Exploiting flavour preferences of common marmosets to increase palatability of a dry pellet diet

Although commercially available complete diets exist for common marmosets, the animals’ consumption of these diets (available in dry pellet form) is typically very low. Increasing consumption of the pellet diet could have positive consequences for the welfare of the marmosets as the pellets are designed specifically to meet their full nutritional requirements, and therefore an increase in intake should help to ensure that they take in an appropriate balance of nutrients. We carried out a series of studies targeted towards improving the palatability, and hence increasing the intake, of a complete dry pellet diet for marmosets. In Study 1 we attempted to determine which of a wide range of flavours appeared to be preferred by the marmosets. In Study 2 we tested the marmosets’ preferences for a smaller number of highly preferred flavours (as determined in Study 1) when actually added to the dry pellet diet in a series of paired preference tests. Finally, in Study 3 we tested whether adding the most highly preferred flavours (as determined in Study 2) to the dry pellet diet would in fact increase consumption of these pellets in comparison with unflavoured pellets. Despite finding strong and consistent preferences for particular flavours amongst the marmosets, we found that adding these to the pellets did not significantly increase consumption. Reasons for this are discussed, along with other potential modifications which might prove more successful in increasing consumption of pellet diets for marmosets

An Adaptive Optics Survey of Stellar Variability at the Galactic Center

We present a $\approx 11.5$ year adaptive optics (AO) study of stellar variability and search for eclipsing binaries in the central $\sim 0.4$ pc ($\sim 10''$) of the Milky Way nuclear star cluster. We measure the photometry of 563 stars using the Keck II NIRC2 imager ($K'$-band, $\lambda_0 = 2.124 \text{ } \mu \text{m}$). We achieve a photometric uncertainty floor of $\Delta m_{K'} \sim 0.03$ ($\approx 3\%$), comparable to the highest precision achieved in other AO studies. Approximately half of our sample ($50 \pm 2 \%$) shows variability. $52 \pm 5\%$ of known early-type young stars and $43 \pm 4 \%$ of known late-type giants are variable. These variability fractions are higher than those of other young, massive star populations or late-type giants in globular clusters, and can be largely explained by two factors. First, our experiment time baseline is sensitive to long-term intrinsic stellar variability. Second, the proper motion of stars behind spatial inhomogeneities in the foreground extinction screen can lead to variability. We recover the two known Galactic center eclipsing binary systems: IRS 16SW and S4-258 (E60). We constrain the Galactic center eclipsing binary fraction of known early-type stars to be at least $2.4 \pm 1.7\%$. We find no evidence of an eclipsing binary among the young S-stars nor among the young stellar disk members. These results are consistent with the local OB eclipsing binary fraction. We identify a new periodic variable, S2-36, with a 39.43 day period. Further observations are necessary to determine the nature of this source.Comment: 69 pages, 28 figures, 12 tables. Accepted for publication in The Astrophysical Journa

Inhibition of delta-like ligand 4 induces luteal hypervascularization followed by functional and structural luteolysis in the primate ovary

Using specific inhibitors established that angiogenesis in the ovarian follicle and corpus luteum is driven by vascular endothelial growth factor. Recently, it has been demonstrated that the Notch ligand, delta-like ligand 4 (Dll4) negatively regulates vascular endothelial growth factor-mediated vessel sprouting and branching. To investigate the role of Dll4 in regulation of the ovarian vasculature, we administered a neutralizing antibody to Dll4 to marmosets at the periovulatory period. The vasculature was examined on luteal d 3 or d 10: angiogenesis was determined by incorporation of bromodeoxyuridine, staining for CD31 and cell death by staining for activated caspase-3. Ovulatory progesterone rises were monitored to determine effects of treatment on luteal function and time to recover normal cycles in a separate group of animals. Additionally, animals were treated in the follicular or midluteal phase to determine effects of Dll4 inhibition on follicular development and luteal function. Controls were treated with human IgG (Fc). Corpora lutea from marmosets treated during the periovulatory period exhibited increased angiogenesis and increased vascular density on luteal d 3, but plasma progesterone was significantly suppressed. By luteal d 10, corpora lutea in treated ovaries were significantly reduced in size, with involution of luteal cells, increased cell death, and suppressed plasma progesterone concentrations. In contrast, initiation of anti-Dll4 treatment during the midluteal phase produced only a slight suppression of progesterone for the remainder of the cycle. Moreover, Dll4 inhibition had no appreciable effect on follicular development. These results show that Dll4 has a specific and critical role in the development of the normal luteal vasculature

