Geogenic lead isotope signatures from meat products in Great Britain: potential for use in food authentication and supply chain traceability

This paper presents lead (Pb) isotope data from samples of farm livestock raised in three areas of Britain that have elevated natural Pb levels: Central Wales, the Mendips and the Derbyshire Peak District. This study highlights three important observations; that the Pb found in modern British meat from these three areas is geogenic and shows no clear evidence of modern tetraethyl anthropogenic Pb contribution; that the generally excellent match between the biological samples and the ore field data, particularly for the Mendip and Welsh data, suggests that this technique might be used to provenance biological products to specific ore sites, under favourable conditions; and that modern systems reflect the same process of biosphere averaging that is analogous to cultural focusing in human archaeological studies that is the process of biological averaging leading to an homogenised isotope signature with increasing Pb concentration

Thymic plasmacytoid dendritic cells are susceptible to productive HIV-1 infection and efficiently transfer R5 HIV-1 to thymocytes in vitro

<p>Abstract</p> <p>Background</p> <p>HIV-1 infection of the thymus contributes to the defective regeneration and loss of CD4⁺T cells in HIV-1-infected individuals. As thymic dendritic cells (DC) are permissive to infection by HIV-1, we examined the ability of thymic DC to enhance infection of thymocytes which may contribute to the overall depletion of CD4⁺T cells. We compared productive infection in isolated human thymic and blood CD11c⁺myeloid DC (mDC) and CD123⁺plasmacytoid DC (pDC) using enhanced green fluorescent protein (EGFP) CCR5 (R5)-tropic NL(AD8) and CXCR4 (X4)-tropic NL4-3 HIV-1 reporter viruses. Transfer of productive HIV-1 infection from thymic mDC and pDC was determined by culturing these DC subsets either alone or with sorted thymocytes.</p> <p>Results</p> <p>Productive infection was observed in both thymic pDC and mDC following exposure to R5 HIV-1 and X4 HIV-1. Thymic pDC were more frequently productively infected by both R5 and X4 HIV-1 than thymic mDC (p = 0.03; n = 6). Thymic pDC efficiently transferred productive R5 HIV-1 infection to both CD3^hi(p = 0.01; mean fold increase of 6.5; n = 6) and CD3^lothymocytes (mean fold increase of 1.6; n = 2). In comparison, transfer of productive infection by thymic mDC was not observed for either X4 or R5 HIV-1.</p> <p>Conclusions</p> <p>The capacity of thymic pDC to efficiently transfer R5 HIV-1 to both mature and immature thymocytes that are otherwise refractory to R5 virus may represent a pathway to early infection and impaired production of thymocytes and CD4⁺T cells in HIV-1-infected individuals.</p

The effect of tyramine infusion and exercise on blood flow, coagulation and clot microstructure in healthy individuals

BackgroundThe long term benefits of exercise on the cardiovascular status of a patient have been proven, however, their benefit/risk relationship with exercise intensity is unclear. Furthermore, many thromboembolic diseases such as myocardial infarction and ischaemic stroke are associated with profound catecholamine release. In this study we explore the relationship between catecholamine release and hemodynamic changes and their effect on coagulation.Materials and methodsTwelve healthy recreationally active males were recruited. Local anesthesia was given and catheters were placed under aseptic conditions, in the femoral artery and vein of the experimental leg. The first experiment involved tyramine infusion into the femoral artery at a dose of 1.0 μmol·min−1·L leg volume−1. The second experiment involved single leg knee-extensor exercise performed at 30 W for 15 min. Venous blood was collected at each time point to assess clot microstructure using the df biomarker.Results and conclusionsTyramine infusion causes a local noradrenaline release in the leg. The increase in noradrenaline was associated with a significant increase in clot microstructure formation (df increased from 1.692 ± 0.029 to 1.722 ± 0.047, p = 0.016). Additionally moderate intensity single leg knee extensor exercise, which minimally alters sympathetic activity, also induced an increases in df (from 1.688 ± 0.025 to 1.723 ± 0.023, p = 0.001). This suggests that exercise can alter clot microstructure formation both via an increase in catecholeamine levels and by factors related to muscle activity per se, such as increased blood flow and consequent shear. These findings have implications for recommendations of exercise in patients at risk of cardiovascular events

Planning for Sustainability in Small Municipalities: The Influence of Interest Groups, Growth Patterns, and Institutional Characteristics

How and why small municipalities promote sustainability through planning efforts is poorly understood. We analyzed ordinances in 451 Maine municipalities and tested theories of policy adoption using regression analysis.We found that smaller communities do adopt programs that contribute to sustainability relevant to their scale and context. In line with the political market theory, we found that municipalities with strong environmental interests, higher growth, and more formal governments were more likely to adopt these policies. Consideration of context and capacity in planning for sustainability will help planners better identify and benefit from collaboration, training, and outreach opportunities

Ethical climate in healthcare: a systematic review and meta-analysis

Background: Ethical climate refers to the shared perception of ethical norms and sets the scope for what is ethical and acceptable behaviours within teams. Aim: This paper sought to explore perceptions of ethical climate amongst healthcare workers as measured by the Ethical Climate Questionnaire (ECQ), the Hospital Ethical Climate Survey (HECS) and the Ethics Environment Questionnaire (EEQ). Methods: A systematic review and meta-analysis was utilised. PSYCINFO, CINAHL, WEB OF SCIENCE, MEDLINE and EMBASE were searched, and papers were included if they sampled healthcare workers and used the ECQ, HECS or EEQ. Ethical consideration: Ethical approval was not required. Results: The search returned 1020 results. After screening, 61 papers were included (n = 43 HECS, n = 15 ECQ, n = 3 EEQ). The overall sample size was over 17,000. The pooled mean score for the HECS was 3.60. Mean scores of individual studies ranged from 2.97 to 4.5. For the HECS studies, meta-regression was carried out. No relationship was found between the country of the studies, the study setting (ICU v non-ICU settings) or the mean years of experience that the sample had. For the ECQ, subscales had mean scores ranging from 3.41 (instrumental) to 4.34 (law) and were all observed to have significant and substantial heterogeneity. Three studies utilised the EEQ so further analysis was not carried out. Conclusions: The above results provide insight into the variability of scores as measured by the HECS, ECQ and EEQ. To some extent this variability is not surprising with studies carried out across 21 countries and in a range of healthcare systems. Results also suggest that it may be that more local and context specific factors are more important when it comes to predicting ethical climate

Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host

Schmallenberg virus (SBV) is an emerging orthobunyavirus of ruminants associated with outbreaks of congenital malformations in aborted and stillborn animals. Since its discovery in November 2011, SBV has spread very rapidly to many European countries. Here, we developed molecular and serological tools, and an experimental in vivo model as a platform to study SBV pathogenesis, tropism and virus-host cell interactions. Using a synthetic biology approach, we developed a reverse genetics system for the rapid rescue and genetic manipulation of SBV. We showed that SBV has a wide tropism in cell culture and “synthetic” SBV replicates in vitro as efficiently as wild type virus. We developed an experimental mouse model to study SBV infection and showed that this virus replicates abundantly in neurons where it causes cerebral malacia and vacuolation of the cerebral cortex. These virus-induced acute lesions are useful in understanding the progression from vacuolation to porencephaly and extensive tissue destruction, often observed in aborted lambs and calves in naturally occurring Schmallenberg cases. Indeed, we detected high levels of SBV antigens in the neurons of the gray matter of brain and spinal cord of naturally affected lambs and calves, suggesting that muscular hypoplasia observed in SBV-infected lambs is mostly secondary to central nervous system damage. Finally, we investigated the molecular determinants of SBV virulence. Interestingly, we found a biological SBV clone that after passage in cell culture displays increased virulence in mice. We also found that a SBV deletion mutant of the non-structural NSs protein (SBVΔNSs) is less virulent in mice than wild type SBV. Attenuation of SBV virulence depends on the inability of SBVΔNSs to block IFN synthesis in virus infected cells. In conclusion, this work provides a useful experimental framework to study the biology and pathogenesis of SBV

