The discovery of SB-435495. A potent,orally active inhibitor of lipoprotein-associated phospholipase A(2) for evaluation in man

The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.     

BACE-1 hydroxyethylamine inhibitors using novel edge-to-face interaction with Arg-296

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer’s disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296.     

Mass administration of medicines in changing contexts: Acceptability,adaptability and community directed approaches in Kaduna and Ogun States,Nigeria

Nigeria has the highest burden of NTDs in sub-Saharan Africa. Commitments to reach the control and elimination of many Neglected Tropical Diseases (NTDs), particularly those amenable to preventive chemotherapy (onchocerciasis, schistosomiasis, soil transmitted helminths, lymphatic filariasis and trachoma) by 2020 are detailed in the London declaration. Strategies to reach targets build on existing approaches, one of which is the use of community directed intervention (CDI) methods to deliver the mass administration of medicines (MAM). However, treatment using this approach has been inconsistent and there are questions about the acceptability and adaptability of these interventions during periods of programmatic, social, and political change. This paper explores the current strengths and weaknesses of CDI approaches in MAM delivery. We consider the acceptability and adaptability of existing MAM approaches to ensure equity in access to essential treatments. Using qualitative methods, we explore implementer perspectives of MAM delivery. We purposively selected programme implementers to ensure good programmatic knowledge and representation from the different levels of health governance in Nigeria. Data collection took place across two States (Kaduna and Ogun). Our results indicate that CDI approaches have underpinned many historic successes in NTD programme acceptance in Nigeria, specifically in Kaduna and Ogun State. However, our results also show that in some contexts, factors that underpin the success of CDI have become disrupted presenting new challenges for programme implementers. Capturing the tacit knowledge of health implementers at varying levels of the health system, we present the current and changing context of MAM delivery in Kaduna and Ogun States and consolidate a platform of evidence to guide future programme delivery and research studies. We situate our findings within the broader NTD literature, specifically, in identifying how our findings align to existing reviews focused on factors that shape individual acceptance of MAM.     

Expression of estrogen receptors in the pelvic floor of pre- and post-menopausal women presenting pelvic organ prolapse

The precise role of estrogen in the pathogenesis of pelvic organ prolapse (POP) is still unclear, while the results concerning the effect of selective estrogen receptor modulators on pelvic organ prolapse are contradictory. Our aim was to test whether alteration in the expression of estrogen receptors in the pelvic floor of pre- and post-menopausal women is related to genital prolapse status. The mRNA levels of ERα and ERβ in 60 biopsy specimens were measured. Significantly higher expression of ERα and higher ERα/ERβ ratio were demonstrated in post-menopausal women compared to pre-menopausal women. Higher expression of ERα and higher ERα/ERβ ratio were detected in all studied groups with POP, thus it did not reach significance in the post-menopausal group. Pre-menopausal and post-menopausal women presenting pelvic organ prolapse had no difference in the ERα expression. Our preliminary study may indicate that pelvic organ prolapse is associated with higher expression of ERα/ERβ in the pelvic floor of both pre- and post-menopausal women; thus not reaching statistical significance in the post-menopausal women was probably due to the group's size. We believe that the inevitable changes in the estrogen receptor expression over women's different lifetimes may affect the risk of genital prolapse progression, and might contribute to the further search for appropriate selective estrogen receptor modulators as a treatment for women with pelvic organ prolapse.     

Effects of Chicory/Perennial Ryegrass Swards Compared with Perennial Ryegrass Swards on the Performance and Carcass Quality of Grazing Beef Steers

An experiment investigated whether the inclusion of chicory (Cichorium intybus) in swards grazed by beef steers altered their performance, carcass characteristics or parasitism when compared to steers grazing perennial ryegrass (Lolium perenne). Triplicate 2-ha plots were established with a chicory/ryegrass mix or ryegrass control. Forty-eight Belgian Blue-cross steers were used in the first grazing season and a core group (n = 36) were retained for finishing in the second grazing season. The experiment comprised of a standardisation and measurement period. During standardisation, steers grazed a ryegrass/white clover pasture as one group. Animals were allocated to treatment on the basis of liveweight, body condition and faecal egg counts (FEC) determined 7 days prior to the measurement period. The measurement period ran from 25 May until 28 September 2010 and 12 April until 11 October 2011in the first and second grazing year. Steers were weighed every 14 days at pasture or 28 days during housing. In the first grazing year, faecal samples were collected for FEC and parasite cultures. At the end of the first grazing year, individual blood samples were taken to determine O. ostertagi antibody and plasma pepsinogen levels. During winter, animals were housed as one group and fed silage. In the second grazing year, steers were slaughtered when deemed to reach fat class 3. Data on steer performance showed no differences in daily live-weight gain which averaged 1.04 kg/day. The conformation, fat grade and killing out proportion of beef steers grazing chicory/ryegrass or ryegrass were not found to differ. No differences in FEC, O. ostertagi antibody or plasma pepsinogen levels of beef steers grazing either chicory/ryegrass or ryegrass were observed. Overall, there were no detrimental effects of including chicory in swards grazed by beef cattle on their performance, carcass characteristics or helminth parasitism, when compared with steers grazing ryegrass.     

