Changes in urinary metabolomic profile during relapsing renal vasculitis

Current biomarkers of renal disease in systemic vasculitis lack predictive value and are insensitive to early damage. To identify novel biomarkers of renal vasculitis flare, we analysed the longitudinal urinary metabolomic profile of a rat model of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Wistar-Kyoto (WKY) rats were immunised with human myeloperoxidase (MPO). Urine was obtained at regular intervals for 181 days, after which relapse was induced by re-challenge with MPO. Urinary metabolites were assessed in an unbiased fashion using nuclear magnetic resonance (NMR) spectroscopy, and analysed using partial least squares discriminant analysis (PLS-DA) and partial least squares regression (PLS-R). At 56 days post-immunisation, we found that rats with vasculitis had a significantly different urinary metabolite profile than control animals; the observed PLS-DA clusters dissipated between 56 and 181 days, and re-emerged with relapse. The metabolites most altered in rats with active or relapsing vasculitis were trimethylamine N-oxide (TMAO), citrate and 2-oxoglutarate. Myo-inositol was also moderately predictive. The key urine metabolites identified in rats were confirmed in a large cohort of patients using liquid chromatography-mass spectrometry (LC-MS). Hypocitraturia and elevated urinary myo-inositol remained associated with active disease, with the urine myo-inositol:citrate ratio being tightly correlated with active renal vasculitis

Trust and influence in the Gulf of Mexico's fishery public management network

© 2019 by the authors. Sustainable fishery management is a complex multi-sectoral challenge requiring substantial interagency coordination, collaboration, and knowledge sharing. While scholars of public management network theory and natural resource management have identified trust as one of the key ideational network properties that facilitates such interaction, relatively few studies have operationalized and measured the multiple dimensions of trust and their influence on collaboration. This article presents the results of an exploratory study examining the Gulf of Mexico fishery management network comprised of more than 30 stakeholder organizations. Using an empirically validated survey instrument, the distribution of four types of trust, three gradations of influence, and the degree of formality and informality in actor communications were assessed across the fishery public management network. The analysis reveals generally low levels of interorganizational procedural trust and a high degree of network fragmentation along the international border. Civil servants based at U.S. organizations reported nearly no interactions with Mexican agencies, and vice versa. Rational (calculative) trust was the most important in bringing about reported change in other organizations, while dispositional distrust and affnitive (relational) trust also had significant effects. The results suggest that, although transactional interorganizational relationships prevail in Gulf of Mexico fishery governance, well-developed professional relationships contribute meaningfully to the reported success of public fishery network management and warrants further policy attention in order to help ensure sustainability

Anti-müllerian hormone is not associated with cardiometabolic risk factors in adolescent females

<p>Objectives: Epidemiological evidence for associations of Anti-Müllerian hormone (AMH) with cardiometabolic risk factors is lacking. Existing evidence comes from small studies in select adult populations, and findings are conflicting. We aimed to assess whether AMH is associated with cardiometabolic risk factors in a general population of adolescent females.</p> <p>Methods: AMH, fasting insulin, glucose, HDLc, LDLc, triglycerides and C-reactive protein (CRP) were measured at a mean age 15.5 years in 1,308 female participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Multivariable linear regression was used to examine associations of AMH with these cardiometabolic outcomes.</p> <p>Results: AMH values ranged from 0.16–35.84 ng/ml and median AMH was 3.57 ng/ml (IQR: 2.41, 5.49). For females classified as post-pubertal (n = 848) at the time of assessment median (IQR) AMH was 3.81 ng/ml (2.55, 5.82) compared with 3.25 ng/ml (2.23, 5.05) in those classed as early pubertal (n = 460, P≤0.001). After adjusting for birth weight, gestational age, pubertal stage, age, ethnicity, socioeconomic position, adiposity and use of hormonal contraceptives, there were no associations with any of the cardiometabolic outcomes. For example fasting insulin changed by 0% per doubling of AMH (95%CI: −3%,+2%) p = 0.70, with identical results if HOMA-IR was used. Results were similar after additional adjustment for smoking, physical activity and age at menarche, after exclusion of 3% of females with the highest AMH values, after excluding those that had not started menarche and after excluding those using hormonal contraceptives.</p> <p>Conclusion: Our results suggest that in healthy adolescent females, AMH is not associated with cardiometabolic risk factors.</p&gt

