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Zinc oxide nanoparticles (ZnONPs) are widely used in industry and biomedicine. A growing body of evidence demonstrates that ZnONPs exposure may possess toxic effects to a variety of tissues, including brain. Therefore, the objective of the present review was to summarize existing evidence on neurotoxic effects of ZnONPs and discuss the underlying molecular mechanisms. The existing laboratory data demonstrate that both in laboratory rodents and other animals ZnONPs exposure results in a significant accumulation of Zn in brain and nervous tissues, especially following long-term exposure. As a result, overexposure to ZnONPs causes oxidative stress and cell death, both in neurons and glial cells, by induction of apoptosis, necrosis and ferroptosis. In addition, ZnONPs may induce neuroinflammation through the activation of nuclear factor kappa B (NF-κB), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and lipoxygenase (LOX) signaling pathways. ZnONPs exposure is associated with altered cholinergic, dopaminergic, serotoninergic, as well as glutamatergic and γ-aminobutyric acid (GABA)-ergic neurotransmission, thus contributing to impaired neuronal signal transduction. Cytoskeletal alterations, as well as impaired autophagy and mitophagy also contribute to ZnONPs-induced brain damage. It has been posited that some of the adverse effects of ZnONPs in brain are mediated by altered microRNA expression and dysregulation of gut-brain axis. Furthermore, in vivo studies have demonstrated that ZnONPs exposure induced anxiety, motor and cognitive deficits, as well as adverse neurodevelopmental outcome. At the same time, the relevance of ZnONPs-induced neurotoxicity and its contribution to pathogenesis of neurological diseases in humans are still unclear. Further studies aimed at estimation of hazards of ZnONPs to human brain health and the underlying molecular mechanisms are warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

An increase in total drug (small molecules and biologics) approvals by the Food and Drug Administration (FDA) was seen in 2023 compared with the previous year. Cancer remained the disease most targeted by monoclonal antibodies (mAbs), followed by autoimmune conditions. Our data reveal the prevalence of approvals for biologics even during years when the total number of authorizations was low, such as in 2022. Over half the drugs that received the green light in 2023 benefited from expedited programs, as the incidence of many diseases increased. In addition, over half of the biologics approved received Orphan Drug Designation from the FDA. This narrative review delves into details of the most significant approvals in 2023, including mAbs, enzymes, and proteins, explaining their mechanisms of action, differences from previous drugs, placebo, and standards of care, and outcomes in clinical trials. Given the varying number of drugs authorized annually by the U.S. health authority, this review also examines the limits of external influences over the FDA's decisions and independence regarding drug approvals and withdrawals.

Purpose: Hyperthyroidism guidelines have not been updated over the past five years, despite numerous data on the subject, and recent studies providing a wide variation in treatment success rates. We aim to compare the effectiveness and safety of treatment modalities in patients with Graves' disease or toxic nodular disease., Methods: Single center retrospective cohort study of Graves' disease and toxic nodular disease patients treated between 1983 and 2023., Results: A total of 411 patients were treated for hyperthyroidism, 245 due to Graves' disease and 166 due to or toxic nodular disease, followed for a median of 7 years. In Graves' disease, 90.2% were treated with antithyroid drugs over 250 cycles, achieving 41.7% cumulative remission. Half of all relapses (50.9%) occurred in the first year, 76.3% in the first three years, and 98.3% within nine years. Treatment periods of 12-24 months showed higher remission and lower relapse rates than longer periods. I-131 was used in 103 cycles with 82.5% remission and 7.1% relapse. A total of 29 thyroidectomies resulted in 100% remission, with no relapse. In toxic nodular disease, surgery was the most frequently used treatment (54.5%), followed by I-131 (37.1%)., Conclusion: Our findings support antithyroid drugs as the preferential first-line treatment for Graves' disease, allowing for euthyroidism with minimal adverse effects. Given the propensity for relapse, we suggest a rigorous monitoring, particularly within the first three years. In toxic nodular disease, surgery should be the preferred option, with I-131 being reserved for single adenomas and small goiters., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Manganese (Mn) is an essential trace element involved in various physiological processes, but excessive exposure may lead to toxicity. The vascular endothelium, a monolayer of endothelial cells within blood vessels, is a primary target of Mn toxicity. This review provides a comprehensive overview of the impact of Mn on vascular endothelium, focusing on both peripheral and brain endothelial cells. In vitro studies have demonstrated that high concentrations of Mn can induce endothelial cell cytotoxicity, increase permeability, and disrupt cell-cell junctions through mechanisms involving oxidative stress, mitochondrial damage, and activation of signaling pathways, such as Smad2/3-Snail. Conversely, low concentrations of Mn may protect endothelial cells from the deleterious effects of high glucose and advanced glycation end-products. In the central nervous system, Mn can cross the blood-brain barrier (BBB) and accumulate in the brain parenchyma, leading to neurotoxicity. Several transport mechanisms, including ZIP8, ZIP14, and SPCA1, have been identified for Mn uptake by brain endothelial cells. Mn exposure can impair BBB integrity by disrupting tight junctions and increasing permeability. In vivo studies have corroborated these findings, highlighting the importance of endothelial barriers in mediating Mn toxicity in the brain and kidneys. Maintaining optimal Mn homeostasis is crucial for preserving endothelial function, and further research is needed to develop targeted therapeutic strategies to prevent or mitigate the adverse effects of Mn overexposure., Competing Interests: Conflict of interestThe authors declared that they have no conflict of interest., (© The Author(s) 2024.)

