When can we declare a success? A Bayesian framework to assess the recovery rate of impaired freshwater ecosystems.

Evaluating the degree of improvement of an impaired freshwater ecosystem resembles the statistical null-hypothesis testing through which the prevailing conditions are compared against a reference state. The pillars of this process involve the robust delineation of what constitutes an achievable reference state; the establishment of threshold values for key environmental variables that act as proxies of the degree of system impairment; and the development of an iterative decision-making process that takes advantage of monitoring data to assess the system-restoration progress and revisit management actions accordingly. Drawing the dichotomy between impaired and non-impaired conditions is a challenging exercise that is surrounded by considerable uncertainty stemming from the variability that natural systems display over time and space, the presence of ecosystem feedback loops (e.g., internal loading) that actively influence the degree of recovery, and our knowledge gaps about biogeochemical processes directly connected to the environmental problem at hand. In this context, we reappraise the idea of probabilistic water quality criteria, whereby the compliance rule stipulates that no more than a stated number of pre-specified water quality extremes should occur within a given number of samples collected over a compliance assessment domain. Our case study is the Bay of Quinte, Ontario, Canada; an embayment lying on the northeastern end of Lake Ontario with a long history of eutrophication problems. Our study explicitly accounts for the covariance among multiple water quality variables and illustrates how we can assess the degree of improvement for a given number of violations of environmental goals and samples collected from the system. The present framework offers a robust way to impartially characterize the degree of restoration success and minimize the influence of the conflicting perspectives among decision makers/stakeholders and conscious (or unconscious) biases pertaining to water quality management.

Arterial Responses to Acute Low-Level Ergot Exposure in Hereford Cows.

Ergot alkaloids are toxic secondary metabolites produced by the fungus Claviceps purpurea that contaminate cereal grains. Current Canadian standards allow 2 to 3 parts per million of ergot alkaloids in animal feed. The purpose of this study was to determine whether hemodynamic parameters were altered when beef cows were fed permissible levels of ergot alkaloids (i.e., <3 ppm) on a short-term basis. A dose-response relationship between ergot alkaloid concentration and hemodynamic changes in caudal (coccygeal), median sacral, and internal iliac arteries was hypothesized. Beef cows were randomly allocated to: Control (<15 µg total ergot alkaloids/kg dry matter), Low (132 µg/kg), Medium (529 µg/kg), and High (2115 µg/kg) groups (n = 4 per group). Animals were fed 8.8 kg of dry matter daily for 4 days (pre-treatment), 7 days (treatment), and 4 days (post-treatment). The caudal, median sacral, and internal iliac arteries were examined daily using ultrasonography in B-mode and Doppler (color and spectral) mode and hemodynamics endpoints were analyzed by repeated measures mixed model analyses. Caudal artery diameter decreased in the Medium (p = 0.004) and High (p < 0.001) groups compared to pre-treatment values and the pulsatility index increased (p ≤ 0.033) in all ergot treatments during the post-exposure period compared to the Control group. Blood volume per pulse (mL) and blood flow (mL/min) through the caudal artery during the treatment period were reduced in the Medium (-1.0 mL reduction; p ≤ 0.004) and High (-1.1 mL p ≤ 0.006) groups compared to pre-treatment values. The median sacral artery diameter decreased in the Medium (p = 0.006) and High (p = 0.017) treatments compared to the Control group. No differences were detected in any hemodynamic endpoints for the internal iliac artery except changes in pulse rate (p = 0.011). There was no treatment (p > 0.554) or Treatment*Time interaction (p > 0.471) for plasma prolactin concentration or body temperature. In conclusion, alterations in caudal artery hemodynamics were detected when cows were fed 529 and 2115 µg ergot alkaloids per kg dry matter per day for 1 week. The caudal artery was more sensitive to ergot alkaloids than the median sacral and internal iliac arteries. Our results partially support the hypothesis of a dose-response effect of ergot alkaloids in feed on hemodynamics.

Cytocompatibility and Cellular Internalization of PEGylated "Clickable" Nucleic Acid Oligomers.

