Developmental neurotoxicity of environmentally relevant pharmaceuticals and mixtures thereof in a zebrafish embryo behavioural test

Humans are exposed daily to complex mixtures of chemical substances via food intake, inhalation, and dermal contact. Developmental neurotoxicity is an understudied area and entails one of the most complex areas in toxicology. Animal studies for developmental neurotoxicity (DNT) are hardly performed in the context of regular hazard studies, as they are costly and time consuming and provide only limited information as to human relevance. There is a need for a combination of in vitro and in silico tests for the assessment of chemically induced DNT in humans. The zebrafish (Danio rerio) embryo (ZFE) provides a powerful model to study DNT because it shows fast neurodevelopment with a large resemblance to the higher vertebrate, including the human system. One of the suitable readouts for DNT testing in the zebrafish is neurobehaviour (stimulus-provoked locomotion) since this provides integrated information on the functionality and status of the entire nervous system of the embryo. In the current study, environmentally relevant pharmaceuticals and their mixtures were investigated using the zebrafish light-dark transition test. Zebrafish embryos were exposed to three neuroactive compounds of concern, carbamazepine (CBZ), fluoxetine (FLX), and venlafaxine (VNX), as well as their main metabolites, carbamazepine 10,11-epoxide (CBZ 10,11E), norfluoxetine (norFLX), and desvenlafaxine (desVNX). All the studied compounds, except CBZ 10,11E, dose-dependently inhibited zebrafish locomotor activity, providing a distinct behavioural phenotype. Mixture experiments with these pharmaceuticals identified that dose addition was confirmed for all the studied binary mixtures (CBZ-FLX, CBZ-VNX, and VNX-FLX), thereby supporting the zebrafish embryo as a model for studying the cumulative effect of chemical mixtures in DNT. This study shows that pharmaceuticals and a mixture thereof affect locomotor activity in zebrafish. The test is directly applicable in environmental risk assessment; however, further studies are required to assess the relevance of these findings for developmental neurotoxicity in humans

Self-replenishing ability of cross-linked low surface energy polymer films investigated by a complementary experimental-simulation approach

Nowadays, many self-healing strategies are available for recovering mechanical damage of bulk polymeric materials. The recovery of surface-dependent functionalities on polymer films is, however, equally important and has been less investigated. In this work we study the ability of low surface energy cross-linked poly(ester urethane) networks containing perfluorinated dangling chains to self-replenish their surface, after being submitted to repeated surface damage. For this purpose we used a combined experimental-simulation approach. Experimentally, the cross-linked films were intentionally damaged by cryo-microtoming to remove top layers and create new surfaces which were characterized by water Contact Angle measurements and X-Ray Photoelectron Spectroscopy. The same systems were simultaneously represented by a Dissipative Particles Dynamics simulation method, where the damage was modeled by removing the top film layers in the simulation box and replacing it by new "air" beads. The influence of different experimental parameters, such as the concentration of the low surface energy component and the molecular mobility span of the dangling chains, on the surface recovery is discussed. The combined approach reveals important details of the self-replenishing ability of damaged polymer films such as the occurrence of multiple-healing events, the self-replenishing efficiency, and the minimum "healing agent" concentration for a maximum recovery

Antihypertensive drug concentration measurement combined with personalized feedback in resistant hypertension:a randomized controlled trial

Background:Adherence to antihypertensive drugs (AHDs) is crucial for controlling blood pressure (BP). We aimed to determine the effectiveness of measuring AHD concentrations using a dried blood spot (DBS) sampling method to identify nonadherence, combined with personalized feedback, in reducing resistant hypertension.Methods:We conducted a multicenter, randomized, controlled trial (RHYME-RCT, ICTRP NTR6914) in patients with established resistant hypertension. Patients were randomized to receive either an intervention with standard of care (SoC) or SoC alone. SoC consisted of BP measurement and DBS sampling at baseline, 3 months (t3), 6 months (t6), and 12 months (t12); AHD concentrations were measured but not reported in this arm. In the intervention arm, results on AHD concentrations were discussed during a personalized feedback conversation at baseline and t3. Study endpoints included the proportion of patients with RH and AHD adherence at t12.Results:Forty-nine patients were randomized to receive the intervention+SoC, and 51 were randomized to receive SoC alone. The proportion of adherent patients improved from 70.0 to 92.5% in the intervention+SoC arm (P = 0.008, n = 40) and remained the same in the SoC arm (71.4%, n = 42). The difference in adherence between the arms was statistically significant (P = 0.014). The prevalence of resistant hypertension decreased to 75.0% in the intervention+SoC arm (P &lt; 0.001, n = 40) and 59.5% in the SoC arm (P &lt; 0.001, n = 42) at t12; the difference between the arms was statistically nonsignificant (P = 0.14).Conclusion:Personalized feedback conversations based on DBS-derived AHD concentrations improved AHD adherence but did not reduce the prevalence of RH.</p

Stars and dark matter in the spiral gravitational lens 2237+0305

We construct a mass model for the spiral lens galaxy 2237+0305, at redshift z_l=0.04, based on gravitational-lensing constraints, HI rotation, and new stellar-kinematic information, based on data taken with the ESI spectrograph on the 10m Keck-II Telescope. High resolution rotation curves and velocity dispersion profiles along two perpendicular directions, close to the major and minor axes of the lens galaxy, were obtained by fitting the Mgb-Fe absorption line region. The stellar rotation curve rises slowly and flattens at r~1.5" (~1.1 kpc). The velocity dispersion profile is approximately flat. A combination of photometric, kinematic and lensing information is used to construct a mass model for the four major mass components of the system -- the dark matter halo, disc, bulge, and bar. The best-fitting solution has a dark matter halo with a logarithmic inner density slope of gamma=0.9+/-0.3 for rho_DM propto r^-gamma, a bulge with M/L_B=6.6+/-0.3 Upsilon_odot, and a disc with M/L_B =1.2+/-0.3 Upsilon_odot, in agreement with measurements of late-type spirals. The bulge dominates support in the inner regions where the multiple images are located and is therefore tightly constrained by the observations. The disc is sub-maximal and contributes 45+/-11 per cent of the rotational support of the galaxy at 2.2r_d. The halo mass is (2.0+/-0.6) x 10^12 M_odot, and the stellar to virial mass ratio is 7.0+/-2.3 per cent, consistent with typical galaxies of the same mass.Comment: 14 pages, 6 figures, MNRAS, in pres