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Assessment of platelet function in patients with stroke using multiple electrode platelet aggregometry: a prospective observational study

Background There is a link between high on-treatment platelet reactivity (HPR) and adverse vascular events in stroke. This study aimed to compare multiple electrode platelet aggregometry (MEA), in healthy subjects and ischaemic stroke patients, and between patients naive to antiplatelet drugs (AP) and those on regular low dose AP. We also aimed to determine prevalence of HPR at baseline and at 3–5 days after loading doses of aspirin. Methods Patients with first ever ischaemic stroke were age and sex-matched to a healthy control group. Three venous blood samples were collected: on admission before any treatment given (baseline); at 24 h and 3–5 days after standard treatment. MEA was determined using a Mutliplate® analyser and agonists tested were arachidonic acid (ASPI), adenosine diphosphate (ADP) and collagen (COL). Results Seventy patients (mean age 73 years [SD 13]; 42 men, 28 women) were age and sex-matched to 72 healthy subjects. Thirty-three patients were on antiplatelet drugs (AP) prior to stroke onset and 37 were AP-naive. MEA results for all agonists were significantly increased in AP-naive patients compared to healthy subjects: ADP 98 ± 31 vs 81 ± 24, p < 0.005; ASPI 117 ± 31 vs 98 ± 27, p < 0.005; COL 100 ± 25 vs 82 ± 20, p < 0.005. For patients on long term AP, 33% (10/30) of patients were considered aspirin-resistant. At 3–5 days following loading doses of aspirin, only 11.1% were aspirin resistant based on an ASPI cut-off value of 40 AU*min. Conclusions Many patients receiving low dose aspirin met the criteria of aspirin resistance but this was much lower at 3–5 days following loading doses of aspirin. Future studies are needed to establish the causes of HPR and potential benefits of individualizing AP treatment based on platelet function testing

The 100-month Swift catalogue of supergiant fast X-ray transients

Context. Supergiant fast X-ray transients (SFXTs) are high mass X-ray binaries (HMXBs) that are defined by their hard X-ray flaring behaviour. During these flares they reach peak luminosities of 10–10 erg s−1 for a few hours (in the hard X-ray), which are much shorter timescales than those characterizing Be/X-ray binaries. Aims. We investigate the characteristics of bright flares (detections in excess of 5σ) for a sample of SFXTs and their relation to the orbital phase. Methods. We have retrieved all Swift/BAT Transient Monitor light curves and collected all detections in excess of 5σ from both dailyand orbital-averaged light curves in the time range of 2005 February 12 to 2013 May 31 (MJD 53 413–56 443). We also considered all on-board detections as recorded in the same time span and selected those in excess of 5σ and within 4 arcmin of each source in our sample. Results. We present a catalogue of over a thousand BAT flares from 11 SFXTs, down to 15–150 keV fluxes of ∼6×10−10 erg cm−2 s−1 (daily timescale) and ∼1.5×10−9 erg cm−2 s−1 (orbital timescale, averaging ∼800 s); the great majority of these flares are unpublished. The catalogue spans 100 months. This population is characterized by short (a few hundred seconds) and relatively bright (in excess of 100 mCrab, 15–50 keV) events. In the hard X-ray, these flares last generally much less than a day. Clustering of hard X-ray flares can be used to indirectly measure the length of an outburst, even when the low-level emission is not detected. We construct the distributions of flares, of their significance (in terms of σ), and of their flux as a function of orbital phase to infer the properties of these binary systems. In particular, we observe a trend of clustering of flares at some phases as Porb increases, which is consistent with a progression from tight circular or mildly eccentric orbits at short periods to wider and more eccentric orbits at longer orbital periods. Finally, we estimate the expected number of flares for a given source for our limiting flux and provide the recipe for calculating them for the limiting flux of future hard X-ray observatories