Evaluating the use of a 22-pathogen TaqMan array card for rapid diagnosis of respiratory pathogens in Intensive Care

Introduction. Pneumonia is highly prevalent in intensive care units (ICUs), with high associated mortality. Empirical treatment prioritizes breadth of coverage while awaiting laboratory diagnosis, often at the expense of antimicrobial stewardship. Microarrays use multiple parallel polymerase chain reactions to enable a rapid syndromic approach to laboratory diagnosis. Aim. To evaluate the clinical and laboratory implications of introducing a bespoke 22-pathogen TaqMan Array Card (TAC) for rapid pathogen detection in deep respiratory samples from adult ICUs. Methodology. TAC results from all ICU patients prospectively tested over a 9-month period at Cambridge’s Clinical Microbiology and Public Health Laboratory were compared to those of corresponding conventional microbiological assays (culture-, PCR- or serology-based) in terms of result agreement and time-to-result availability. Clinical impact was assessed by retrospective review of medical records. Results. Seventy-one patients were included [45 (63 %) male, median age 59). Overall result agreement was 94 %, with TAC detecting more pathogens than conventional methods. TAC detected Streptococcus pneumoniae more readily than culture (7 vs 0 cases; P=0.02). TAC did not detect Aspergillus spp. in eight culture- or galactomannan-positive cases. The median turnaround time (1 day) was significantly shorter than that of bacterial/fungal culture, Pneumocystis jirovecii PCR and galactomannan testing (each 3 days; P<0.001), atypical bacteria serology (13 days; P<0.001) and Mycobacterium tuberculosis culture (46 days; P<0.001). Earlier result availability prompted discontinuation of unnecessary antimicrobials in 15/71 (21 %) cases, but had no bearing on patient isolation/deisolation. Conclusion. TAC provided greater overall yield of pathogen detection and faster turnaround times, permitting earlier discontinuation of unnecessary antimicrobials.A. C. M. is supported by a Wellcome Trust Clinical Research Career Development Fellowship (WT 2055214/Z/16/Z)

Size-tuneable synthesis of nickel nanoparticles

A facile method is described for synthesising nickel nanoparticles via the thermal decomposition of an organometallic precursor in the presence of excess n-trioctylphosphine as a capping ligand. For the first time, alkylamines with different chain lengths were employed as size-limiting agents in this synthesis. A direct correlation is demonstrated between the size of the alkylamine ligands used and the mean diameter of the nickel nanoparticles obtained. The use of bulky oleylamine as a size-limiting agent over a reaction period of 30 min led to the growth of nickel nanoparticles with a mean diameter of 2.8 ± 0.9 nm. The employment of less bulky N,N-dimethylhexadecylamine groups led to the growth of nickel nanoparticles with a mean diameter of 4.4 ± 0.9 nm. By increasing the reaction time from 30 to 240 min, while employing oleylamine as the size-limiting agent, the mean diameter of the nickel nanoparticles was increased from 2.8 ± 0.9 to 5.1 ± 0.7 nm. Decreasing the amount of capping ligand present in the reaction system allowed further growth of the nickel nanoparticles to 17.8 ± 1.3 nm. The size, structure and morphology of the nanoparticles synthesised were characterised by transmission electron microscopy and powder X-ray diffraction; while magnetic measurements indicated that the particles were superparamagnetic in nature

Three-weekly doses of azithromycin for Indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo-controlled trial

Background: Bronchiolitis is a major health burden in infants globally, particularly among Indigenous populations. It is unknown if 3 weeks of azithromycin improve clinical outcomes beyond the hospitalization period. In an international, double-blind randomized controlled trial, we determined if 3 weeks of azithromycin improved clinical outcomes in Indigenous infants hospitalized with bronchiolitis.Methods: Infants aged &le;24 months were enrolled from three centers and randomized to receive three once-weekly doses of either azithromycin (30 mg/kg) or placebo. Nasopharyngeal swabs were collected at baseline and 48 h later. Primary endpoints were hospital length of stay (LOS) and duration of oxygen supplementation monitored every 12 h until judged ready for discharge. Secondary outcomes were: day-21 symptom/signs, respiratory rehospitalizations within 6 months post-discharge and impact upon nasopharyngeal bacteria and virus shedding at 48 h.Results: Two hundred nineteen infants were randomized (n = 106 azithromycin, n = 113 placebo). No significant between-group differences were found for LOS (median 54 h for each group, difference = 0 h, 95% CI: &minus;6, 8; p = 0.8), time receiving oxygen (azithromycin = 40 h, placebo = 35 h, group difference = 5 h, 95% CI: &minus;8, 11; p = 0.7), day-21 symptom/signs, or rehospitalization within 6 months (azithromycin n = 31, placebo n = 25 infants, p = 0.2). Azithromycin reduced nasopharyngeal bacterial carriage (between-group difference 0.4 bacteria/child, 95% CI: 0.2, 0.6; p &lt; 0.001), but had no significant effect upon virus detection rates.Conclusion: Despite reducing nasopharyngeal bacterial carriage, three large once-weekly doses of azithromycin did not confer any benefit over placebo during the bronchiolitis illness or 6 months post hospitalization. Azithromycin should not be used routinely to treat infants hospitalized with bronchiolitis.Clinical trial registration: The trial was registered with the Australian and New Zealand Clinical Trials Register: Clinical trials number: ACTRN1261000036099

The NICE-GUT trial protocol:A randomised, placebo controlled trial of oral nitazoxanide for the empiric treatment of acute gastroenteritis among Australian Aboriginal children

Diarrhoeal disease is the second leading cause of death in children under 5 years globally, killing 525 000 annually. Australian Aboriginal and Torres Strait Islander (hereafter Aboriginal) children suffer a high burden of disease. Randomised trials in other populations suggest nitazoxanide accelerates recovery for children with Giardia, amoebiasis, Cryptosporidium, Rotavirus and Norovirus gastroenteritis, as well as in cases where no enteropathogens are found. This double blind, 1:1 randomised, placebo controlled trial is investigating the impact of oral nitazoxanide on acute gastroenteritis in hospitalised Australian Aboriginal children aged 3 months to <5 years. Dosing is based on age-based dosing. The primary endpoint is the time to resolution of 'significant illness' defined as the time from randomisation to the time of clinical assessment as medically ready for discharge, or to the time of actual discharge from hospital, whichever occurs first. Secondary endpoints include duration of hospitalisation, symptom severity during the period of significant illness and following treatment, duration of rehydration and drug safety. Patients will be followed for medically significant events for 60 days. Analysis is based on Bayesian inference. Subgroup analysis will occur by pathogen type (bacteria, virus or parasite), rotavirus vaccination status, age and illness severity. Ethics approval has been granted by the Central Australian Human Research Ethics Committee (HREC-14-221) and the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (HREC2014-2172). Study investigators will ensure that the trial is conducted in accordance with the principles of the Declaration of Helsinki. Individual participant consent will be obtained. Results will be disseminated via peer-reviewed publication. ACTRN12614000381684

Dietary nitrate supplementation reduces circulating platelet-derived extracellular vesicles in coronary artery disease patients on clopidogrel therapy: a randomised, double-blind, placebo-controlled study

