One Health ethics: The need for policy before research and action

One Health implies a strong emphasis on ethics, recognising the interdependent relationships of humans, animals and the environment. We argue that the universal ethical principles for human-subject research, presented in the Belmont report as Respect for Persons, Beneficence and Justice, should be applied to custodians of animals and the environment. Drawing on published and unpublished research, we highlight the challenges and opportunities of this approach in practice and policy. Respect for Persons is demonstrated through informed consent. We describe the high rate of consent received in livestock research projects, raising questions around legitimacy, and outline a study to improve comprehension and engagement in the informed consent process for livestock keepers. Beneficence dictates that benefits to research participants are maximized. We outline how a long-term impact assessment was designed with intrinsic value for farmers, using participatory photography. Additionally, we describe efforts towards non-maleficence through providing participants with research board contacts. We provide new data on low contact-rates and discuss possible causes. Justice requires that research risks and benefits are distributed equally. We show how the requirement to sign written consent forms may preclude those working in informal livestock markets from participating in, and therefore sharing risks and benefits of research projects

3D-electrical resistivity tomography monitoring of salt transport in homogeneous and layered soil samples

Monitoring transport of dissolved substances in soil deposits is particularly relevant where safety is concerned, as in the case of geo-environmental barriers. Geophysical methods are very appealing, since they cover a wide domain, localising possible preferential flow paths and providing reliable links between geophysical quantities and hydrological variables. This paper describes a 3D laboratory application of Electrical Resistivity Tomography (ERT) used to monitor solute transport processes. Dissolution and transport tests on both homogeneous and heterogeneous samples were conducted in an instrumented oedometer cell. ERT was used to create maps of electrical conductivity of the monitored domain at different time intervals and to estimate concentration variations within the interstitial fluid. Comparisons with finite element simulations of the transport processes were performed to check the consistency of the results. Tests confirmed that the technique can monitor salt transport, infer the hydro-chemical behaviour of heterogeneous geomaterials and evaluate the performances of clay barrier

Diagnostic test accuracy of ultrasonography for synovitis in rheumatoid arthritis: systematic review and meta-analysis

Objective. To evaluate diagnostic test accuracy of US compared with MRI for the detection of synovitis in RA patients. Methods. A systematic literature search was performed in the PubMed, EMBASE, Cochrane Library and Web of Science Core Collection databases. Studies evaluating the diagnostic test accuracy of US for synovitis detected by MRI as the reference standard for wrist, MCP, PIP and knee joints were included. To assess the overall accuracy, we calculated the diagnostic odds ratio using a DerSimonian–Laird random effects model and the area under the curve (AUC) for the hierarchical summary receiver operating characteristics using Holling’s proportional hazards models. The summary estimate of the sensitivity and specificity were obtained using the bivariate model. Results. Fourteen of 601 identified articles were included in the review. The diagnostic odds ratio was 11.6 (95% CI 5.6, 24; I2 = 0%), 28 (95% CI 12, 66; I2 = 11%), 23 (95% CI 6.5, 84; I2 = 19%) and 5.3 (95% CI 0.60, 48; I2 = 0%) and the AUC was 0.81, 0.91, 0.91 and 0.61 for wrist, MCP, PIP and knee joints, respectively. The summary estimates of sensitivity and specificity were 0.73 (95% CI 0.51, 0.87)/0.78 (95% CI 0.46, 0.94), 0.64 (95% CI 0.43, 0.81)/0.93 (95% CI 0.88, 0.97), 0.71 (95% CI 0.33, 0.93)/0.94 (95% CI 0.89, 0.97) and 0.91 (95% CI 0.56, 0.99)/0.60 (95% CI 0.20, 0.90) for wrist, MCP, PIP and knee joints, respectively. Conclusion. US is a valid and reproducible technique for detecting synovitis in the wrist and finger joints. It may be considered for routine use as part of the standard diagnostic tools in RA

The cytokine tumor necrosis factor-like weak inducer of apoptosis and its receptor fibroblast growth factor-inducible 14 have a neuroprotective effect in the central nervous system

<p>Abstract</p> <p>Background</p> <p>Cerebral cortical neurons have a high vulnerability to the harmful effects of hypoxia. However, the brain has the ability to detect and accommodate to hypoxic conditions. This phenomenon, known as preconditioning, is a natural adaptive process highly preserved among species whereby exposure to sub-lethal hypoxia promotes the acquisition of tolerance to a subsequent lethal hypoxic injury. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are found in neurons and their expression is induced by exposure to sub-lethal hypoxia. Accordingly, in this work we tested the hypothesis that the interaction between TWEAK and Fn14 induces tolerance to lethal hypoxic and ischemic conditions.</p> <p>Methods</p> <p>Here we used <it>in vitro </it>and <it>in vivo </it>models of hypoxic and ischemic preconditioning, an animal model of transient middle cerebral artery occlusion and mice and neurons genetically deficient in TWEAK, Fn14, or tumor necrosis factor alpha (TNF-α) to investigate whether treatment with recombinant TWEAK or an increase in the expression of endogenous TWEAK renders neurons tolerant to lethal hypoxia. We used enzyme-linked immunosorbent assay to study the effect of TWEAK on the expression of neuronal TNF-α, Western blot analysis to investigate whether the effect of TWEAK was mediated by activation of mitogen-activated protein kinases and immunohistochemical techniques and quantitative real-time polymerase chain reaction analysis to study the effect of TWEAK on apoptotic cell death.</p> <p>Results</p> <p>We found that either treatment with recombinant TWEAK or an increase in the expression of TWEAK and Fn14 induce hypoxic and ischemic tolerance <it>in vivo </it>and <it>in vitro</it>. This protective effect is mediated by neuronal TNF-α and activation of the extracellular signal-regulated kinases 1 and 2 pathway via phosphorylation and inactivation of the B-cell lymphoma 2-associated death promoter protein.</p> <p>Conclusions</p> <p>Our work indicate that the interaction between TWEAK and Fn14 triggers the activation of a cell signaling pathway that results in the induction of tolerance to lethal hypoxia and ischemia. These data indicate that TWEAK may be a potential therapeutic strategy to protect the brain from the devastating effects of an ischemic injury.</p