In a world where physical activity and social participation are fundamental pillars of a full and healthy life, confidence in walking has emerged as a fundamental aspect to assess, especially for older adults. Therefore, the purpose of this study was to develop a Portuguese (European) version of the Ambulatory Self-Confidence Questionnaire (ASCQ) that was both linguistically and psychometrically adapted. To do so, a translation method was used, followed by an assessment of its validity and reliability. The Portuguese version was completed by 173 older adults. To assess reliability, Cronbach's alpha and intraclass correlation coefficients (ICCs) were used. For sociodemographic and clinical characterization, as well as questionnaire scoring, descriptive statistical analysis was used. Pearson's correlation (r), Student's t -test, and one-way ANOVA were used to analyze criterion and construction validity. The Portuguese interactions with ASCQ were effectively translated and adjusted, revealing exceptional internal consistency and test-retest reliability, as reflected in Cronbach's alpha and ICC values of 0.95. No floor effect was observed; however, a ceiling effect was identified (3.5%). The criterion and construct validity were verified as all the correlations established were statistically significant. The adaptation of the ASCQ to Portuguese culture is adequate, making it valid for use within the Portuguese population.

A differential diet with royal jelly (RJ) during early larval development in honeybees shapes the phenotype, which is probably mediated by epigenetic regulation of gene expression. Evidence indicates that small molecules in RJ can modulate gene expression in mammalian cells, such as the fatty acid 10-hydroxy-2-decenoic acid (10-HDA), previously associated with the inhibition of histone deacetylase enzymes (HDACs). Therefore, we combined computational (molecular docking simulations) and experimental approaches for the screening of potential HDAC inhibitors (HDACi) among 32 RJ-derived fatty acids. Biochemical assays and gene expression analyses (Reverse Transcriptase - quantitative Polymerase Chain Reaction) were performed to evaluate the functional effects of the major RJ fatty acids, 10-HDA and 10-HDAA (10-hydroxy-decanoic acid), in two human cancer cell lines (HCT116 and MDA-MB-231). The molecular docking simulations indicate that these fatty acids might interact with class I HDACs, specifically with the catalytic domain of human HDAC2, likewise well-known HDAC inhibitors (HDACi) such as SAHA (suberoylanilide hydroxamic acid) and TSA (Trichostatin A). In addition, the combined treatment with 10-HDA and 10-HDAA inhibits the activity of human nuclear HDACs and leads to a slight increase in the expression of HDAC-coding genes in cancer cells. Our findings indicate that royal jelly fatty acids collectively contribute to HDAC inhibition and that 10-HDA and 10-HDAA are weak HDACi that facilitate the acetylation of lysine residues of chromatin, triggering an increase in gene expression levels in cancer cells.