The control of attentional target selection in a colour/colour conjunction task

To investigate the time course of attentional object selection processes in visual search tasks where targets are defined by a combination of features from the same dimension, we measured the N2pc component as an electrophysiological marker of attentional object selection during colour/colour conjunction search. In Experiment 1, participants searched for targets defined by a combination of two colours, while ignoring distractor objects that matched only one of these colours. Reliable N2pc components were triggered by targets and also by partially matching distractors, even when these distractors were accompanied by a target in the same display. The target N2pc was initially equal in size to the sum of the two N2pc components to the two different types of partially matching distractors, and became superadditive from about 250 ms after search display onset. Experiment 2 demonstrated that the superadditivity of the target N2pc was not due to a selective disengagement of attention from task-irrelevant partially matching distractors. These results indicate that attention was initially deployed separately and in parallel to all target-matching colours, before attentional allocation processes became sensitive to the presence of both matching colours within the same object. They suggest that attention can be controlled simultaneously and independently by multiple features from the same dimension, and that feature-guided attentional selection processes operate in parallel for different target-matching objects in the visual field

Electrophysiological Evidence of Atypical Spatial Attention in Those with a High Level of Self-reported Autistic Traits

Selective attention is atypical in individuals with autism spectrum conditions. Evidence suggests this is also the case for those with high levels of autistic traits. Here we investigated the neural basis of spatial attention in those with high and low levels of self-reported autistic traits via analysis of ERP deflections associated with covert attention, target selection and distractor suppression (the N2pc, NT and PD). Larger N2pc and smaller PD amplitude was observed in those with high levels of autistic traits. These data provide neural evidence for differences in spatial attention, specifically, reduced distractor suppression in those with high levels of autistic traits, and may provide insight into the experience of perceptual overload often reported by individuals on the autism spectrum

Assessing the influence of international environmental treaty secretariats using a relational network approach

The influential role of international treaty secretariats in coordinating bureaucracies across jurisdictional boundaries has been highlighted in recent years. While we now better understand how their influence occurs, the field still faces a substantial difficulty in answering the basic quantitative question of “how influential?” By employing network analysis, we devised and tested a survey to quantify secretariat influence within an international environmental regime. We applied the survey tool to two transboundary fisheries governance networks in North America and here focus on the Great Lakes Fishery Commission (GLFC) as our primary case study. The results demonstrate a high ability of treaty secretariat to influence the management decisions of federal and state/provincial agencies. Primary interview data collected with the GLFC secretariat staff helps explain this finding. This study advances the reconceptualization of secretariat influence via relational metrics, and offers a way to estimate secretariat influence despite their typically veiled modes of operation

Rethinking therapeutic strategies in cancer: wars, fields, anomalies and monsters

This article argues that the excessive focus on cancer as an insidious living defect that needs to be destroyed has obscured the fact that cancer develops inside human beings. Therefore, in order to contribute to debates about new cancer therapies, we argue that it is important to gain a broader understanding of what cancer is and how it might be otherwise. First, in order to reframe the debate, we utilize Pierre Bourdieu’s field analysis in order to gain a stronger understanding of the structure of the (sub)field of cancer research. In doing so, we are able to see that those in a dominant position in the field, with high levels of scientific capital at their disposal, are in the strongest position to determine the type of research that is carried out and, more significantly, how cancer is perceived. Field analysis enables us to gain a greater understanding of the complex interplay between the field of science (and, more specifically, the subfield of cancer research) and broader sources of power. Second, we draw attention to new possible ways of understanding cancer in its evolutionary context. One of the problems facing cancer research is the narrow time frame within which cancer is perceived: the lives of cancer cells are considered from the moment the cells initially change. In contrast, the approach put forward here requires a different way of thinking: we take a longer view and consider cancer as a living entity, with cancer perceived as anomalous rather than abnormal. Third, we theorize the possibility of therapeutic strategies that might involve the redirection (rather than the eradication) of cancer cells. This approach also necessitates new ways of perceiving cancer

Examination of the Effects of Heterogeneous Organization of RyR Clusters, Myofibrils and Mitochondria on Ca2+ Release Patterns in Cardiomyocytes

