Barrier dysfunction or drainage reduction: differentiating causes of CSF protein increase

BACKGROUND Cerebrospinal fluid (CSF) protein analysis is an important element in the diagnostic chain for various central nervous system (CNS) pathologies. Among multiple existing approaches to interpreting measured protein levels, the Reiber diagram is particularly robust with respect to physiologic inter-individual variability, as it uses multiple subject-specific anchoring values. Beyond reliable identification of abnormal protein levels, the Reiber diagram has the potential to elucidate their pathophysiologic origin. In particular, both reduction of CSF drainage from the cranio-spinal space as well as blood-CNS barrier dysfunction have been suggested ρas possible causes of increased concentration of blood-derived proteins. However, there is disagreement on which of the two is the true cause. METHODS We designed two computational models to investigate the mechanisms governing protein distribution in the spinal CSF. With a one-dimensional model, we evaluated the distribution of albumin and immunoglobulin G (IgG), accounting for protein transport rates across blood-CNS barriers, CSF dynamics (including both dispersion induced by CSF pulsations and advection by mean CSF flow) and CSF drainage. Dispersion coefficients were determined a priori by computing the axisymmetric three-dimensional CSF dynamics and solute transport in a representative segment of the spinal canal. RESULTS Our models reproduce the empirically determined hyperbolic relation between albumin and IgG quotients. They indicate that variation in CSF drainage would yield a linear rather than the expected hyperbolic profile. In contrast, modelled barrier dysfunction reproduces the experimentally observed relation. CONCLUSIONS High levels of albumin identified in the Reiber diagram are more likely to originate from a barrier dysfunction than from a reduction in CSF drainage. Our in silico experiments further support the hypothesis of decreasing spinal CSF drainage in rostro-caudal direction and emphasize the physiological importance of pulsation-driven dispersion for the transport of large molecules in the CSF

Land Cover and Rainfall Interact to Shape Waterbird Community Composition

Human land cover can degrade estuaries directly through habitat loss and fragmentation or indirectly through nutrient inputs that reduce water quality. Strong precipitation events are occurring more frequently, causing greater hydrological connectivity between watersheds and estuaries. Nutrient enrichment and dissolved oxygen depletion that occur following these events are known to limit populations of benthic macroinvertebrates and commercially harvested species, but the consequences for top consumers such as birds remain largely unknown. We used non-metric multidimensional scaling (MDS) and structural equation modeling (SEM) to understand how land cover and annual variation in rainfall interact to shape waterbird community composition in Chesapeake Bay, USA. The MDS ordination indicated that urban subestuaries shifted from a mixed generalist-specialist community in 2002, a year of severe drought, to generalist-dominated community in 2003, of year of high rainfall. The SEM revealed that this change was concurrent with a sixfold increase in nitrate-N concentration in subestuaries. In the drought year of 2002, waterbird community composition depended only on the direct effect of urban development in watersheds. In the wet year of 2003, community composition depended both on this direct effect and on indirect effects associated with high nitrate-N inputs to northern parts of the Bay, particularly in urban subestuaries. Our findings suggest that increased runoff during periods of high rainfall can depress water quality enough to alter the composition of estuarine waterbird communities, and that this effect is compounded in subestuaries dominated by urban development. Estuarine restoration programs often chart progress by monitoring stressors and indicators, but rarely assess multivariate relationships among them. Estuarine management planning could be improved by tracking the structure of relationships among land cover, water quality, and waterbirds. Unraveling these complex relationships may help managers identify and mitigate ecological thresholds that occur with increasing human land cover

Financial system

Background-Lanoteplase (nPA) is a rationally designed variant of tissue plasminogen activator with greater fibrinolytic potency and slower plasma clearance than alteplase. Methods and Results-InTIME (Intravenous nPA for Treatment of Infarcting Myocardium Early), a multicenter, double-blind, randomized, double-placebo angiographic trial, evaluated the close-response relationship and safety of single-bolus, weight-adjusted lanoteplase. Patients (n=602) presenting within 6 hours of acute myocardial infarction were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60, or 120 kU/kg) or accelerated alteplase. The primary objective was to determine TIMI grade flow at 60 minutes. Angiographic assessments were also performed at 90 minutes and on days 3 to 5. Follow-up was continued for 30 days. Lanoteplase achieved its primary objective, demonstrating a dose-response in TIMI grade 3 flow at 60 minutes (23.6% to 47.1% of subjects, P Conclusions-Lanoteplase, a single-bolus, weight-adjusted agent, increased coronary patency at 60 and 90 minutes in a dose-dependent fashion. Coronary patency at 90 Minutes was achieved more frequently with 120 kU/kg lanoteplase than alteplase. In this study, safety with lanoteplase and alteplase was comparable. InTIME-II, a worldwide mortality trial, will evaluate efficacy and safety with this promising new agent