Background: The age at onset (AO) of Machado-Joseph disease (SCA3/MJD), a disorder due to an expanded CAG repeat (CAGexp) in ATXN3, is quite variable and the role of environmental factors is still unknown. Caffeine was associated with protective effects against other neurodegenerative diseases, and against SCA3/MJD in transgenic mouse models. We aimed to evaluate whether caffeine consumption and its interaction with variants of caffeine signaling/metabolization genes impact the AO of this disease., Methods: a questionnaire on caffeine consumption was applied to adult patients and unrelated controls living in Rio Grande do Sul, Brazil. AO and CAGexp were previously determined. SNPs rs5751876 (ADORA2A), rs2298383 (ADORA2A), rs762551 (CYP1A2) and rs478597 (NOS1) were genotyped. AO of subgroups were compared, adjusting the CAGexp to 75 repeats (p < 0.05)., Results: 171/179 cases and 98/100 controls consumed caffeine. Cases with high and low caffeine consumption (more or less than 314.5 mg of caffeine/day) had mean (SD) AO of 35.05 (11.44) and 35.43 (10.08) years (p = 0.40). The mean (SD) AO of the subgroups produced by the presence or absence of caffeine-enhancing alleles in ADORA2A (T allele at rs5751876 and rs2298383), CYP1A2 (C allele) and NOS1 (C allele) were all similar (p between 0.069 and 0.516)., Discussion: Caffeine consumption was not related to changes in the AO of SCA3/MJD, either alone or in interaction with protective genotypes at ADORA2A, CYP1A2 and NOS1., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Severe malarial anemia (SMA) increases the morbidity and mortality of Plasmodium , the causative agent of malaria. SMA is mainly developed by children and pregnant women in response to the infection. It is characterized by ineffective erythropoiesis caused by impaired erythropoietin (EPO) signaling. To gain new insights into the pathogenesis of SMA, we investigated the relationship between the immune system and erythropoiesis, conducting comparative analyses in a mouse model of malaria. Red blood cell (RBC) production was evaluated in infected and reinfected animals to mimic endemic occurrences. Higher levels of circulating EPO were observed in response to (re)infection. Despite no major differences in bone marrow erythropoiesis, compensatory mechanisms of splenic RBC production were significantly reduced in reinfected mice. Concomitantly, a pronounced immune response activation was observed in erythropoietic organs of reinfected animals in relation to single-infected mice. Aged mice were also used to mimic the occurrence of malaria in the elderly. The increase in symptom severity was correlated with the enhanced activation of the immune system, which significantly impaired erythropoiesis. Immunocompromised mice further support the existence of an immune-shaping regulation of RBC production. Overall, our data reveal the strict correlation between erythropoiesis and immune cells, which ultimately dictates the severity of SMA.

This study aimed to characterise the market-driven fortification of vitamins and minerals in packaged foods targeted at children in Brazil. We analysed 535 food labels using data collected in a census-type method (n = 5620) of food labels in a Brazilian supermarket in 2013. Micronutrients declared in nutrition claims and the ingredients list (synthetic compounds) were considered to be added for commercial purposes. Analysis of the ingredients list and nutrition claims showed that market-driven fortification of vitamins and minerals was present in 27.1% of foods. The main vitamins and minerals were vitamins A, B complex, C, D, calcium, iron and zinc. The food groups 'Milk and dairy products' and 'Sugars, sugary foods and snacks' had the highest frequencies of micronutrients declared in the ingredients list. Calcium, iron, phosphorus, zinc and all vitamins, except B7, were found to be added for commercial purposes. Micronutrients were found to be commonly added to packaged foods as a marketing strategy directed at parents and their children. Future studies should assess the amount of vitamins and minerals added to packaged foods targeted at children and whether intakes of vitamins and minerals in children are potentially excessive., (© 2024 British Nutrition Foundation.)

