Central nervous system vasculitis in VEXAS syndrome: A rare involvemen.

INTRODUCTION: VEXAS (Vacuoles, E1 Enzyme, X-linked, autoinflammatory, Somatic) syndrome is a recently described severe adult-onset autoinflammatory disorder mediated by X-linked gene UBA1 somatic mutations, responsible of recurrent fever, skin involvement, chondritis, macrocytic anemia and inflammatory syndrome. Neurological manifestations are rarely described, and predominantly involve peripheral nervous system (PNS) impairment. RESULTS: We report the first central nervous system (CNS) vasculitis in VEXAS syndrome, characterized by headache, cognitive dysfunction and focal signs (cerebellar ataxia). Magnetic resonance imaging (MRI) revealed multifocal white-matter lesions corresponding to recent ischemic strokes, combined with cortical hemorrhagic lesions and gadolinium enhancement of the distal wall vessels. Treatment with methylprednisone, ruxolitinib and tocilizumab led to clinical improvement and a decrease of the inflammatory syndrome. The patient died few months after due to infectious complications. CONCLUSION: CNS vasculitis, occurring as a manifestation of the systemic auto-inflammatory state of VEXAS syndrome, might be a rare but severe complication. We suggest that it be added to the list of inflammatory vasculopathies. More prospective studies are needed to optimize the treatment.

Toxicogenomics of Five Cytostatics in Fathead Minnow (Pimephales promelas) Larvae.

In this study, the toxicogenomic effects of five cytostatics (tamoxifen, methotrexate, capecitabine, cyclophosphamide, and ifosfamide) on fathead minnow (Pimephales promelas) larvae were evaluated. Post-fertilization eggs were exposed to increasing concentrations of the drugs for six days. The expression levels of two genetic biomarkers for toxicity and four thyroid hormone-related gene pathways were measured. Interestingly, the results showed that all concentrations of the five cytostatics affect the transcription levels of both toxicity biomarker genes. Additionally, the thyroid hormone-related genes had different expression levels than the control, with the most significant changes observed in those larvae exposed to cyclophosphamide and ifosfamide. While a previous study found no effects on fish morphology, this study suggests that the five cytostatics modify subtle molecular responses of P. promelas, highlighting the importance of assessing multibiological level endpoints throughout the lifecycle of animals to understand the full portrait of potential effects of cytostatics and other contaminants.

An exploratory spatial contaminant assessment for polar bear (Ursus maritimus) liver, fat, and muscle from northern Canada.

Since the industrial era, chemicals have been ubiquitous in worldwide ecosystems. Despite the discontinued release of highly toxic persistent organic pollutants (POPs) in the environment, the levels of some POPs are still being measured in the Canadian Arctic. These contaminants are of great concern due to their persistence, toxicity, and levels of bioaccumulation in food chains. Animals occupying top trophic positions in the Canadian Arctic, particularly polar bears, are exposed to these contaminants mainly through their diet. Our study investigated the levels of 30 metals (including total and methyl mercury) alkaline and alkaline earth metals, 15 polycyclic aromatic compounds and their alkyl congeners (PACs), 6 chlordanes (CHLs), and 20 polychlorinated biphenyls (PCBs), in 49 polar bears from the Canadian Arctic. Contaminant burden was measured in liver, muscle, and fat in bears of different sex, age, and locations. A principal component analysis did not distinguish differences between age and sex profiles for most contaminants. However, the concentrations measured and their distribution in the tissues confirm findings observed in past studies. This study highlights the importance of continual monitoring of polar bear health (e.g., newly detected PACs were measured within this study) and evaluating those impacts for the next generations of polar bears.

Permeability of polydisperse solid foams.

The effect of polydispersity on foam permeability is investigated by numerical simulations. Foam structures are first generated by Laguerre tessellations via the Neper software and relaxed to minimize the surface energy via the Surface Evolver software. The fluid flow and permeability are then calculated by means of pore-network simulations, by considering either fully open-cell foams or foams with randomly selected closed windows. Different configurations of window aperture are used, including identical window aperture size, identical window aperture ratio, or random window aperture ratio. The main results are obtained for the case of foams having identical and uniform window aperture ratios. For such foams and at constant mean pore size, foam permeability is found to strongly increase with the polydispersity degree. The numerical results are employed to discuss the validity of the mean pressure field assumption used to calculate the foam permeability, the effect of small pores, and the definition of an equivalent Kelvin foam size. We show that as long as the fluctuations of the window aperture ratio remain low, foam permeability can be estimated by using the mean pressure field hypothesis. The weak effect of small pores on permeability is related to their small contribution to the overall fluid volume fraction. Finally, various estimations of the equivalent Kelvin foam size based on pore-size distribution are proposed.

Innovation in regulatory approaches for endocrine disrupting chemicals: The journey to risk assessment modernization in Canada.

Globally, regulatory authorities grapple with the challenge of assessing the hazards and risks to human and ecosystem health that may result from exposure to chemicals that disrupt the normal functioning of endocrine systems. Rapidly increasing number of chemicals in commerce, coupled with the reliance on traditional, costly animal experiments for hazard characterization - often with limited sensitivity to many important mechanisms of endocrine disruption -, presents ongoing challenges for chemical regulation. The consequence is a limited number of chemicals for which there is sufficient data to assess if there is endocrine toxicity and hence few chemicals with thorough hazard characterization. To address this challenge, regulatory assessment of endocrine disrupting chemicals (EDCs) is benefiting from a revolution in toxicology that focuses on New Approach Methodologies (NAMs) to more rapidly identify, prioritize, and assess the potential risks from exposure to chemicals using novel, more efficient, and more mechanistically driven methodologies and tools. Incorporated into Integrated Approaches to Testing and Assessment (IATA) and guided by conceptual frameworks such as Adverse Outcome Pathways (AOPs), emerging approaches focus initially on molecular interactions between the test chemical and potentially vulnerable biological systems instead of the need for animal toxicity data. These new toxicity testing methods can be complemented with in silico and computational toxicology approaches, including those that predict chemical kinetics. Coupled with exposure data, these will inform risk-based decision-making approaches. Canada is part of a global network collaborating on building confidence in the use of NAMs for regulatory assessment of EDCs. Herein, we review the current approaches to EDC regulation globally (mainly from the perspective of human health), and provide a perspective on how the advances for regulatory testing and assessment can be applied and discuss the promises and challenges faced in adopting these novel approaches to minimize risks due to EDC exposure in Canada, and our world.

Impacts of endocrine disrupting chemicals on reproduction in wildlife and humans.

Endocrine disrupting chemicals (EDCs) are ubiquitous in aquatic and terrestrial environments. The main objective of this review was to summarize the current knowledge of the impacts of EDCs on reproductive success in wildlife and humans. The examples selected often include a retrospective assessment of the knowledge of reproductive impacts over time to discern how the effects of EDCs have changed over the last several decades. Collectively, the evidence summarized here within reinforce the concept that reproduction in wildlife and humans is negatively impacted by anthropogenic chemicals, with several altering endocrine system function. These observations of chemicals interfering with different aspects of the reproductive endocrine axis are particularly pronounced for aquatic species and are often corroborated by laboratory-based experiments (i.e. fish, amphibians, birds). Noteworthy, many of these same indicators are also observed in epidemiological studies in mammalian wildlife and humans. Given the vast array of reproductive strategies used by animals, it is perhaps not surprising that no single disrupted target is predictive of reproductive effects. Nevertheless, there are some general features of the endocrine control of reproduction, and in particular, the critical role that steroid hormones play in these processes that confer a high degree of susceptibility to environmental chemicals. New research is needed on the implications of chemical exposures during development and the potential for long-term reproductive effects. Future emphasis on field-based observations that can form the basis of more deliberate, extensive, and long-term population level studies to monitor contaminant effects, including adverse effects on the endocrine system, are key to addressing these knowledge gaps.

Antifouling properties of amphiphilic poly(3-hydroxyalkanoate): an environmentally-friendly coating.

The development of biofouling is a major problem for marine industries. The conception of antifouling and fouling release coatings, with controlled physical-chemical properties is a promising strategy. Among them, amphiphilic systems, such as those composed of a hydrophobic polydimethylsiloxane matrix and a hydrophilic polyethyleneglycol additive are the most efficient and up to date. Despite their effectiveness, these systems are questioned due to the petrochemical origin of PDMS. The aim of this project was to substitute the PDMS matrix with a biopolymer, poly(3-hydroxybuyrate-co-3-hydroxyvalerate) and to improve its anti-adhesion properties through the elaboration of an amphiphilic system, via the addition of PEG or PHBHHx-b-PEG copolymer. The results, including the physico-chemical properties of PHBHV based coatings and static adhesion tests on a marine bacterium, Bacillus 4J6 and a diatom, Phaeodactylum tricornutum are compared with those of PDMS and PEG-modified PDMS coatings. Real antiadhesion activity was obtained for the PHBHV/PHBHHx-b-PEG system for a promising eco-friendly strategy.

Embryotoxicity of Five Cytostatics in Fathead Minnow (Pimephales promelas) Larvae.

Cytostatics are compounds used in chemotherapy, known to be genotoxic, mutagenic, and teratogenic at low concentrations. The amount of cytostatic drugs prescribed increases every year as does their release into the aquatic ecosystems, which possibly is a major concern for the health of aquatic organisms. This study aimed to evaluate the putative toxicity of five cytostatics to fathead minnow (Pimephales promelas) larvae: tamoxifen, capecitabine, methotrexate, cyclophosphamide, and ifosfamide. Eggs collected post-fertilization were exposed for 6 days to a range of concentrations, including one above environmental level. At all environmental concentrations, no significant difference in mortality, hatching time, length, heart rate, and presence of malformations were found. Altogether, these cytostatics do not seem embryotoxic to fish. Although, an increased proportion of complete swim bladder were found after ifosfamide's exposure, suggesting an interaction with the thyroid axis, involved in swim bladder development. Complementary work should address other endpoints, such as behavioral changes, reproductive success, and transgenerational effects.

A new foam-based method for the (bio)degradation of hydrocarbons in contaminated vadose zone.

An innovative foam-based method for Fenton reagents (FR) and bacteria delivery was assessed for the in situ remediation of a petroleum hydrocarbon-contaminated unsaturated zone. The surfactant foam was first injected, then reagent solutions were delivered and propagated through the network of foam lamellae with a piston-like effect. Bench-scale experiments demonstrated the feasibility of the various treatments with hydrocarbon (HC) removal efficiencies as high as 96 %. Compared to the direct injection of FR solutions, the foam-based method led to larger radii of influence and more isotropic reagents delivery, whereas it did not show any detrimental effect regarding HC oxidation. Despite 25 % of HCs were expelled from the treated zone because of high foam viscosity, average degradation rates were increased by 20 %. At field-scale, foam and reagent solutions injections in soil were tracked both using visual observation and differential electric resistivity tomography. The latter demonstrated the controlled delivery of the reactive solutions using the foam-based method. Even if the foam-based method duration is about 5-times longer than the direct injection of amendment solutions, it provides important benefits, such as the confinement of harmful volatile hydrocarbons during Fenton treatments, the enhanced reagents delivery and the 30 % lower consumption of the latter.

Acoustics of monodisperse open-cell foam: An experimental and numerical parametric study.

This article presents an experimental and numerical parametric study of the acoustical properties of monodisperse open-cell solid foam. Solid foam samples are produced with very good control of both the pore size (from 0.2 to 1.0 mm) and the solid volume fraction (from 6% to 35%). Acoustical measurements are performed by the three-microphone impedance tube method. From these measurements, the visco-thermal parameters-namely, viscous permeability, tortuosity, viscous characteristic length, thermal permeability, and thermal characteristic length-are determined for an extensive number of foam samples. By combining Surface Evolver and finite-element method calculations, the visco-thermal parameters of body centered cubic (bcc) foam numerical samples are also calculated on the whole range of solid volume fraction (from 0.5% to 32%), compared to measured values and to theoretical model predictions [Langlois et al. (2019). Phys. Rev. E 100(1), 013115]. Numerical results are then used to find approximate formulas of visco-thermal parameters. A systematic comparison between measurements and predictions of the Johnson-Champoux-Allard-Lafarge (JCAL) model using measured visco-thermal parameters as input parameters, reveals a consistent agreement between them. From this first step, a calculation of the optimal microstructures maximizing the sound absorption coefficient is performed.

Polycyclic aromatic compounds (PACs) in the Canadian environment: The challenges of ecological risk assessments.

Ecological risk assessments (ERAs) of polycyclic aromatic compounds (PACs), as single congeners or in mixtures, present technical challenges that raise concerns about their accuracy and validity for Canadian environments. Of more than 100,000 possible PAC structures, the toxicity of fewer than 1% have been tested as individual compounds, limiting the assessment of complex mixtures. Because of the diversity in modes of PAC action, the additivity of mixtures cannot be assumed, and mixture compositions change rapidly with weathering. In vertebrates, PACs are rapidly oxygenated by cytochrome P450 enzymes, often to metabolites that are more toxic than the parent compound. The ability to predict the ecological fate, distribution and effects of PACs is limited by toxicity data derived from tests of a few responses with a limited array of test species, under optimal laboratory conditions. Although several models are available to predict PAC toxicity and rank species sensitivity, they were developed with data biased by test methods, and the reported toxicities of many PACs exceed their solubility limits. As a result, Canadian Environmental Quality Guidelines for a few individual PACs provide little support for ERAs of complex mixtures in emissions and at contaminated sites. These issues are illustrated by reviews of three case studies of PAC-contaminated sites relevant to Canadian ecosystems. Interactions among ecosystem characteristics, the behaviour, fate and distribution of PACs, and non-chemical stresses on PAC-exposed species prevented clear associations between cause and effect. The uncertainties of ERAs can only be reduced by estimating the toxicity of a wider array of PACs to species typical of Canada's diverse geography and environmental conditions. Improvements are needed to models that predict toxicity, and more field studies of contaminated sites in Canada are needed to understand the ecological effects of PAC mixtures.

Polycyclic aromatic compounds (PACs) in the Canadian environment: Exposure and effects on wildlife.

Polycyclic aromatic compounds (PACs) are ubiquitous in the environment. Wildlife (including fish) are chronically exposed to PACs through air, water, sediment, soil, and/or dietary routes. Exposures are highest near industrial or urban sites, such as aluminum smelters and oil sands mines, or near natural sources such as forest fires. This review assesses the exposure and toxicity of PACs to wildlife, with a focus on the Canadian environment. Most published field studies measured PAC concentrations in tissues of invertebrates, fish, and birds, with fewer studies of amphibians and mammals. In general, PAC concentrations measured in Canadian wildlife tissues were under the benzo[a]pyrene (BaP) guideline for human consumption. Health effects of PAC exposure include embryotoxicity, deformities, cardiotoxicity, DNA damage, changes to DNA methylation, oxidative stress, endocrine disruption, and impaired reproduction. Much of the toxicity of PACs can be attributed to their bioavailability, and the extent to which certain PACs are transformed into more toxic metabolites by cytochrome P450 enzymes. As most mechanistic studies are limited to individual polycyclic aromatic hydrocarbons (PAHs), particularly BaP, research on other PACs and PAC-containing complex mixtures is required to understand the environmental significance of PAC exposure and toxicity. Additional work on responses to PACs in amphibians, reptiles, and semi-aquatic mammals, and development of molecular markers for early detection of biological responses to PACs would provide a stronger biological and ecological justification for regulating PAC emissions to protect Canadian wildlife.

Sub-lethal effects of calcium dinonylnaphthalenesulfonate on Western clawed frog embryos.

Naphthalene sulfonic acids (NSAs) are used as additives in lubricants, dyes, and greases and commonly act as surfactants in many industrial processes. The calcium salt of dinonyl NSA (calcium dinonylnaphthalenesulfonate; CaDNS) is listed among thousands of chemicals identified as priorities for assessment by the Government of Canada's Chemical Management Plan due to the limited toxicity data. The purpose of this study was two-fold: 1) to establish the toxicity of CaDNS to Western clawed frog (Silurana tropicalis) embryos and 2) to assess the sub-lethal effects and mechanisms of toxicity of CaDNS in amphibians through targeted gene expression and metabolite analyses. Frog embryos were exposed to water overlying sand spiked with a range of concentrations of CaDNS (17-1393 µg/g) over a 72-h period. Results indicated significantly higher mortality and presence of malformations in frog larvae exposed to over 672 µg/g CaDNS in the sand (14 ng/mL CaDNS in the water) compared to control treatments. An overall decrease in the glutathione redox cycle was observed, including decreases in relative mRNA levels of enzymes (glutathione S-transferase (gst), glutathione reductase (gsr), glutathione peroxidase (gpx)) and decreases in the glutathione (GSH) and glutathione disulfide (GSSG) metabolite concentrations. In addition, transcript levels of genes involved in antioxidant capacity and essential amino acid metabolites decreased significantly in embryos exposed to low levels of CaDNS. This is the first study to assess the toxicity of NSAs in amphibians, contributing important data to aid in the assessment of NSAs.

Electrical conductivity and tortuosity of solid foam: Effect of pore connections.

Numerical and analytical methods at both micro- and mesoscales are used to study how the electrical resistivity and the high-frequency tortuosity of solid foam are modified by the presence of membranes that partially or totally close the cell windows connecting neighbor pores. Finite-element-method simulations are performed on two pores connected by a single-holed membrane and on well-ordered Kelvin foam. For two pores connected by a single-holed membrane, we show that the equation for pore access resistance obtained by Sahu and Zwolak [Phys. Rev. E 98, 012404 (2018)2470-004510.1103/PhysRevE.98.012404] can predict, after a few modifications, the electrical resistivity at the membrane scale for a large range of membrane apertures. Considering these analytical results, we build a pore-network model by using two kinds of conductances at the pore scale: interpore conductance and intrapore conductance. Local interpore resistances govern foam electrical conductivity at small membrane aperture size, but when the membrane aperture has the same order of magnitude as the pore size, the intrapore resistances are no longer negligible. An important success of this pore-network model is that it can be used to study the effects of percolation on the foam electrical conductivity by using pore-network simulations on larger samples containing a few thousand pores and having different proportions of closed membrane randomly distributed over the sample. The tortuosity is found to be drastically larger than one in foam containing membranes with small apertures or a significant fraction of closed membranes.

Morphological and molecular effects of two diluted bitumens on developing fathead minnow (Pimephales promelas).

Canada has experienced a significant increase in the transport of diluted bitumen (dilbit), a predominant oil sands product that combines bitumen with diluents derived from oil-gas condensates and other proprietary compounds. The toxicity of dilbit to fish embryos, which are immobile and thus at a high risk of exposure to oil in the event of a spill, remains largely unknown for most species. This study assessed the toxicity of water accommodated fractions (WAF) and chemically enhanced water accommodated fractions (CEWAF) of two winter dilbit blends, Access Western Blend (AWB) and Cold Lake Blend (CLB), to fathead minnow (Pimephales promelas) embryos. The TPH-F EC50s for malformations were 834 and 1058 µg/L for AWB WAF and CEWAF, respectively, and 500 and 715 µg/L for CLB WAF and CEWAF, respectively. Levels of cyp1a mRNA increased up to 46- and 69-fold, respectively, reflecting increasing exposure to polycyclic aromatic compounds (PACs) in AWB and CLB. Similarly, levels of gst mRNA were elevated up to 3.8-fold and 2.7-fold with increasing total concentrations of PACs in AWB and CLB, respectively. However, there were no significant changes in mRNA levels of p53, sod, cat, and gsr. These results suggest that the expression of cyp1a and gst may serve as biomarkers for dilbit exposure in fathead minnow, furthering our understanding of dilbit-responsive indicators of toxicity in fish species native to North America. This study is important as it utilizes the same exposure methodology to examine the toxicity of two commonly used Canadian dilbits, facilitating comparison of dilbit toxicity.

Thyroid hormones and androgens differentially regulate gene expression in testes and ovaries of sexually mature Silurana tropicalis.

A series of ex vivo exposures using testicular and ovarian tissues of sexually mature Western clawed frogs (Silurana tropicalis) were designed to examine molecular mechanisms of thyroid hormone (TH) and androgen crosstalk sans hypophyseal feedback as well as investigate potential sex-specific differences. Tissues were exposed ex vivo to either triiodothyronine (T3), iopanoic acid (IOP), one co-treatment of IOP + 5α-dihydrotestosterone (5α-DHT), 5α-DHT, 5ß-dihydrotestosterone (5ß-DHT), or testosterone (T). Direct exposure to different androgens led to androgen specific increases in thyroid receptor and deiodinase transcripts in testes (trß and dio1) but a decrease in expression in ovaries (trß and dio3), suggesting that male and female frogs can be differently affected by androgenic compounds. Moreover, exposure to select androgens differentially increased estrogen-related transcription (estrogen receptor alpha (erα) and aromatase (cyp19)) and production (estradiol) in ovaries and testes indicating the activation of alternate metabolic pathways yielding estrogenic metabolites. Sex-steroid-related transcription (i.e., steroid 5α-reductase type 2 (srd5α2) and erα) and production (i.e., 5α-DHT) were also differentially regulated by THs. The presence and frequency of transcription factor binding sites in the putative promoter regions of TH- and sex steroid-related genes were also examined in S. tropicalis, rodent, and fish models using in silico analysis. In summary, this study provides an improved mechanistic understanding of TH- and androgen-mediated actions and reveals differential transcriptional effects as a function of sex in frogs.