Comparison of trace elements in tissue of beaver (Castor canadensis) and local vegetation from a rural region of southern Ontario, Canada.

Beavers have been analyzed in several studies examining trace elements (TEs) in wildlife; however, most of these studies were undertaken in areas with known environmental pollutants. To understand and quantify natural enrichments of TEs in beaver tissue, samples of kidney, liver, muscle from 28 animals were compared with bark from 40 species of trees and shrubs, from the same, uncontaminated watershed. Pearson correlation and factor analysis show that conservative, lithophile elements such as Al, Ga, Th, and Y, all surrogates for mineral dust particles, explain 61% of the variation in the bark data. In contrast, Cd, Co, Cu, Mn, Mo, Ni, Rb, Se, Sr, and Tl in bark are independent of Al, and therefore most likely occur in non-mineral forms. Comparing tissue concentrations of beaver and bark, the organs are enriched in micronutrients such as Cu, Fe, Mo, Se, and Zn, but also non-essential, benign elements such as Cs and Rb, and potentially toxic elements such as Cd and Tl. Thus, the elements most enriched in beaver organs are those that apparently occur in biological form in the plant tissue. The elements enriched in these animals, relative to bark, appear to offer the most promise for monitoring environmental contamination by TEs using beavers. The majority of TEs of environmental relevance are most abundant in beaver kidney. However, monitoring studies must consider the variation in TE concentrations in beaver tissue, including those due to sex and age. Also, due consideration must be given to background concentrations of TEs in the vegetation composing the diet of the animals. The natural enrichment in the case of elements such as Cd, in beaver tissue relative to bark, is profound. These data establish critical baseline values for TEs in beavers in an unpolluted environment, thereby allowing for their use as model organisms in tracking how heavy metal pollutants may affect wildlife.

The safety of oral antifungals for the treatment of onychomycosis.

INTRODUCTION: Oral antifungals are used for the treatment of moderate-severe onychomycosis. Terbinafine and itraconazole are approved for onychomycosis treatment in North America; additionally, fluconazole is indicated for onychomycosis in Europe. Other oral antifungals such as ketoconazole and griseofulvin are no longer used for the treatment of onychomycosis due to safety concerns and relatively lower efficacy. SEARCH STRATEGY: On 7 March 2023, we conducted a comprehensive search in PubMed and Google Scholar, while also manually examining selected article bibliographies and package inserts. AREAS COVERED: Terbinafine, itraconazole, and fluconazole have several interactions with cytochrome-p450, and either alone, or when co-administered with other drugs these interactions can facilitate a multitude of adverse events. This article identifies possible hepatic, renal, cutaneous, cardiovascular, neurological, hemopoietic, and obstetric adverse events. We have also compared the rates of hepatotoxicity, clinically apparent liver injury, and alanine transaminase elevations between oral antifungals, and recommendations for hepatic monitoring. EXPERT OPINION: We recommend laboratory testing of liver function tests prior to the administration of any oral antifungals, especially when clinically indicated. In the event of a first treatment failure, the diagnosis of onychomycosis must be confirmed, and consideration given to antifungal susceptibility testing. Antifungal stewardship will help reduce the incidence of antifungal resistance.

Utility of devices for onychomycosis: a review.

Onychomycosis is difficult to treat due to long treatment durations, poor efficacy rates of treatments, high relapse rates, and safety issues when using systemic antifungal agents. Device-based treatments are targeted to specific regions of the nail, have favorable safely profiles, and do not interfere with systemic agents. They may be an effective alternative therapy for onychomycosis especially with increasing reports of squalene epoxidase gene mutations and potential resistance to terbinafine therapy. In this review, we discuss four devices used as antifungal treatments and three devices used as penetration enhancers for topical agents. Lasers, photodynamic therapy, microwaves, and non-thermal plasma have the capacity to inactivate fungal pathogens demonstrated through in vivo studies. Efficacy rates for these devices, however, remain relatively low pointing toward the need to further optimize device or usage parameters. Ultrasound, nail drilling, and iontophoresis aid in improving the permeability of topical agents through the nail and have been investigated as adjunctive therapies. Due to the paucity in clinical data, their efficacy in treating onychomycosis has not yet been established. While the results of clinical studies point toward the potential utility of devices for onychomycosis, further large-scale randomized clinical trials following regulatory guidelines are required to confirm current results.

Characterization of proteins, mRNAs, and miRNAs of circulating extracellular vesicles from prostate cancer patients compared to healthy subjects.

Prostate cancer (PC) is the fifth leading cause of death in men globally. Measurement of the blood PSA level is still considered the gold-standard biomarker test for PC despite its high rate of delivering false positives and negatives that result in an inappropriate medical response, including overtreatment. We collected extracellular vesicles (EVs) from the blood plasma of PC patients with organ-confined, extracapsular-invading, and seminal vesicle-invading tumors and from healthy subjects. We examined the protein, mRNA, and miRNA content of these EVs using mass spectrometry (MS), a human PC PCR array, and a miScript miRNA PCR array, respectively. The proteomic analysis showed distinct groups of proteins that are differently expressed in each group of patients, as well as in healthy subjects. Samples from healthy subjects and each tumor type were used for both mRNA and miRNA arrays. The mRNA analysis showed distinct groups of mRNAs that were overexpressed in healthy or in one of the three tumor types but not in the EVs of the other groups. The miRNA analysis showed distinct groups of miRNAs as well. The fold of regulation in the expression of the identified mRNA and miRNA of each stage of the disease from healthy subjects showed that various mRNAs and miRNAs could discriminate the disease stage. Overall, our data suggest many molecular marker candidates for distinguishing between healthy subjects and PC patients using the cargo of circulating vesicles, as well as markers to discriminate between the different tumor types. Once verified, these markers might have a diagnostic value for PC.

Effects of Two Distinct Psychoactive Microbes, Lacticaseibacillus rhamnosus JB-1 and Limosilactobacillus reuteri 6475, on Circulating and Hippocampal mRNA in Male Mice.

Discovery of the microbiota-gut-brain axis has led to proposed microbe-based therapeutic strategies in mental health, including the use of mood-altering bacterial species, termed psychobiotics. However, we still have limited understanding of the key signaling pathways engaged by specific organisms in modulating brain function, and evidence suggests that bacteria with broadly similar neuroactive and immunomodulatory actions can drive different behavioral outcomes. We sought to identify pathways distinguishing two psychoactive bacterial strains that seemingly engage similar gut-brain signaling pathways but have distinct effects on behaviour. We used RNAseq to identify mRNAs differentially expressed in the blood and hippocampus of mice following Lacticaseibacillus rhamnosus JB-1, and Limosilactobacillus reuteri 6475 treatment and performed Gene Set Enrichment Analysis (GSEA) to identify enrichment in pathway activity. L. rhamnosus, but not L. reuteri treatment altered several pathways in the blood and hippocampus, and the rhamnosus could be clearly distinguished based on mRNA profile. In particular, L. rhamnosus treatment modulated the activity of interferon signaling, JAK/STAT, and TNF-alpha via NF-KB pathways. Our results highlight that psychobiotics can induce complex changes in host gene expression, andin understanding these changes, we may help fine-tune selection of psychobiotics for treating mood disorders.

A Budding Relationship: Bacterial Extracellular Vesicles in the Microbiota-Gut-Brain Axis.

The discovery of the microbiota-gut-brain axis has revolutionized our understanding of systemic influences on brain function and may lead to novel therapeutic approaches to neurodevelopmental and mood disorders. A parallel revolution has occurred in the field of intercellular communication, with the realization that endosomes, and other extracellular vesicles, rival the endocrine system as regulators of distant tissues. These two paradigms shifting developments come together in recent observations that bacterial membrane vesicles contribute to inter-kingdom signaling and may be an integral component of gut microbe communication with the brain. In this short review we address the current understanding of the biogenesis of bacterial membrane vesicles and the roles they play in the survival of microbes and in intra and inter-kingdom communication. We identify recent observations indicating that bacterial membrane vesicles, particularly those derived from probiotic organisms, regulate brain function. We discuss mechanisms by which bacterial membrane vesicles may influence the brain including interaction with the peripheral nervous system, and modulation of immune activity. We also review evidence suggesting that, unlike the parent organism, gut bacteria derived membrane vesicles are able to deliver cargo, including neurotransmitters, directly to the central nervous system and may thus constitute key components of the microbiota-gut-brain axis.

Circulating microvesicle protein is associated with renal transplant outcome.

Renal transplantation is an effective therapy with improved long-term outcomes compared with other therapies for end stage renal disease. Present methods for evaluating kidney allograft function, such as serum creatinine or allograft biopsy, are not sensitive and identify pathological changes only after any potential intervention would be effective. Thus, there is a necessity for biomarkers that would provide early prognostic information about kidney transplant outcomes. Circulating microvesicles represent an attractive source of biomarkers for different diseases including renal failure. We have studied the proteins of the circulating microvesicles from two populations of kidney transplant recipients (n = 20) with poor transplant outcomes (n = 10) or good transplant outcome (n = 10), according to their estimated glomerular filtration rate (eGFR). Microvesicles from age-matched healthy subjects (n = 10) were used as a control. Also, we performed a pilot study to assess the microvesicle protein in kidney transplant recipients before and six months after kidney transplant (n = 6), compared to healthy subjects. Proteomic analysis of microvesicles could discriminate between transplant recipients and healthy subjects, and between transplant patients based on eGFR. Our results shed light on the potential of blood microvesicles to provide a novel tool for the prediction of the outcome of kidney transplants.

The role of circulating extracellular vesicles in breast cancer classification and molecular subtyping.

Currently, tumor biopsies are used for breast cancer molecular subtyping. Biopsies are associated with various pathological changes and are thought to contribute to the dissemination of tumor cells. Extracellular vesicles shed by tumor cells into circulation exhibit the molecular signature of the parent cells. Herein, we show that proteomic analysis of circulating EV can discriminate BC patients from healthy subjects and indicate stage of the disease. Also, we performed a correlation between the BC molecular subtype using plasma EV and immunohistochemistry of tumor biopsies. Circulating EV may represent a useful, non-invasive tool to study the molecular makeup of BC tumors.

Thrombotic characteristics of extracellular vesicles derived from prostate cancer cells.

BACKGROUND: Prostate cancer (PC) patients in advanced stages of the disease have high risk of blood coagulation complications. The procoagulant molecule Tissue factor (TF), and the fibrinolysis inhibitor plasminogen activator inhibitor-1 PAI-1 play important role in this complication. Extracellular vesicles (EV) shed from cancer cells may contribute to the regulation of TF and PAI-1. The procoagulant activity of EV can be associated with the oncogenic and metastatic characteristics of their cells. METHODS: We have expressed EGFRvIII in DU145 cells to assess the role of this oncogene in the procoagulant activity of EV. The intercellular exchange of TF via EV was assessed by downregulating its expression in DU145 cells using shRNA vector, and determining the transfer of TF via EV enriched with the protein. Two PC cell lines with different metastatic potential were used to assess the correlation between the procoagulant activity of EV and the metastatic potential of PC cells. Photometric assays were used to determine FXa-activity and thrombin generation as indicators for the procoagulant activity of EV. Double-tagged proteinase-activated receptor 1(PAR-1) expressed in CHO cells to assess its activation by EV. RESULTS: The expression of EGFRvIII in DU145 cells led to increased mRNA levels for TF and PAI-1, but the increase in these proteins expression was detected mostly in the EV. EV with enhanced levels of TF protein conferred higher TF procoagulant activity on the acceptor cells by intercellular exchange of this protein. Procoagulant activity of EV, assessed by FXa activity, and thrombin generation, was correlated with the oncogenic and metastatic potential of PC cells. The ability of EV to generate thrombin led to the activation of PAR-1, which was evident by the truncation of tagged-PAR-1. CONCLUSION: The active oncogene EGFRvIII increases the concentration of TF and PAI-1 in EV. The procoagulant activity of EV is associated with the oncogenic and metastatic characteristics of their PC cells. Also, EV may contribute to the high procoagulant activity in the tumour microenvironment by the intercellular exchange of TF. Finally, through the generation of thrombin, EV can activate PAR-1, which evidently contributes to cancer progression, linking the coagulation system to tumor progression.

Trace metals in the dissolved fraction (<0.45µm) of the lower Athabasca River: Analytical challenges and environmental implications.

Water samples were collected on the Athabasca River (AR), upstream and downstream from bitumen mines and upgrading facilities, to identify changes in water quality due to industrial activities in this region of northern Alberta, Canada. Starting upstream of Fort McMurray and proceeding downstream ca. 100km, waters were collected in duplicate at 13 locations on the main stem of the river, as well as 5 tributary streams, using ultraclean sampling protocols developed for polar snow and ice. To estimate potential bioaccessibility, trace elements of concern (Ag, Cd, Pb, Sb, Tl) were determined in the dissolved fraction (<0.45µm) along with metals known for their enrichments in bitumen (V, Ni, Mo, Re) and those found mainly in ionic (Li, Sr) or colloidal forms (Al, Co, Cr, Fe, Ga, Mn, Th, Y). Analyses were performed in the metal-free, ultraclean SWAMP lab using quadrupole and sector-field ICP-MS. Concentrations of Ag, Cd, Pb, Sb and Tl were extremely low, not significantly more abundant downstream of industry and probably reflect "background" values. In contrast, V, Ni, Mo and Re concentrations were all significantly (p<0.05) greater downstream of industry. However, chloride also increased downstream, due to natural inputs of saline groundwaters and it is unclear whether the increases in V, Ni, Mo and Re are due to natural or anthropogenic inputs to the river. Although it had been claimed that the industrial development of the Athabasca Bituminous Sands (ABS) is a significant source of Ag, Cd, Pb, Sb and Tl to the river, our study failed to find any evidence to support this. Here we provide a first, robust (accurate and precise) description of baseline values for these trace elements in the AR, and suggest that V, Ni, Mo and Re are more valuable tracers for environmental monitoring and source assessment.