Direct interaction between EgFABP1, a fatty acid binding protein from echinococcus granulosus, and phospholipid membranes

<p>Background: Growth and maintenance of hydatid cysts produced by Echinococcus granulosus have a high requirement for host lipids for biosynthetic processes, membrane building and possibly cellular and developmental signalling. This requires a high degree of lipid trafficking facilitated by lipid transporter proteins. Members of the fatty acid binding protein (FABP) family have been identified in Echinococcus granulosus, one of which, EgFABP1 is expressed at the tegumental level in the protoscoleces, but it has also been described in both hydatid cyst fluid and secretions of protoscoleces. In spite of a considerable amount of structural and biophysical information on the FABPs in general, their specific functions remain mysterious.</p> <p>Methodology/Principal Findings: We have investigated the way in which EgFABP1 may interact with membranes using a variety of fluorescence-based techniques and artificial small unilamellar vesicles. We first found that bacterial recombinant EgFABP1 is loaded with fatty acids from the synthesising bacteria, and that fatty acid binding increases its resistance to proteinases, possibly due to subtle conformational changes induced on EgFABP1. By manipulating the composition of lipid vesicles and the ionic environment, we found that EgFABP1 interacts with membranes in a direct contact, collisional, manner to exchange ligand, involving both ionic and hydrophobic interactions. Moreover, we observed that the protein can compete with cytochrome c for association with the surface of small unilamellar vesicles (SUVs).</p> <p>Conclusions/Significance: This work constitutes a first approach to the understanding of protein-membrane interactions of EgFABP1. The results suggest that this protein may be actively involved in the exchange and transport of fatty acids between different membranes and cellular compartments within the parasite.</p&gt

Validating and comparing stroke prognosis scales

Objective: To compare the prognostic accuracy of various acute stroke prognostic scales using a large, independent, clinical trials dataset. Methods: We directly compared 8 stroke prognostic scales, chosen based on focused literature review (Acute Stroke Registry and Analysis of Lausanne [ASTRAL]; iSCORE; iSCORE-revised; preadmission comorbidities, level of consciousness, age, and neurologic deficit [PLAN]; stroke subtype, Oxfordshire Community Stroke Project, age, and prestroke modified Rankin Scale [mRS] [SOAR]; modified SOAR; Stroke Prognosis Instrument 2 [SPI2]; and Totaled Health Risks in Vascular Events [THRIVE]) using individual patient-level data from a clinical trials archive (Virtual International Stroke Trials Archive [VISTA]). We calculated area under receiver operating characteristic curves (AUROC) for each scale against 90-day outcomes of mRS (dichotomized atmRS.2), Barthel Index (.85), and mortality. We performed 2 complementary analyses: the first limited to patients with complete data for all components of all scales (simultaneous) and the second using as many patients as possible for each individual scale (separate). We compared AUROCs and performed sensitivity analyses substituting extreme outcome values for missing data. Results: In total, 10,777 patients contributed to the analyses. Our simultaneous analyses suggested that ASTRAL had greatest prognostic accuracy for mRS, AUROC 0.78 (95% confidence interval [CI] 0.75–0.82), and SPI2 had poorest AUROC, 0.61 (95%CI 0.57–0.66). Our separate analyses confirmed these results: ASTRAL AUROC 0.79 (95% CI 0.78–0.80 and SPI2 AUROC 0.60 (95% CI 0.59–0.61). On formal comparative testing, there was a significant difference in modified Rankin Scale AUROC between ASTRAL and all other scales. Sensitivity analysis identified no evidence of systematic bias from missing data. Conclusions: Our comparative analyses confirm differences in the prognostic accuracy of stroke scales. However, even the best performing scale had prognostic accuracy that may not be sufficient as a basis for clinical decision-making

Buried treasure—marine turtles do not ‘disguise’ or ‘camouflage’ their nests but avoid them and create a decoy trail

After laying their eggs and refilling the egg chamber, sea turtles scatter sand extensively around the nest site. This is presumed to camouflage the nest, or optimize local conditions for egg development, but a consensus on its function is lacking. We quantified activity and mapped the movements of hawksbill (Eretmochelys imbricata) and leatherback (Dermochelys coriacea) turtles during sand-scattering. For leatherbacks, we also recorded activity at each sand-scattering position. For hawksbills, we recorded breathing rates during nesting as an indicator of metabolic investment and compared with published values for leatherbacks. Temporal and inferred metabolic investment in sand-scattering was substantial for both species. Neither species remained near the nest while sand-scattering, instead moving to several other positions to scatter sand, changing direction each time, progressively displacing themselves from the nest site. Movement patterns were highly diverse between individuals, but activity at each sand-scattering position changed little between completion of egg chamber refilling and return to the sea. Our findings are inconsistent with sand-scattering being to directly camouflage the nest, or primarily for modifying the nest-proximal environment. Instead, they are consistent with the construction of a series of dispersed decoy nests that may reduce the discovery of nests by predators

The spectral gap for some spin chains with discrete symmetry breaking

We prove that for any finite set of generalized valence bond solid (GVBS) states of a quantum spin chain there exists a translation invariant finite-range Hamiltonian for which this set is the set of ground states. This result implies that there are GVBS models with arbitrary broken discrete symmetries that are described as combinations of lattice translations, lattice reflections, and local unitary or anti-unitary transformations. We also show that all GVBS models that satisfy some natural conditions have a spectral gap. The existence of a spectral gap is obtained by applying a simple and quite general strategy for proving lower bounds on the spectral gap of the generator of a classical or quantum spin dynamics. This general scheme is interesting in its own right and therefore, although the basic idea is not new, we present it in a system-independent setting. The results are illustrated with an number of examples.Comment: 48 pages, Plain TeX, BN26/Oct/9