The objective of the present review is to discuss epidemiological evidence demonstrating the association between toxic metal (Cd, Pb, Hg, As, Sn, Ti, Tl) exposure and retinal pathology, along with the potential underlying molecular mechanisms. Epidemiological studies demonstrate that Cd, and to a lesser extent Pb exposure, are associated with age-related macular degeneration (AMD), while the existing evidence on the levels of these metals in patients with diabetic retinopathy is scarce. Epidemiological data on the association between other toxic metals and metalloids including mercury (Hg) and arsenic (As), are limited. Clinical reports and laboratory in vivo studies have shown structural alterations in different layers of retina following metal exposure. Examination of retina samples demonstrate that toxic metals can accumulate in the retina, and the rate of accumulation appears to increase with age. Experimental studies in vivo and in vitro studies in APRE-19 and D407 cells demonstrate that toxic metal exposure may cause retinal damage through oxidative stress, apoptosis, DNA damage, mitochondrial dysfunction, endoplasmic reticulum stress, impaired retinogenesis, and retinal inflammation. However, further epidemiological as well as laboratory studies are required for understanding the underlying molecular mechanisms and identifying of the potential therapeutic targets and estimation of the dose-response effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The purpose of this study was to investigate the relationships between the abundance and occurrence of juvenile Atlantic goliath grouper and physicochemical variables in a tropical mangrove ecosystem, employing a non-lethal methodology. Juvenile Atlantic goliath grouper individuals were captured biweekly, using blue crab traps, across three locations within the São Mateus estuary (18°36'S, 39°44'W), from August 2021 to July 2022. Simultaneously, the physicochemical water variables were assessed during each trap inspection. The physicochemical water variables influence on the abundance and occurrence of Atlantic goliath grouper juveniles were assessed using the Zero-Inflated Binomial (ZIB) and the Poisson (ZIP) generalized linear mixed-effects models (GLMMs). A total of 66 Atlantic goliath grouper juveniles were sampled (Pontal do Sul = 50, Lagoa Creek = 13, and Pitangueiras Creek = 3), ranging from 32 to 319 mm in total length. The best model fitted to presence-absence data (AIC = 278.6) consisted of location, depth, and salinity, with only location having a significant influence on the likelihood of species occurrence. Regarding abundance data, the best model (AIC = 336.4) included location, depth, and turbidity, with only location and depth showing a significant impact on abundance variation, with lower abundance at deeper areas. Although our results indicate a weak significant influence of physicochemical variables on juvenile Atlantic goliath grouper distribution, it is imperative to continue this monitoring effort, considering that additional data may be required to gain a deeper understanding of these patterns., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The objective of the present narrative review was to synthesize existing clinical and epidemiological findings linking manganese (Mn) exposure biomarkers to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and to discuss key pathophysiological mechanisms of neurodevelopmental disorders that may be affected by this metal. Existing epidemiological data demonstrated both direct and inverse association between Mn body burden and ASD, or lack of any relationship. In contrast, the majority of studies revealed significantly higher Mn levels in subjects with ADHD, as well as direct relationship between Mn body burden with hyperactivity and inattention scores in children, although several studies reported contradictory results. Existing laboratory studies demonstrated that impaired attention and hyperactivity in animals following Mn exposure was associated with dopaminergic dysfunction and neuroinflammation. Despite lack of direct evidence on Mn-induced neurobiological alterations in patients with ASD and ADHD, a plethora of studies demonstrated that neurotoxic effects of Mn overexposure may interfere with key mechanisms of pathogenesis inherent to these neurodevelopmental disorders. Specifically, Mn overload was shown to impair not only dopaminergic neurotransmission, but also affect metabolism of glutamine/glutamate, GABA, serotonin, noradrenaline, thus affecting neuronal signaling. In turn, neurotoxic effects of Mn may be associated with its ability to induce oxidative stress, apoptosis, and neuroinflammation, and/or impair neurogenesis. Nonetheless, additional detailed studies are required to evaluate the association between environmental Mn exposure and/or Mn body burden and neurodevelopmental disorders at a wide range of concentrations to estimate the potential dose-dependent effects, as well as environmental and genetic factors affecting this association., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Introduction Our department conducted a retrospective cohort study to compare the efficacy of continuous glucose monitoring devices versus capillary blood glucose in the glycemic control of inpatient type 2 diabetes on intensive insulin therapy in a Portuguese hospital. The use of continuous glucose monitoring devices was associated with improved glycemic control, including an increased number of glucose readings within target range and reduced hyperglycemic events, being safe concerning hypoglycemias. This is the cost-effectiveness analysis associated with these results. Aim The primary objective was to compare the cost-effectiveness of achieving glycemic control, defined as the number of patients within glycemic goals, between groups. Secondary endpoints included cost-effectiveness analyses of each time in range goal, and each percentual increment in time in range. Methods We defined each glycemic goal as: "readings within range (70-180 mg/dL) >70%", "readings below range (below 70 mg/dL) <4%", "severe hypoglycemia (below 54 mg/dL) <1%", "readings above range (above 180 mg/dL) <25%", "very high glycemic readings (above 250 mg/dL) <5%". Results Continuous glucose monitoring showed lower median cost per effect for the primary outcome (€11.1 vs. €34.9/patient), with lower cost for readings in range (€7.8 vs. €11.6/patient) and for both readings above range goals ("above 180mg/dL": €7.4 vs. €9.9/patient, and "above 250mg/dL": €6.9 vs. €17.4/patient). Conclusions There are no published data regarding the cost-effectiveness of continuous glucose monitoring devices in inpatient settings. Our results show that continuous glucose monitoring devices were associated with an improved glycemic control, at a lower cost, and endorse the feasibility of incorporating these devices into hospital settings, presenting a favorable cost-effective option compared to capillary blood glucose., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Veríssimo et al.)

