted for publication in MNRA

Decoding the Pre-Eruptive Magnetic Field Configurations of Coronal Mass Ejections

A clear understanding of the nature of the pre-eruptive magnetic field configurations of Coronal Mass Ejections (CMEs) is required for understanding and eventually predicting solar eruptions. Only two, but seemingly disparate, magnetic configurations are considered viable; namely, sheared magnetic arcades (SMA) and magnetic flux ropes (MFR). They can form via three physical mechanisms (flux emergence, flux cancellation, helicity condensation) . Whether the CME culprit is an SMA or an MFR, however, has been strongly debated for thirty years. We formed an International Space Science Institute (ISSI) team to address and resolve this issue and report the outcome here. We review the status of the field across modeling and observations, identify the open and closed issues, compile lists of SMA and MFR observables to be tested against observations and outline research activities to close the gaps in our current understanding. We propose that the combination of multi-viewpoint multi-thermal coronal observations and multi-height vector magnetic field measurements is the optimal approach for resolving the issue conclusively. We demonstrate the approach using MHD simulations and synthetic coronal images. Our key conclusion is that the differentiation of pre-eruptive configurations in terms of SMAs and MFRs seems artificial. Both observations and modeling can be made consistent if the pre-eruptive configuration exists in a hybrid state that is continuously evolving from an SMA to an MFR. Thus, the 'dominant' nature of a given configuration will largely depend on its evolutionary stage (SMA-like early-on, MFR-like near the eruption).Comment: Space Science Reviews, accepted for publicatio