The Impact of Using Alternative Forages on the Nutrient Value within Slurry and Its Implications for Forage Productivity in Agricultural Systems

Alternative forages can be used to provide valuable home-grown feed for ruminant livestock. Utilising these different forages could affect the manure value and the implications of incorporating these forages into farming systems, needs to be better understood. An experiment tested the hypothesis that applying slurries from ruminants, fed ensiled red clover (Trifolium pratense), lucerne (Medicago sativa) or kale (Brassica oleracea) would improve the yield of hybrid ryegrass (Lolium hybridicum), compared with applying slurries from ruminants fed ensiled hybrid ryegrass, or applying inorganic N alone. Slurries from sheep offered one of four silages were applied to ryegrass plots (at 35 t ha⁻¹) with 100 kg N ha⁻¹ inorganic fertiliser; dry matter (DM) yield was compared to plots only receiving ammonium nitrate at rates of 0, 100 and 250 kg N ha⁻¹ year⁻¹. The DM yield of plots treated with 250 kg N, lucerne or red clover slurry was significantly higher than other treatments (P<0.001). The estimated relative fertiliser N equivalence (FNE) (fertiliser-N needed to produce same yield as slurry N), was greatest for lucerne (114 kg) >red clover (81 kg) >kale (44 kg) >ryegrass (26 kg ha⁻¹ yr⁻¹). These FNE values represent relative efficiencies of 22% (ryegrass), 52% (kale), 47% (red clover) and 60% for lucerne slurry, with the ryegrass slurry efficiency being lowest (P = 0.005). Soil magnesium levels in plots treated with legume slurry were higher than other treatments (P<0.001). Overall, slurries from ruminants fed alternative ensiled forages increased soil nutrient status, forage productivity and better N efficiency than slurries from ruminants fed ryegrass silage. The efficiency of fertiliser use is one of the major factors influencing the sustainability of farming systems, these findings highlight the cascade in benefits from feeding ruminants alternative forages, and the need to ensure their value is effectively captured to reduce environmental risks.     

Development of a Prototype Lateral Flow Immunoassay (LFI) for the Rapid Diagnosis of Melioidosis

Burkholderia pseudomallei is a soil-dwelling bacterium and the causative agent of melioidosis. Isolation of B. pseudomallei from clinical samples is the “gold standard” for the diagnosis of melioidosis; results can take 3–7 days to produce. Alternatively, antibody-based tests have low specificity due to a high percentage of seropositive individuals in endemic areas. There is a clear need to develop a rapid point-of-care antigen detection assay for the diagnosis of melioidosis. Previously, we employed In vivo Microbial Antigen Discovery (InMAD) to identify potential B. pseudomallei diagnostic biomarkers. The B. pseudomallei capsular polysaccharide (CPS) and numerous protein antigens were identified as potential candidates. Here, we describe the development of a diagnostic immunoassay based on the detection of CPS. Following production of a CPS-specific monoclonal antibody (mAb), an antigen-capture immunoassay was developed to determine the concentration of CPS within a panel of melioidosis patient serum and urine samples. The same mAb was used to produce a prototype Active Melioidosis Detect Lateral Flow Immunoassay (AMD LFI); the limit of detection of the LFI for CPS is comparable to the antigen-capture immunoassay (∼0.2 ng/ml). The analytical reactivity (inclusivity) of the AMD LFI was 98.7% (76/77) when tested against a large panel of B. pseudomallei isolates. Analytical specificity (cross-reactivity) testing determined that 97.2% of B. pseudomallei near neighbor species (35/36) were not reactive. The non-reactive B. pseudomallei strain and the reactive near neighbor strain can be explained through genetic sequence analysis. Importantly, we show the AMD LFI is capable of detecting CPS in a variety of patient samples. The LFI is currently being evaluated in Thailand and Australia; the focus is to optimize and validate testing procedures on melioidosis patient samples prior to initiation of a large, multisite pre-clinical evaluation.     

Analyzing the Movement of the Nauplius 'Artemia salina' by Optical Tracking of Plasmonic Nanoparticles

We demonstrate how optical tweezers may provide a sensitive tool to analyze the fluidic vibrations generated by the movement of small aquatic organisms. A single gold nanoparticle held by an optical tweezer is used as a sensor to quantify the rhythmic motion of a Nauplius larva (Artemia salina) in a water sample. This is achieved by monitoring the time dependent displacement of the trapped nanoparticle as a consequence of the Nauplius activity. A Fourier analysis of the nanoparticle''s position then yields a frequency spectrum that is characteristic to the motion of the observed species. This experiment demonstrates the capability of this method to measure and characterize the activity of small aquatic larvae without the requirement to observe them directly and to gain information about the position of the larvae with respect to the trapped particle. Overall, this approach could give an insight on the vitality of certain species found in an aquatic ecosystem and could expand the range of conventional methods for analyzing water samples.     

Egg load dynamics and the risk of egg and time limitation experienced by an aphid parasitoid in the field

Insect parasitoids and herbivores must balance the risk of egg limitation and time limitation in order to maximize reproductive success. Egg and time limitation are mediated by oviposition and egg maturation rates as well as by starvation risk and other determinants of adult lifespan. Here, we assessed egg load and nutritional state in the soybean aphid parasitoid Binodoxys communis under field conditions to estimate its risk of becoming either egg‐ or time‐limited. The majority of female B. communis showed no signs of egg limitation. Experimental field manipulations of B. communis females suggested that an average of 4–8 eggs were matured per hour over the course of a day. Regardless, egg loads remained constant over the course of the day at approximately 80 eggs, suggesting that egg maturation compensates for oviposition. This is the first case of such “egg load buffering” documented for a parasitoid in the field. Despite this buffering, egg loads dropped slightly with increasing host (aphid) density. This suggests that egg limitation could occur at very high host densities as experienced in outbreak years in some locations in the Midwestern USA. Biochemical analyses of sugar profiles showed that parasitoids fed upon sugar in the field at a remarkably high rate. Time limitation through starvation thus seems to be very low and aphid honeydew is most likely a source of dietary sugar for these parasitoids. This latter supposition is supported by the fact that body sugar levels increase with host (aphid) density. Together, these results suggest that fecundity of B. communis benefits from both dynamic egg maturation strategies and sugar‐feeding.