Resorcinolic lipids are described as potential examples of selective chemotherapeutic adjuvants that can enhance the effects of cyclophosphamide ( CYC ) while promoting cell death without causing DNA damage. Therefore, the current study attempted to describe how the resorcinolic lipid methyl 3,5-dimethoxy-2-octanoylbenzoate ( AMS35BB ) interacted with DNA (DNA docking) and how this compound affected genetic toxicology models and other biological characteristics when combined with CYC . We observed that AMS35BB , used alone (7.5 and 10 mg/kg), increases the frequency of genomic damage (comet assay) but not chromosomal damage (micronuclei assay), lowers phagocytosis, and promotes cell death in Swiss male mice. When used in association with CYC , AMS35BB can reduce the risk of genomic damage by up to 33.8% as well as chromosomal damage, splenic phagocytosis, cell death, and lymphocyte frequency. Molecular docking showed that AMS35BB had a higher affinity than the active metabolite of CYC for binding to the DNA double helix major groove. As a result, AMS35BB has the potential to be both an adjuvant when used in association with CYC and a therapeutic candidate for the development of a selective chemotherapeutic drug.

The objective of the present review was to summarize the molecular mechanisms associated with the effects of the vitamins A, C, E and K, and group B vitamins on bone and their potential roles in the development of osteoporosis. Epidemiological findings have demonstrated an association between vitamin deficiency and a higher risk of developing osteoporosis; vitamins are positively related to bone health upon their intake at the physiological range. Excessive vitamin intake can also adversely affect bone formation, as clearly demonstrated for vitamin A. Vitamins E (tocopherols and tocotrienols), K2 (menaquinones 4 and 7) and C have also been shown to promote osteoblast development through bone morphogenetic protein (BMP)/Smad and Wnt/β‑catenin signaling, as well as the TGFβ/Smad pathway (α‑tocopherol). Vitamin A metabolite (all‑trans retinoic acid) exerts both inhibitory and stimulatory effects on BMP‑ and Wnt/β‑catenin‑mediated osteogenesis at the nanomolar and micromolar range, respectively. Certain vitamins significantly reduce receptor activator of nuclear factor kappa‑B ligand (RANKL) production and RANKL/RANK signaling, while increasing the level of osteoprotegerin (OPG), thus reducing the RANKL/OPG ratio and exerting anti‑osteoclastogenic effects. Ascorbic acid can both promote and inhibit RANKL signaling, being essential for osteoclastogenesis. Vitamin K2 has also been shown to prevent vascular calcification by activating matrix Gla protein through its carboxylation. Therefore, the maintenance of a physiological intake of vitamins should be considered as a nutritional strategy for the prevention of osteoporosis.

The existing data demonstrate that probiotic supplementation affords protective effects against neurotoxicity of exogenous (e.g., metals, ethanol, propionic acid, aflatoxin B1, organic pollutants) and endogenous (e.g., LPS, glucose, Aβ, phospho-tau, α-synuclein) agents. Although the protective mechanisms of probiotic treatments differ between various neurotoxic agents, several key mechanisms at both the intestinal and brain levels seem inherent to all of them. Specifically, probiotic-induced improvement in gut microbiota diversity and taxonomic characteristics results in modulation of gut-derived metabolite production with increased secretion of SFCA. Moreover, modulation of gut microbiota results in inhibition of intestinal absorption of neurotoxic agents and their deposition in brain. Probiotics also maintain gut wall integrity and inhibit intestinal inflammation, thus reducing systemic levels of LPS. Centrally, probiotics ameliorate neurotoxin-induced neuroinflammation by decreasing LPS-induced TLR4/MyD88/NF-κB signaling and prevention of microglia activation. Neuroprotective mechanisms of probiotics also include inhibition of apoptosis and oxidative stress, at least partially by up-regulation of SIRT1 signaling. Moreover, probiotics reduce inhibitory effect of neurotoxic agents on BDNF expression, on neurogenesis, and on synaptic function. They can also reverse altered neurotransmitter metabolism and exert an antiamyloidogenic effect. The latter may be due to up-regulation of ADAM10 activity and down-regulation of presenilin 1 expression. Therefore, in view of the multiple mechanisms invoked for the neuroprotective effect of probiotics, as well as their high tolerance and safety, the use of probiotics should be considered as a therapeutic strategy for ameliorating adverse brain effects of various endogenous and exogenous agents.