The recently developed synthetic oligonucleotides referred to as "click" nucleic acids (CNAs) are promising due to their relatively simple synthesis based on thiol-X reactions with numerous potential applications in biotechnology, biodetection, gene silencing, and drug delivery. Here, the cytocompatibility and cellular uptake of rhodamine tagged, PEGylated CNA copolymers (PEG-CNA-RHO) were evaluated. NIH 3T3 fibroblast cells treated for 1 h with 1, 10, or 100 µg/mL PEG-CNA-RHO maintained an average cell viability of 86%, which was not significantly different from the untreated control. Cellular uptake of PEG-CNA-RHO was detected within 30 s, and the amount internalized increased over the course of 1 h. Moreover, these copolymers were internalized within cells to a higher degree than controls consisting of either rhodamine tagged PEG or the rhodamine alone. Uptake was not affected by temperature (i.e., 4 or 37 °C), suggesting a passive uptake mechanism. Subcellular colocalization analysis failed to indicate significant correlations between the internalized PEG-CNA-RHO and the organelles examined (mitochondria, endoplasmic reticulum, endosomes and lysosomes). These results indicate that CNA copolymers are cytocompatible and are readily internalized by cells, supporting the idea that CNAs are a promising alternative to DNA in antisense therapy applications.

Integrative analysis of the Lake Simcoe watershed (Ontario, Canada) as a socio-ecological system.

Striving for long-term sustainability in catchments dominated by human activities requires development of interdisciplinary research methods to account for the interplay between environmental concerns and socio-economic pressures. In this study, we present an integrative analysis of the Lake Simcoe watershed, Ontario, Canada, as viewed from the perspective of a socio-ecological system. Key features of our analysis are (i) the equally weighted consideration of environmental attributes with socioeconomic priorities and (ii) the identification of the minimal number of key socio-hydrological variables that should be included in a parsimonious watershed management framework, aiming to establish linkages between urbanization trends and nutrient export. Drawing parallels with the concept of Hydrological Response Units, we used Self-Organizing Mapping to delineate spatial organizations with similar socio-economic and environmental attributes, also referred to as Socio-Environmental Management Units (SEMUs). Our analysis provides evidence of two SEMUs with contrasting features, the "undisturbed" and "anthropogenically-influenced", within the Lake Simcoe watershed. The "undisturbed" cluster occupies approximately half of the Lake Simcoe catchment (45%) and is characterized by low landscape diversity and low average population density <0.4 humans ha-1. By contrast, the socio-environmental functional properties of the "anthropogenically-influenced" cluster highlight the likelihood of a stability loss in the long-run, as inferred from the distinct signature of urbanization activities on the tributary nutrient export, and the loss of subwatershed sensitivity to natural mechanisms that may ameliorate the degradation patterns. Our study also examines how the SEMU concept can augment the contemporary integrated watershed management practices and provides directions in order to promote environmental programs for lake conservation and to increase public awareness and engagement in stewardship initiatives.

Interleukin-10 blunts the human inflammatory response to lipopolysaccharide without affecting the cardiovascular response.

OBJECTIVE: The objective of this study was to assess the efficacy of variations in dose and timing of administration of recombinant human IL-10 (rhIL-10) on inflammatory and cardiovascular responses in a human endotoxemia model of sepsis. DESIGN: The authors conducted a randomized, placebo-controlled, double-blind trial. SETTING: The study was conducted in a procedure room of an intensive-care unit. PARTICIPANTS: The study comprised 24 healthy male volunteers. INTERVENTIONS: Interventions consisted of intravenous administration of rhIL-10 at 1, 10, or 25 microg/kg either 2 mins or 2 hrs before Escherichia coli lipopolysaccharide (4 ng/kg) or placebo. MEASUREMENTS AND RESULTS: The placebo group receiving lipopolysaccharide alone demonstrated significant, time-dependent changes in vital signs, white blood cell counts, inflammatory cytokine/cortisol levels, and hemodynamic/cardiovascular (including echocardiographic) parameters over the duration of the study. rhIL-10, administered immediately before (concurrent) lipopolysaccharide resulted in decreased temperature and heart rate responses as well as decreased serum levels of proinflammatory cytokines (tumor necrosis factor-alpha, IL-6), IL-1 receptor antagonist, cortisol, and total leukocytes/neutrophils compared with lipopolysaccharide alone. Dose-dependent effects were absent. In contrast, rhIL-10 administration 2 hrs before endotoxin augmented the endotoxin-induced IL-beta and IL-1 receptor antagonist response. rhIL-10 failed to modulate major cardiovascular responses (cardiac output, stroke volume index, ejection fraction, peak systolic pressure/end-systolic volume ratio) to endotoxin in both study groups as assessed by echocardiography. CONCLUSION: Concurrent administration of rhIL-10 suppresses the human inflammatory/stress response but has no effect on the hemodynamic/cardiovascular response to endotoxin. Early administration of rhIL-10 can potentially augment elements of the cytokine inflammatory response to lipopolysaccharide. These findings suggest significant limitations of rhIL-10 as a potential immunomodulatory therapy for sepsis.