Extracellular vesicles (EVs) are implicated in the pathogenesis of cardiovascular disease (CVD). Specifically, platelet-derived EVs are highly pro-coagulant, promoting thrombin generation and fibrin clot formation. Nitrate supplementation exerts beneficial effects in CVD, via an increase in nitric oxide (NO) bioavailability. Clopidogrel is capable of producing NO-donating compounds, such as S-nitrosothiols (RSNO) in the presence of nitrite and low pH. The aim of this study was to assess the effect of nitrate supplementation with versus without clopidogrel therapy on circulating EVs in coronary artery disease (CAD) patients. In this randomized, double-blind, placebo-controlled study, CAD patients with (n = 10) or without (n = 10) clopidogrel therapy received a dietary nitrate supplement (SiS nitrate gel) or identical placebo. NO metabolites and platelet activation were measured using ozone-based chemiluminescence and multiple electrode aggregometry. EV concentration and origin were determined using nanoparticle tracking analysis and time-resolved fluorescence. Following nitrate supplementation, plasma RSNO was elevated (4.7 ± 0.8 vs 0.2 ± 0.5 nM) and thrombin-receptor mediated platelet aggregation was reduced (−19.9 ± 6.0 vs 4.0 ± 6.4 U) only in the clopidogrel group compared with placebo. Circulating EVs were significantly reduced in this group (−1.183e11 ± 3.15e10 vs −9.93e9 ± 1.84e10 EVs/mL), specifically the proportion of CD41+ EVs (−2,120 ± 728 vs 235 ± 436 RFU [relative fluorescence unit]) compared with placebo. In vitro experiments demonstrated clopidogrel–SNO can reduce platelet-EV directly (6.209e10 ± 4.074e9 vs 3.94e11 ±  1.91e10 EVs/mL). In conclusion, nitrate supplementation reduces platelet-derived EVs in CAD patients on clopidogrel therapy, increasing patient responsiveness to clopidogrel. Nitrate supplementation may represent a novel approach to moderating the risk of thrombus formation in CAD patients

The Biosynthesis of Capuramycin-type Antibiotics: Identification of the A-102395 Biosynthetic Gene Cluster, Mechanism of Self-Resistence, and Formation of Uridine-5\u27-Carboxamide

A-500359s, A-503083s, and A-102395 are capuramycin-type nucleoside antibiotics that were discovered using a screen to identify inhibitors of bacterial translocase I, an essential enzyme in peptidoglycan cell wall biosynthesis. Like the parent capuramycin, A-500359s and A-503083s consist of three structural components: a uridine-5\u27-carboxamide (CarU), a rare unsaturated hexuronic acid, and an aminocaprolactam, the last of which is substituted by an unusual arylamine-containing polyamide in A-102395. The biosynthetic gene clusters for A-500359s and A-503083s have been reported, and two genes encoding a putative non-heme Fe(II)-dependent α-ketoglutarate:UMP dioxygenase and an l-Thr:uridine-5\u27-aldehyde transaldolase were uncovered, suggesting that C-C bond formation during assembly of the high carbon (C6) sugar backbone of CarU proceeds from the precursors UMP and l-Thr to form 5\u27-C-glycyluridine (C7) as a biosynthetic intermediate. Here, isotopic enrichment studies with the producer of A-503083s were used to indeed establish l-Thr as the direct source of the carboxamide of CarU. With this knowledge, the A-102395 gene cluster was subsequently cloned and characterized. A genetic system in the A-102395-producing strain was developed, permitting the inactivation of several genes, including those encoding the dioxygenase (cpr19) and transaldolase (cpr25), which abolished the production of A-102395, thus confirming their role in biosynthesis. Heterologous production of recombinant Cpr19 and CapK, the transaldolase homolog involved in A-503083 biosynthesis, confirmed their expected function. Finally, a phosphotransferase (Cpr17) conferring self-resistance was functionally characterized. The results provide the opportunity to use comparative genomics along with in vivo and in vitro approaches to probe the biosynthetic mechanism of these intriguing structures