Aggressive angiomyxoma is a rare mesenchymal tumour, which usually appears in the pelvic region of women in their reproductive age. Although benign, it is a locally infiltrative tumour with frequent recurrence. We report a case of a pregnant woman in her 30s with a vulvar aggressive angiomyxoma which was initially misdiagnosed. Features of this case are discussed, highlighting the difficulty in its diagnosis and the challenge of the follow-up and treatment of recurrences., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Invasive Aspergillosis (IA) is a disease of significant clinical relevance, especially among immunosuppressed patients, and is associated with high mortality rates. In this study, we evaluated the epidemiological features and clinical outcomes in children and adults with IA., Methods: This was an observational, multicentre, prospective surveillance study of inpatients with IA at two different hospitals in Campinas, Brazil, between 2018 and 2021., Results: A total of 44 patients were identified (54.5% males), with a median age of 42 years (interquartile range (IQR):19.25-59 years, varying between 1 and 89 years). The following baseline conditions were identified: 61.4% were oncohaematological patients and 20.5% were solid organ transplant recipients. Among oncohaematological patients, 77.8% exhibited severe or persistent neutropenia. The median time between the onset of neutropenia and the diagnosis of fungal infection was 20 days (IQR: 10.5-26 days; range, 0-68 days). The interval between neutropenia onset and fungal infection was longer in paediatric than in general hospital (average, 29 vs. 13.4 days; median 26 vs 11 days; p=0.010). After the diagnosis of IA, the survival rates were 44.2% and 30.0% at 180 and 360 days, respectively. Survival was greater in patients aged ≤ 21 years (p = 0.040; log-rank test). They observed no difference in IA mortality related to COVID-19 pandemic., Conclusion: High mortality associated with IA was observed in both hospitals. Individuals over the age of 21 have a lower survival rate than younger patients., Competing Interests: Declaration of Competing Interest No potential conflict of interest has been reported by the author(s). All authors have reviewed and approved the manuscript. All authors have contributed significantly to the work. The manuscript has not been previously published nor is it being considered for publication elsewhere., (Copyright © 2023 SFMM. Published by Elsevier Masson SAS. All rights reserved.)

Dermatophytosis, paracoccidioidomycosis and sporotrichosis are mycoses caused by different fungal species with significant prevalence in Brazil and other countries. In some situations, they affect quality of life, especially in the most vulnerable populations. Antifungal drug therapy is the conventional treatment for these diseases, although some difficulties may occur. Adjunctive use of antimicrobial photodynamic therapy (aPDT) may reduce these challenges. Three patients were treated with aPDT and conventional antifungals. In all cases, the patients did not report pain, discomfort or side effects during or after the aPDT intervention. The adjunctive use of aPDT in the cases presented proved to be a safe, low-cost tool that may be promising for the treatment of different mycoses.