Experimental human endotoxemia is associated with depression of load-independent contractility indices: prevention by the lipid a analogue E5531.

OBJECTIVE: To evaluate the efficacy of a novel lipopolysaccharide (LPS) antagonist, E5531, in blocking LPS-induced cardiac responses including myocardial depression (as assessed by relatively load-independent echocardiographic indices of contractility) in a human model of experimental endotoxemia. DESIGN: Randomized, prospective, placebo-controlled, double-blind trial. SETTING: ICU procedure room. PARTICIPANTS: Thirty-two healthy, male volunteers. INTERVENTIONS: Administration of LPS (4 ng/kg) and either a placebo or one of four sequential doses of E5531 (100 microg, 250 microg, 500 microg, or 1,000 microg) followed by volumetric echocardiography before and during 4-L saline solution infusion (3 L over 3 h, followed by 1 L over 2 h). RESULTS: In addition to the generation of a hyperdynamic circulation throughout the study period, administration of LPS resulted in a biphasic contractility response. Ejection fraction (EF), rate-corrected mean velocity of circumferential fiber shortening (Vcfc), peak systolic BP (SBP)/end-systolic volume index (ESVI) ratio, and end-systolic pressure (Pes)/ESVI ratio increased at the 3-h post-LPS assessment, compared to a control group of subjects receiving only similar amounts of saline solution (minimum p < 0.001). End-systolic myocardial wall stress (sigmaes)/ESVI ratio, one of the most load independent of the contractility indices, was unchanged. At 5 h after endotoxin, EF, Vcfc, SBP/ESVI, Pes/ESVI, and sigmaes/ESVI were all decreased (minimum p < 0.01), indicating myocardial depression. When present, early (3 h after LPS), apparent enhancement of myocardial contractility and later (5 h after LPS) myocardial depression were substantially blunted by administration of E5531 (minimum p < 0.025), typically in a concentration-dependent manner. CONCLUSIONS: Endotoxin generates significant myocardial depression when measured using highly load-independent indices of cardiac contractility. E5531 is a potent inhibitor of the early hyperdynamic cardiovascular and later myocardial depression response seen in experimental human endotoxemia.

Preload-independent mechanisms contribute to increased stroke volume following large volume saline infusion in normal volunteers: a prospective interventional study.

INTRODUCTION: Resuscitation with saline is a standard initial response to hypotension or shock of almost any cause. Saline resuscitation is thought to generate an increase in cardiac output through a preload-dependent (increased end-diastolic volume) augmentation of stroke volume. We sought to confirm this to be the mechanism by which high-volume saline administration (comparable to that used in resuscitation of shock) results in improved cardiac output in normal healthy volunteers. METHODS: Using a standardized protocol, 24 healthy male (group 1) and 12 healthy mixed sex (group 2) volunteers were infused with 3 l normal (0.9%) saline over 3 hours in a prospective interventional study. Individuals were studied at baseline and following volume infusion using volumetric echocardiography (group 1) or a combination of pulmonary artery catheterization and radionuclide cineangiography (group 2). RESULTS: Saline infusion resulted in minor effects on heart rate and arterial pressures. Stroke volume index increased significantly (by approximately 15-25%; P < 0.0001). Biventricular end-diastolic volumes were only inconsistently increased, whereas end-systolic volumes decreased almost uniformly. Decreased end-systolic volume contributed as much as 40-90% to the stroke volume index response. Indices of ventricular contractility including ejection fraction, ventricular stroke work and peak systolic pressure/end-systolic volume index ratio all increased significantly (minimum P < 0.01). CONCLUSION: The increase in stroke volume associated with high-volume saline infusion into normal individuals is not only mediated by an increase in end-diastolic volume, as standard teaching suggests, but also involves a consistent and substantial decrease in end-systolic volumes and increases in basic indices of cardiac contractility. This phenomenon may be consistent with either an increase in biventricular contractility or a decrease in afterload.

Effect of large volume infusion on left ventricular volumes, performance and contractility parameters in normal volunteers.

OBJECTIVE: Characterize the normal human cardiovascular response to large volume infusion of normal saline. DESIGN: Prospective, interventional trial. SETTING: ICU procedure room. PARTICIPANTS: Healthy male volunteers ( n=32). INTERVENTIONS. Volumetric echocardiography during 4-L saline infusion (3 L over 3 h followed by 1 L over 2 h). MEASUREMENTS AND RESULTS: Following 3-L saline infusion, stroke volume and cardiac output increased approximately 10% without a significant change in heart rate or blood pressure. A decrease in end-systolic volume contributed to the increase in stroke volume to an extent similar to that provided by the increase in end-diastolic volume. All contractility indices except end-systolic wall stress/end-systolic volume index were increased at 3 h post-initiation of saline infusion. Stroke volume but not cardiac output remained elevated at 5 h with persistence of ventricular volume responses; only ejection fraction was significantly elevated among the contractility indices. Afterload measures including total peripheral resistance and end-systolic wall stress were significantly decreased after 3-L infusion but were unchanged compared to baseline following infusion of an additional 1 L over 2 h. Modeled blood viscosity studies demonstrate that changes in apparent contractility after 3-L saline infusion can be explained solely by viscosity reduction associated with hypervolemic hemodilution. CONCLUSION: The initial increase in stroke volume associated with high volume saline infusion in normal volunteers is associated with increases of most load-dependent and ostensibly load-independent parameters of left ventricular contractility. This phenomenon is unlikely to represent a true increase in contractility and appears to be caused by reduced afterload as a consequence of decreased blood viscosity. This decrease in blood viscosity may complicate analysis of some previous in vivo studies examining the effect of volume loading on cardiac function using low-viscosity solutions.

Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects.

OBJECTIVE: Pulmonary artery occlusion pressure and central venous pressure have been considered to be reliable measures of left and right ventricular preload in patients requiring invasive hemodynamic monitoring. Studies in recent years have questioned the correlation between these estimates of ventricular filling pressures and ventricular end-diastolic volumes/cardiac performance variables in specific patient groups, but clinicians have continued to consider the relationship valid in the broader context. The objective of this study was to assess the relationship between pressure estimates of ventricular preload (pulmonary artery occlusion pressure, central venous pressure) and end-diastolic ventricular volumes/cardiac performance in healthy volunteers. DESIGN: Prospective, nonrandomized, nonblinded interventional study. SETTING: Cardiac catheterization and echocardiography laboratories. SUBJECTS: Normal healthy volunteers (n = 12 group 1, n = 32 group 2). INTERVENTIONS: Pulmonary catheterization and radionuclide cineangiography (group 1) and volumetric echocardiography (group 2) during 3 L of normal saline infusion over 3 hrs. MEASUREMENTS AND MAIN RESULTS: In group 1, the initial pulmonary artery occlusion pressure and central venous pressure did not correlate significantly with initial end-diastolic ventricular volume indexes or cardiac performance (cardiac index and stroke volume index). Changes in pulmonary artery occlusion pressure and central venous pressure following saline infusion also did not correlate with changes in end-diastolic ventricular volume indexes or cardiac performance. In contrast, initial end-diastolic ventricular volume indexes and changes in these ventricular volume indexes in response to 3 L of normal saline loading correlated well with initial stroke volume index and changes in stroke volume index, respectively. The relationship between left ventricular end-diastolic volume index and stroke volume index was confirmed in group 2 subjects using mathematically independent techniques to measure these variables. In addition, initial central venous pressure, right ventricular end-diastolic volume index, pulmonary artery occlusion pressure, and left ventricular end-diastolic volume index failed to correlate significantly with changes in cardiac performance in response to saline infusion in group 1 subjects. CONCLUSIONS: Normal healthy volunteers demonstrate a lack of correlation between initial central venous pressure/pulmonary artery occlusion pressure and both end-diastolic ventricular volume indexes and stroke volume index. Similar results are found with respect to changes in these variables following volume infusion. In contrast, initial end-diastolic ventricular volume indexes and changes in end-diastolic ventricular volume indexes in response to saline loading correlate strongly with initial and postsaline loading changes in cardiac performance as measured by stroke volume index. These data suggest that the lack of correlation of these variables in specific patient groups described in other studies represents a more universal phenomenon that includes normal subjects. Neither central venous pressure nor pulmonary artery occlusion pressure appears to be a useful predictor of ventricular preload with respect to optimizing cardiac performance.