Spatio-temporal dynamics of intracellular calcium, [Ca2+]i, regulate the contractile function of cardiac muscle cells. Measuring [Ca2+]i flux is central to the study of mechanisms that underlie both normal cardiac function and calcium-dependent etiologies in heart disease. However, current imaging techniques are limited in the spatial resolution to which changes in [Ca2+]i can be detected. Using spatial point process statistics techniques we developed a novel method to simulate the spatial distribution of RyR clusters, which act as the major mediators of contractile Ca2+ release, upon a physiologically-realistic cellular landscape composed of tightly-packed mitochondria and myofibrils.We applied this method to computationally combine confocal-scale (~ 200 nm) data of RyR clusters with 3D electron microscopy data (~ 30 nm) of myofibrils and mitochondria, both collected from adult rat left ventricular myocytes. Using this hybrid-scale spatial model, we simulated reaction-diffusion of [Ca2+]i during the rising phase of the transient (first 30 ms after initiation). At 30 ms, the average peak of the simulated [Ca2+]i transient and of the simulated fluorescence intensity signal, F/F0, reached values similar to that found in the literature ([Ca2+]i 1 μM; F/F0 5.5). However, our model predicted the variation in [Ca2+]i to be between 0.3 and 12.7 μM (~3 to 100 fold from resting value of 0.1 μM) and the corresponding F/F0 signal ranging from 3 to 9.5. We demonstrate in this study that: (i) heterogeneities in the [Ca2+]i transient are due not only to heterogeneous distribution and clustering of mitochondria; (ii) but also to heterogeneous local densities of RyR clusters. Further, we show that: (iii) these structureinduced heterogeneities in [Ca2+]i can appear in line scan data. Finally, using our unique method for generating RyR cluster distributions, we demonstrate the robustness in the [Ca2+]i transient to differences in RyR cluster distributions measured between rat and human cardiomyocytes

Universal health coverage from multiple perspectives: a synthesis of conceptual literature and global debates

Background: There is an emerging global consensus on the importance of universal health coverage (UHC), but no unanimity on the conceptual definition and scope of UHC, whether UHC is achievable or not, how to move towards it, common indicators for measuring its progress, and its long-term sustainability. This has resulted in various interpretations of the concept, emanating from different disciplinary perspectives. This paper discusses the various dimensions of UHC emerging from these interpretations and argues for the need to pay attention to the complex interactions across the various components of a health system in the pursuit of UHC as a legal human rights issue. Discussion: The literature presents UHC as a multi-dimensional concept, operationalized in terms of universal population coverage, universal financial protection, and universal access to quality health care, anchored on the basis of health care as an international legal obligation grounded in international human rights laws. As a legal concept, UHC implies the existence of a legal framework that mandates national governments to provide health care to all residents while compelling the international community to support poor nations in implementing this right. As a humanitarian social concept, UHC aims at achieving universal population coverage by enrolling all residents into health-related social security systems and securing equitable entitlements to the benefits from the health system for all. As a health economics concept, UHC guarantees financial protection by providing a shield against the catastrophic and impoverishing consequences of out-of-pocket expenditure, through the implementation of pooled prepaid financing systems. As a public health concept, UHC has attracted several controversies regarding which services should be covered: comprehensive services vs. minimum basic package, and priority disease-specific interventions vs. primary health care. Summary: As a multi-dimensional concept, grounded in international human rights laws, the move towards UHC in LMICs requires all states to effectively recognize the right to health in their national constitutions. It also requires a human rights-focused integrated approach to health service delivery that recognizes the health system as a complex phenomenon with interlinked functional units whose effective interaction are essential to reach the equilibrium called UHC

Neurobiology of rodent self-grooming and its value for translational neuroscience

Self-grooming is a complex innate behaviour with an evolutionarily conserved sequencing pattern and is one of the most frequently performed behavioural activities in rodents. In this Review, we discuss the neurobiology of rodent self-grooming, and we highlight studies of rodent models of neuropsychiatric disorders-including models of autism spectrum disorder and obsessive compulsive disorder-that have assessed self-grooming phenotypes. We suggest that rodent self-grooming may be a useful measure of repetitive behaviour in such models, and therefore of value to translational psychiatry. Assessment of rodent self-grooming may also be useful for understanding the neural circuits that are involved in complex sequential patterns of action.National Institutes of Health (U.S.) (Grant NS025529)National Institutes of Health (U.S.) (Grant HD028341)National Institutes of Health (U.S.) (Grant MH060379