Effects of the Veterinary Pharmaceutical Ivermectin in Indoor Aquatic Microcosms

The effects of the parasiticide ivermectin were assessed in plankton-dominated indoor microcosms. Ivermectin was applied once at concentrations of 30, 100, 300, 1000, 3000, and 10,000 ng/l. The half-life (dissipation time 50%; DT50) of ivermectin in the water phase ranged from 1.1 to 8.3 days. The lowest NOECcommunity that could be derived on an isolated sampling from the microcosm study by means of multivariate techniques was 100 ng/l. The most sensitive species in the microcosm study were the cladocerans Ceriodaphnia sp. (no observed effect concentration, NOEC = 30 ng/l) and Chydorus sphaericus (NOEC = 100 ng/l). The amphipod Gammarus pulex was less sensitive to ivermectin, showing consistent statistically significant reductions at the 1000-ng/l treatment level. Copepoda taxa decreased directly after application of ivermectin in the highest treatment but had already recovered at day 20 posttreatment. Indirect effects (e.g., increase of rotifers, increased primary production) were observed at the highest treatment level starting only on day 13 of the exposure phase. Cladocera showed the highest sensitivity to ivermectin in both standard laboratory toxicity tests as well as in the microcosm study. This study demonstrates that simple plankton-dominated test systems for assessing the effects of ivermectin can produce results similar to those obtained with large complex outdoor systems

Priming by Chemokines Restricts Lateral Mobility of the Adhesion Receptor LFA-1 and Restores Adhesion to ICAM-1 Nano-Aggregates on Human Mature Dendritic Cells

LFA-1 is a leukocyte specific β2 integrin that plays a major role in regulating adhesion and migration of different immune cells. Recent data suggest that LFA-1 on mature dendritic cells (mDCs) may function as a chemokine-inducible anchor during homing of DCs through the afferent lymphatics into the lymph nodes, by transiently switching its molecular conformational state. However, the role of LFA-1 mobility in this process is not yet known, despite that the importance of lateral organization and dynamics for LFA-1-mediated adhesion regulation is broadly recognized. Using single particle tracking approaches we here show that LFA-1 exhibits higher mobility on resting mDCs compared to monocytes. Lymphoid chemokine CCL21 stimulation of the LFA-1 high affinity state on mDCs, led to a significant reduction of mobility and an increase on the fraction of stationary receptors, consistent with re-activation of the receptor. Addition of soluble monomeric ICAM-1 in the presence of CCL21 did not alter the diffusion profile of LFA-1 while soluble ICAM-1 nano-aggregates in the presence of CCL21 further reduced LFA-1 mobility and readily bound to the receptor. Overall, our results emphasize the importance of LFA-1 lateral mobility across the membrane on the regulation of integrin activation and its function as adhesion receptor. Importantly, our data show that chemokines alone are not sufficient to trigger the high affinity state of the integrin based on the strict definition that affinity refers to the adhesion capacity of a single receptor to its ligand in solution. Instead our data indicate that nanoclustering of the receptor, induced by multi-ligand binding, is required to maintain stable cell adhesion once LFA-1 high affinity state is transiently triggered by inside-out signals.Peer ReviewedPostprint (published version

A more active lifestyle in persons with a recent spinal cord injury benefits physical fitness and health

Study design:A prospective cohort study. Objectives:To study the longitudinal relationship between objectively measured everyday physical activity level, and physical fitness and lipid profile in persons with a recent spinal cord injury (SCI).Setting:A rehabilitation centre in the Netherlands and the participant's home environment. Methods:Data of 30 persons with a recent SCI were collected at the start of active rehabilitation, 3 months later, at discharge from inpatient rehabilitation, and 1 year after discharge. Physical activity level (duration of dynamic activities as % of 24 h) was measured with an accelerometry-based activity monitor. Regarding physical fitness, peak oxygen uptake (VO2peak) and peak power output (POpeak) were determined with a maximal wheelchair exercise test, and upper extremity muscle strength was measured with a handheld dynamometer. Fasting blood samples were taken to determine the lipid profile. Results:An increase in physical activity level was significantly related to an increase in VO2peak and POpeak, and an increase in physical activity level favourably affected the lipid profile. A nonsignificant relation was found with muscle strength. Conclusion:Everyday physical activity seems to have an important role in the fitness and health of persons with a recent SCI. An increase in physical activity level was associated with an increase in physical fitness and with a lower risk of cardiovascular disease.Spinal Cord advance online publication, 6 December 2011; doi:10.1038/sc.2011.152

Spillover effects of supplementary on basic health insurance: evidence from the Netherlands

Like many other countries, the Netherlands has a health insurance system that combines mandatory basic insurance with voluntary supplementary insurance. Both types of insurance are founded on different principles. Since basic and supplementary insurance are sold by the same health insurers, both markets may interact. This paper examines to what extent basic and supplementary insurance are linked to each other and whether these links generate spillover effects of supplementary on basic insurance. Our analysis is based on an investigation into supplementary health insurance contracts, underwriting procedures and annual surveys among 1,700–2,100 respondents over the period 2006–2009. We find that health insurers increasingly use a variety of strategies to enforce a joint purchase of basic and supplementary health insurance. Despite incentives for health insurers to use supplementary insurance as a tool for risk selection in basic insurance, we find limited evidence of supplementary insurance being used this way. Only a minority of health insurers uses health questionnaires when people apply for supplementary coverage. Nevertheless, we find that an increasing proportion of high-risk individuals believe that insurers would not be willing to offer them another supplementary insurance contract. We discuss several strategies to prevent or to counteract the observed negative spillover effects of supplementary insurance

Suppression of growth by multiplicative white noise in a parametric resonant system

The author studied the growth of the amplitude in a Mathieu-like equation with multiplicative white noise. The approximate value of the exponent at the extremum on parametric resonance regions was obtained theoretically by introducing the width of time interval, and the exponents were calculated numerically by solving the stochastic differential equations by a symplectic numerical method. The Mathieu-like equation contains a parameter $\alpha$ that is determined by the intensity of noise and the strength of the coupling between the variable and the noise. The value of $\alpha$ was restricted not to be negative without loss of generality. It was shown that the exponent decreases with $\alpha$, reaches a minimum and increases after that. It was also found that the exponent as a function of $\alpha$ has only one minimum at $\alpha \neq 0$ on parametric resonance regions of $\alpha = 0$. This minimum value is obtained theoretically and numerically. The existence of the minimum at $\alpha \neq 0$ indicates the suppression of the growth by multiplicative white noise.Comment: The title and the description in the manuscript are change

Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers–reaching the frontiers of individual risk prediction

Aims: This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model. / Methods and results: Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27-55]. During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75). / Conclusion: This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach