Brain edema : a valid endpoint for measuring hepatic encephalopathy?

Hepatic encephalopathy (HE) is a major complication of liver failure/disease which frequently develops during the progression of end-stage liver disease. This metabolic neuropsychiatric syndrome involves a spectrum of symptoms, including cognition impairment, attention deficits and motor dysfunction which eventually can progress to coma and death. Pathologically, HE is characterized by swelling of the astrocytes which consequently leads to brain edema, a common feature found in patients with acute liver failure (ALF) as well as in cirrhotic patients suffering from HE. The pathogenic factors involved in the onset of astrocyte swelling and brain edema in HE are unresolved. However, the role of astrocyte swelling/brain edema in the development of HE remains ambiguous and therefore measuring brain edema as an endpoint to evaluate HE is questioned. The following review will determine the effect of astrocyte swelling and brain edema on neurological function, discuss the various possible techniques to measure brain edema and lastly to propose a number of neurobehavioral tests to evaluate HE

The Distribution of Mating-Type Bias in Natural Populations of the Anther-Smut Ustilago violacea on Silene alba in Virginia

This is the publisher's version, also available electronically from http://www.jstor.org/stable/info/3761395.Complete individual-wide mating-type bias (retrieval of sporidia of only one mating type from germinated teliospores of one fungal individual) was observed to be a common and widespread feature of the anther-smut fungus, Ustilago violacea, collected from natural populations of its host, Silene alba. The bias was usually to mating type A1, but the frequency of bias and its spatial distribution varied from region to region. Populations with high frequencies of bias still showed high rates of disease transmission. Crosses between A1 mating type sporidial lines from completely biased individuals and A2 mating types from unbiased individuals showed no bias in the progeny. During teliospore germination, biased individuals often showed conjugation among adjacent cells of the promycelium, suggesting that both mating types are present in the germinating teliospore but one mating type is unable to grow as free-living sporidia. The complete bias was most readily interpreted as evidence of "haploid lethals" linked to mating type that cause poor survival or growth of the sporidial stage. The results show that such "haploid lethals" may be a common occurrence in natural populations, and that fungal mating systems may vary considerably over short distances

NanoSIMS results from olivine-hosted melt embayments: Magma ascent rate during explosive basaltic eruptions

The explosivity of volcanic eruptions is governed in part by the rate at which magma ascends and degasses. Because the time scales of eruptive processes can be exceptionally fast relative to standard geochronometers, magma ascent rate remains difficult to quantify. Here we use as a chronometer concentration gradients of volatile species along open melt embayments within olivine crystals. Continuous degassing of the external melt during magma ascent results in diffusion of volatile species from embayment interiors to the bubble located at their outlets. The novel aspect of this study is the measurement of concentration gradients in five volatile elements (CO2, H2O, S, Cl, F) at fine-scale (5–10 μm) using the NanoSIMS. The wide range in diffusivity and solubility of these different volatiles provides multiple constraints on ascent timescales over a range of depths. We focus on four 100–200 μm, olivine-hosted embayments erupted on October 17, 1974 during the sub-Plinian eruption of Volcán de Fuego. H2O, CO2, and S all decrease toward the embayment outlet bubble, while F and Cl increase or remain roughly constant. Compared to an extensive melt inclusion suite from the same day of the eruption, the embayments have lost both H2O and CO2 throughout the entire length of the embayment. We fit the profiles with a 1-D numerical diffusion model that allows varying diffusivities and external melt concentrations as a function of pressure. Assuming a constant decompression rate from the magma storage region at approximately 220 MPa to the surface, H2O, CO2 and S profiles for all embayments can be fit with a relatively narrow range in decompression rates of 0.3–0.5 MPa/s, equivalent to 11–17 m/s ascent velocity and an 8 to 12 minute duration of magma ascent from ~ 10 km depth. A two stage decompression model takes advantage of the different depth ranges over which CO2 and H2O degas, and produces good fits given an initial stage of slow decompression (0.05–0.3 MPa/s) at high pressure (< 145 MPa), with similar decompression rates to the single-stage model for the shallower stage. The magma ascent rates reported here are among the first for explosive basaltic eruptions and demonstrate the potential of the embayment method for quantifying magmatic timescales associated with eruptions of different vigor

Development of a new humanized mouse model to study acute inflammatory arthritis

BACKGROUND: Substantial advances have been generated in understanding the pathogenesis of rheumatoid arthritis (RA). Current murine models of RA-like disease have provided great insights into the molecular mechanism of inflammatory arthritis due to the use of genetically deficient or transgenic mice. However, these studies are limited by differences that exist between human and murine immune systems. Thus, the development of an animal model that utilizes human immune cells, will afford the opportunity to study their function in the initiation and propagation of inflammatory arthritis. METHODS: One to two-day old irradiated NOD-scid IL2rγ(null) (NSG) mice were reconstituted with human CD34+ cord blood stem cells. Leukocytes were analyzed by flow cytometry and circulating antibodies were determined by ELISA. Arthritis was induced by injecting complete Freund’s adjuvant into knee or ankle joints. Mice were also treated with the TNF inhibitor, Etanercept, or PBS and joints were analyzed histologically. RESULTS: Humanized mice were established with high reconstitution rates and were able to spontaneously produce human immunoglobulins as well as specific IgG in response to immunization. Intraperitoneal injection of thioglycolate or injection of complete Freund’s adjuvant into joints resulted in migration of human immune cells to the injected sites. Arthritic humanized mice treated with Etanercept had markedly less inflammation, which was associated with decreased total numbers of human CD45+ cells, including human lymphocytes and neutrophils. CONCLUSIONS: The humanized mouse model is a new model to study inflammatory arthritis disease using human leukocytes without rejection of engrafted tissue. Future studies may adapt this system to incorporate RA patient cord blood and develop a chimeric animal model of inflammatory arthritis using genetically predisposed immune cells

Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, D9-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT2A receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/ kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABAA receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT2A binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes

Random walks in the space of conformations of toy proteins

Monte Carlo dynamics of the lattice 48 monomers toy protein is interpreted as a random walk in an abstract (discrete) space of conformations. To test the geometry of this space, we examine the return probability $P(T)$, which is the probability to find the polymer in the native state after $T$ Monte Carlo steps, provided that it starts from the native state at the initial moment. Comparing computational data with the theoretical expressions for $P(T)$ for random walks in a variety of different spaces, we show that conformational spaces of polymer loops may have non-trivial dimensions and exhibit negative curvature characteristic of Lobachevskii (hyperbolic) geometry.Comment: 4 pages, 3 figure

Evaluation of the first year of the Oxpal Medlink: A web-based partnership designed to address specific challenges facing medical education in the occupied Palestinian territories

Objectives: To (1) evaluate educational needs of clinical students at Al-Quds University Medical School in the West Bank; (2) address these needs where possible using synchronous distance learning, with clinicians in Oxford providing case-based tutorials to undergraduates in the West Bank via an online platform (WizIQ) and (3) assess the impact of this education. Design: Review of online OxPal Medlink database for tutorials held between March 2012 and April 2013. Needs assessment and evaluation of student and tutor experiences through online questionnaires, focus groups and semi-structured interviews. Setting: Oxford University Hospitals, Oxford, UK, and Al-Quds University Medical School, Abu Dies, Palestine. Participants: Doctors at Oxford University Hospitals and fourth-, fifth- and sixth-year medical students and faculty members at Al-Quds Medical School. Main outcome measures Number of tutorials, student participation, student-rated satisfaction and qualitative feedback from tutors and students. Results: Students demonstrated strong theoretical knowledge but struggled to apply this in presentation-based scenarios. Between March 2012 and April 2013, 90 tutorials were delivered to 60 students. Feedback: >95% respondents rated tutorials as ‘Excellent’ or ‘Good’ and ‘Very’ or ‘Fairly’ relevant to their future practice in Palestine. Students reported the programme had modified their approach to patients but requested better synchronization with concurrent attachments and clarification of learning outcomes. Conclusions: OxPal Medlink is a novel, web-based distance-learning partnership designed to overcome some of the challenges to local medical education in the occupied Palestinian territories. Evaluation of the first year indicates teaching is relevant to local practice and of high quality. This approach may have the potential to strengthen local capacity for medical education

Designing topographically textured microparticles for induction and modulation of osteogenesis in mesenchymal stem cell engineering

Mesenchymal stem cells are the focus of intense research in bone development and regeneration. The potential of microparticles as modulating moieties of osteogenic response by utilizing their architectural features is demonstrated herein. Topographically textured microparticles of varying microscale features are produced by exploiting phase-separation of a readily soluble sacrificial component from polylactic acid. The influence of varying topographical features on primary human mesenchymal stem cell attachment, proliferation and markers of osteogenesis is investigated. In the absence of osteoinductive supplements, cells cultured on textured microparticles exhibit notably increased expression of osteogenic markers relative to conventional smooth microparticles. They also exhibit varying morphological, attachment and proliferation responses. Significantly altered gene expression and metabolic profiles are observed, with varying histological characteristics in vivo. This study highlights how tailoring topographical design offers cell-instructive 3D microenvironments which allow manipulation of stem cell fate by eliciting the desired downstream response without use of exogenous osteoinductive factors

Joint analysis of stressors and ecosystem services to enhance restoration effectiveness

With increasing pressure placed on natural systems by growing human populations, both scientists and resource managers need a better understanding of the relationships between cumulative stress from human activities and valued ecosystem services. Societies often seek to mitigate threats to these services through large-scale, costly restoration projects, such as the over one billion dollar Great Lakes Restoration Initiative currently underway. To help inform these efforts, we merged high-resolution spatial analyses of environmental stressors with mapping of ecosystem services for all five Great Lakes. Cumulative ecosystem stress is highest in near-shore habitats, but also extends offshore in Lakes Erie, Ontario, and Michigan. Variation in cumulative stress is driven largely by spatial concordance among multiple stressors, indicating the importance of considering all stressors when planning restoration activities. In addition, highly stressed areas reflect numerous different combinations of stressors rather than a single suite of problems, suggesting that a detailed understanding of the stressors needing alleviation could improve restoration planning. We also find that many important areas for fisheries and recreation are subject to high stress, indicating that ecosystem degradation could be threatening key services. Current restoration efforts have targeted high-stress sites almost exclusively, but generally without knowledge of the full range of stressors affecting these locations or differences among sites in service provisioning. Our results demonstrate that joint spatial analysis of stressors and ecosystem services can provide a critical foundation for maximizing social and ecological benefits from restoration investments. www.pnas.org/lookup/suppl/doi:10.1073/pnas.1213841110/-/DCSupplementa