Continuing or temporarily stopping prestroke antihypertensive medication in acute stroke: an individual patient data meta-analysis

Over 50% of patients are already taking blood pressure–lowering therapy on hospital admission for acute stroke. An individual patient data meta-analysis from randomized controlled trials was undertaken to determine the effect of continuation versus temporarily stopping preexisting antihypertensive medication in acute stroke. Key databases were searched for trials against the following inclusion criteria: randomized design; stroke onset ≤48 hours; investigating the effect of continuation versus stopping prestroke antihypertensive medication; and follow-up of ≥2 weeks. Two randomized controlled trials were identified and included in this meta-analysis of individual patient data from 2860 patients with ≤48 hours of acute stroke. Risk of bias in each study was low. In adjusted logistic regression and multiple regression analyses (using random effects), we found no significant association between continuation of prestroke antihypertensive therapy (versus stopping) and risk of death or dependency at final follow-up: odds ratio 0.96 (95% confidence interval, 0.80–1.14). No significant associations were found between continuation (versus stopping) of therapy and secondary outcomes at final follow-up. Analyses for death and dependency in prespecified subgroups revealed no significant associations with continuation versus temporarily stopping therapy, with the exception of patients randomized ≤12 hours, in whom a difference favoring stopping treatment met statistical significance. We found no significant benefit with continuation of antihypertensive treatment in the acute stroke period. Therefore, there is no urgency to administer preexisting antihypertensive therapy in the first few hours or days after stroke, unless indicated for other comorbid conditions

Understanding the relationship between costs and the modified Rankin Scale: a systematic review, multidisciplinary consensus and recommendations for future studies

Background and purpose: Cost-of-illness studies often describe a single aggregate cost of a disease state. This approach is less helpful for a condition with a spectrum of outcomes like stroke. The modified Rankin Scale is the most commonly used outcome measure for stroke. We sought to describe the existing evidence on the costs of stroke according to individual modified Rankin Scale categories. This may be useful in future cost effectiveness modelling studies of interventions where cost data have not been collected, but disability outcome is known. Methods: Systematic review of the published literature, searching electronic databases between 2004 and 2015 using validated search filters. Results were screened to identify studies presenting costs by individual modified Rankin Scale categories. Results: Of 17,782 unique identified articles, 13 matched all inclusion criteria. In only four of these studies were costs reported by modified Rankin Scale categories. Most studies included direct medical costs only. Societal costs were assessed in two studies. Overall, studies had a high methodological and reporting quality. The heterogeneity in costing methods used in the identified studies prevented meaningful comparison of the reported cost data. Despite this limitation, the costs consistently increased with greater severity (increasing modified Rankin Scale score). Conclusions: Few cost studies of stroke include information based on stroke recovery measured by individual modified Rankin Scale categories and the existing data are limited. To reliably capture this information, future studies are needed that preferably apply standardised costing methods to promote greater potential for use in cost-effectiveness analyses whereby direct collection of patient-level resource use has not been possible

Dependency and health utilities in stroke: data to inform cost-effectiveness analyses

Introduction: Health utilities (HU) assign preference weights to specific health states and are required for costeffectiveness analyses. Existing HU for stroke inadequately reflect the spectrum of post-stroke disability. Using international stroke trial data, we calculated HU stratified by disability to improve precision in future cost-effectiveness analyses. Materials and methods: We used European Quality of Life Score (EQ-5D-3L) data from the Virtual International Stroke Trials Archive (VISTA) to calculate HU, stratified by modified Rankin Scale scores (mRS) at 3 months. We applied published value sets to generate HU, and validated these using ordinary least squares regression, adjusting for age and baseline National Institutes of Health Stroke Scale (NIHSS) scores. Results: We included 3858 patients with acute ischemic stroke in our analysis (mean age: 67.5+-12.5, baseline NIHSS: 12+-5). We derived HU using value sets from 13 countries and observed significant international variation in HU distributions (Wilcoxon signed-rank test p<0.0001, compared with UK values). For mRS=0, mean HU ranged from 0.88 to 0.95; for mRS=5, mean HU ranged from -0.48 to 0.22. OLS regression generated comparable HU (for mRS=0, HU ranged from 0.9 to 0.95; for mRS=5, HU ranged from -0.33 to 0.15). Patients’ mRS scores at 3 months accounted for 65–71% of variation in the generated HU. Conclusion: We have generated HU stratified by dependency level, using a common trial endpoint, and describing expected variability when applying diverse value sets to an international population. These will improve future cost-effectiveness analyses. However, care should be taken to select appropriate value sets

Photodynamic destruction of endometrial tissue with topical 5-aminolevulinic acid in rats and rabbits

ObjectiveThe goal of this study was to determine the optimal parameters for photodynamic endometrial destruction with topically applied 5-aminolevulinic acid, a precursor for the endogenous synthesis of the fluorescent photosensitizer protoporphyrin IX.Study design5-Aminolevulinic acid pharmacokinetics were measured in rat and rabbit models by analyzing tissue frozen sections 3 to 12 hours after topical administration. Dose-response studies were conducted for 100 to 400 mg/ml 5-aminolevulinic acid. Photodynamic therapy was performed intraluminally, and tissue morphologic features were evaluated 3 and 7 days after treatment.ResultsPeak fluorescence was observed 3 hours after topical administration. Glandular fluorescence significantly exceeded stromal and myometrial in all studies, particularly for 200 mg/ml 5-aminolevulinic acid. Histologic studies revealed persistent epithelial destruction with minimal regeneration.ConclusionTopical 5-aminolevulinic acid photodynamic therapy can be used for highly effective, long-lasting destruction of endometrial epithelium. However, optical dosimetry can vary, particularly in the rabbit model, and this appears to have an impact on long-term reepithelialization