Disentangling Baryons and Dark Matter in the Spiral Gravitational Lens B1933+503

Measuring the relative mass contributions of luminous and dark matter in spiral galaxies is important for understanding their formation and evolution. The combination of a galaxy rotation curve and strong lensing is a powerful way to break the disk-halo degeneracy that is inherent in each of the methods individually. We present an analysis of the 10-image radio spiral lens B1933+503 at z_l=0.755, incorporating (1) new global VLBI observations, (2) new adaptive-optics assisted K-band imaging, (3) new spectroscopic observations for the lens galaxy rotation curve and the source redshift. We construct a three-dimensionally axisymmetric mass distribution with 3 components: an exponential profile for the disk, a point mass for the bulge, and an NFW profile for the halo. The mass model is simultaneously fitted to the kinematics and the lensing data. The NFW halo needs to be oblate with a flattening of a/c=0.33^{+0.07}_{-0.05} to be consistent with the radio data. This suggests that baryons are effective at making the halos oblate near the center. The lensing and kinematics analysis probe the inner ~10 kpc of the galaxy, and we obtain a lower limit on the halo scale radius of 16 kpc (95% CI). The dark matter mass fraction inside a sphere with a radius of 2.2 disk scale lengths is f_{DM,2.2}=0.43^{+0.10}_{-0.09}. The contribution of the disk to the total circular velocity at 2.2 disk scale lengths is 0.76^{+0.05}_{-0.06}, suggesting that the disk is marginally submaximal. The stellar mass of the disk from our modeling is log_{10}(M_{*}/M_{sun}) = 11.06^{+0.09}_{-0.11} assuming that the cold gas contributes ~20% to the total disk mass. In comparison to the stellar masses estimated from stellar population synthesis models, the stellar initial mass function of Chabrier is preferred to that of Salpeter by a probability factor of 7.2.Comment: 16 pages, 13 figures, minor revisions based on referee's comments, accepted for publication in Ap

Implementation of Early Next-Generation Sequencing for Inborn Errors of Immunity:A Prospective Observational Cohort Study of Diagnostic Yield and Clinical Implications in Dutch Genome Diagnostic Centers

OBJECTIVE: Inborn errors of immunity (IEI) are a heterogeneous group of disorders, affecting different components of the immune system. Over 450 IEI related genes have been identified, with new genes continually being recognized. This makes the early application of next-generation sequencing (NGS) as a diagnostic method in the evaluation of IEI a promising development. We aimed to provide an overview of the diagnostic yield and time to diagnosis in a cohort of patients suspected of IEI and evaluated by an NGS based IEI panel early in the diagnostic trajectory in a multicenter setting in the Netherlands. STUDY DESIGN: We performed a prospective observational cohort study. We collected data of 165 patients with a clinical suspicion of IEI without prior NGS based panel evaluation that were referred for early NGS using a uniform IEI gene panel. The diagnostic yield was assessed in terms of definitive genetic diagnoses, inconclusive diagnoses and patients without abnormalities in the IEI gene panel. We also assessed time to diagnosis and clinical implications. RESULTS: For children, the median time from first consultation to diagnosis was 119 days versus 124 days for adult patients (U=2323; p=0.644). The median turn-around time (TAT) of genetic testing was 56 days in pediatric patients and 60 days in adult patients (U=1892; p=0.191). A definitive molecular diagnosis was made in 25/65 (24.6%) of pediatric patients and 9/100 (9%) of adults. Most diagnosed disorders were identified in the categories of immune dysregulation (n=10/25; 40%), antibody deficiencies (n=5/25; 20%), and phagocyte diseases (n=5/25; 20%). Inconclusive outcomes were found in 76/165 (46.1%) patients. Within the patient group with a genetic diagnosis, a change in disease management occurred in 76% of patients. CONCLUSION: In this cohort, the highest yields of NGS based evaluation for IEI early in the diagnostic trajectory were found in pediatric patients, and in the disease categories immune dysregulation and phagocyte diseases. In cases where a definitive diagnosis was made, this led to important disease management implications in a large majority of patients. More research is needed to establish a uniform diagnostic pathway for cases with inconclusive diagnoses, including variants of unknown significance

Interprofessional Consensus Regarding Design Requirements for Liquid-Based Perinatal Life Support (PLS) Technology

Liquid-based perinatal life support (PLS) technology will probably be applied in a first-in-human study within the next decade. Research and development of PLS technology should not only address technical issues, but also consider socio-ethical and legal aspects, its application area, and the corresponding design implications. This paper represents the consensus opinion of a group of healthcare professionals, designers, ethicists, researchers and patient representatives, who have expertise in tertiary obstetric and neonatal care, bio-ethics, experimental perinatal animal models for physiologic research, biomedical modeling, monitoring, and design. The aim of this paper is to provide a framework for research and development of PLS technology. These requirements are considering the possible respective user perspectives, with the aim to co-create a PLS system that facilitates physiological growth and development for extremely preterm born infants