Fly piRNA biogenesis: tap dancing with Tej

Piwi-interacting RNAs (piRNAs) protect animal germlines from the deleterious effects of transposon activity. Unlike other small RNA classes like microRNAs (miRNAs) and small interfering RNAs (siRNAs), an exceptionally large number of factors are implicated in the biogenesis of piRNAs. Kai et al. have now added another one to this growing list, which we discuss in the overall context of our current knowledge of the piRNA biogenesis pathway in the Drosophila ovarian germline. See research article: http://www.biomedcentral.com/1741-7007/12/61

The Caenorhabditis elegans HEN1 Ortholog, HENN-1, Methylates and Stabilizes Select Subclasses of Germline Small RNAs

Small RNAs regulate diverse biological processes by directing effector proteins called Argonautes to silence complementary mRNAs. Maturation of some classes of small RNAs involves terminal 2′-O-methylation to prevent degradation. This modification is catalyzed by members of the conserved HEN1 RNA methyltransferase family. In animals, Piwi-interacting RNAs (piRNAs) and some endogenous and exogenous small interfering RNAs (siRNAs) are methylated, whereas microRNAs are not. However, the mechanisms that determine animal HEN1 substrate specificity have yet to be fully resolved. In Caenorhabditis elegans, a HEN1 ortholog has not been studied, but there is evidence for methylation of piRNAs and some endogenous siRNAs. Here, we report that the worm HEN1 ortholog, HENN-1 (HEN of Nematode), is required for methylation of C. elegans small RNAs. Our results indicate that piRNAs are universally methylated by HENN-1. In contrast, 26G RNAs, a class of primary endogenous siRNAs, are methylated in female germline and embryo, but not in male germline. Intriguingly, the methylation pattern of 26G RNAs correlates with the expression of distinct male and female germline Argonautes. Moreover, loss of the female germline Argonaute results in loss of 26G RNA methylation altogether. These findings support a model wherein methylation status of a metazoan small RNA is dictated by the Argonaute to which it binds. Loss of henn-1 results in phenotypes that reflect destabilization of substrate small RNAs: dysregulation of target mRNAs, impaired fertility, and enhanced somatic RNAi. Additionally, the henn-1 mutant shows a weakened response to RNAi knockdown of germline genes, suggesting that HENN-1 may also function in canonical RNAi. Together, our results indicate a broad role for HENN-1 in both endogenous and exogenous gene silencing pathways and provide further insight into the mechanisms of HEN1 substrate discrimination and the diversity within the Argonaute family

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Delayed neuronal cell death in brainstem after transient brainstem ischemia in gerbils

<p>Abstract</p> <p>Background</p> <p>Because of the lack of reproducible brainstem ischemia models in rodents, the temporal profile of ischemic lesions in the brainstem after transient brainstem ischemia has not been evaluated intensively. Previously, we produced a reproducible brainstem ischemia model of Mongolian gerbils. Here, we showed the temporal profile of ischemic lesions after transient brainstem ischemia.</p> <p>Results</p> <p>Brainstem ischemia was produced by occlusion of the bilateral vertebral arteries just before their entry into the transverse foramina of the cervical vertebrae of Mongolian gerbils. Animals were subjected to brainstem ischemia for 15 min, and then reperfused for 0 d (just after ischemia), 1 d, 3 d and 7 d (n = 4 in each group). Sham-operated animals (n = 4) were used as control. After deep anesthesia, the gerbils were perfused with fixative for immunohistochemical investigation. Ischemic lesions were detected by immunostaining for microtubule-associated protein 2 (MAP2). Just after 15-min brainstem ischemia, ischemic lesions were detected in the lateral vestibular nucleus and the ventral part of the spinal trigeminal nucleus, and these ischemic lesions disappeared one day after reperfusion in all animals examined. However, 3 days and 7 days after reperfusion, ischemic lesions appeared again and clusters of ionized calcium-binding adapter molecule-1(IBA-1)-positive cells were detected in the same areas in all animals.</p> <p>Conclusion</p> <p>These results suggest that delayed neuronal cell death took place in the brainstem after transient brainstem ischemia in gerbils.</p