Some ionic liquids (ILs) were shown to display a strong ability to enhance the solubility of phenolic compounds through hydrotropy. However, evidence shows that salt ions in hydrotropic aqueous solutions may change the behavior of molecules by promoting possible interactions between the components of the system, thus causing changes in solubility. Herein, we study the impact of sodium salt anions on the hydrotropic dissolution of syringic acid using 1-butyl-3-methylimidazolium chloride ([C 4 mim]Cl) as a hydrotrope, with a focus on dicyanamide Na[N(CN) 2 ] and thiocyanate Na[SCN] salts. Dynamic light scattering, Raman spectroscopy, and nuclear magnetic resonance spectroscopy were used to investigate how the mixture of IL-salts affects the solvation. The results obtained show that [C 4 mim]Cl is able to increase the solubility of syringic acid 80-fold. Despite their structural similarities, the presence of Na[N(CN) 2 ] or Na[SCN] in an aqueous solution of [C 4 mim]Cl induced opposite solubility trends. The addition of Na[N(CN) 2 ] promotes a higher ability to solubilize syringic acid than in the corresponding IL system due to a pH buffering effect, resulting in the deprotonation of the solute. The addition of Na[SCN], on the other hand, induces a relative decrease in syringic acid solubilization at higher concentrations of ILs due to the negative contribution of the NaCl formed by anion-exchange. These results emphasise the often overlooked pH contribution provided by ILs for biomolecule solubilisation whilst providing experimental insights into the structure of aqueous solutions of ionic liquids and the role it plays in the formation of IL-salt aggregates.

The causes of nigrostriatal cell death in idiopathic Parkinson's disease are unknown, but exposure to toxic chemicals may play some role. We followed up here on suggestions that bacterial secondary metabolites might be selectively cytotoxic to dopaminergic neurons. Extracts from Streptomyces venezuelae were found to kill human dopaminergic neurons (LUHMES cells). Utilizing this model system as a bioassay, we identified a bacterial metabolite known as aerugine (C 10 H 11 NO 2 S; 2-[4-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]phenol) and confirmed this finding by chemical re-synthesis. This 2-hydroxyphenyl-thiazoline compound was previously shown to be a product of a wide-spread biosynthetic cluster also found in the human microbiome and in several pathogens. Aerugine triggered half-maximal dopaminergic neurotoxicity at 3-4 µM. It was less toxic for other neurons (10-20 µM), and non-toxic (at <100 µM) for common human cell lines. Neurotoxicity was completely prevented by several iron chelators, by distinct anti-oxidants and by a caspase inhibitor. In the Caenorhabditis elegans model organism, general survival was not affected by aerugine concentrations up to 100 µM. When transgenic worms, expressing green fluorescent protein only in their dopamine neurons, were exposed to aerugine, specific neurodegeneration was observed. The toxicant also exerted functional dopaminergic toxicity in nematodes as determined by the "basal slowing response" assay. Thus, our research has unveiled a bacterial metabolite with a remarkably selective toxicity toward human dopaminergic neurons in vitro and for the dopaminergic nervous system of Caenorhabditis elegans in vivo. These findings suggest that microbe-derived environmental chemicals should be further investigated for their role in the pathogenesis of Parkinson's disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Stingless bees are major flower visitors in the tropics, but their foraging preferences and behavior are still poorly understood. Studying stingless bee interactions with angiosperms is methodologically challenging due to the high tropical plant diversity and inaccessibility of upper canopy flowers in forested habitats. Pollen DNA metabarcoding offers an opportunity of assessing floral visitation efficiently and was applied here to understand stingless bee floral resources spectra and foraging behavior. We analyzed pollen and honey from nests of three distantly related stingless bee species, with different body size and social behavior: Melipona rufiventris, Scaptotrigona postica and Tetragonisca angustula. Simultaneously, we evaluate the local floristic components through seventeen rapid botanical surveys conducted at different distances from the nests. We discovered a broad set of explored floral sources, with 46.3 plant species per bee species in honey samples and 53.67 in pollen samples. Plant families Myrtaceae, Asteraceae, Euphorbiaceae, Melastomataceae and Malpighiaceae dominated the records, indicating stingless bee preferences for abundant resources that flowers of these families provide in the region. Results also reinforce the preference of stingless bees for forest trees, even if only available at long distances. Our high-resolution results encourage future bee-plant studies using pollen and honey metabarcoding in hyper-diverse tropical environments., (© 2023. Springer Nature Limited.)

Owing to its antimicrobial activity, electrochemically activated water (ECAW) is a potential alternative to chemical disinfectants for eliminating foodborne pathogens, including Salmonella Heidelberg, from food processing facilities. However, their antibiofilm activity remains unclear. This study aimed to evaluate the antibiofilm activity of ECAW against S. Heidelberg biofilms formed on stainless steel and polyethylene and to determine its corrosive capacity. ECAW (200 ppm) and a broad-spectrum disinfectant (0.2%) were tested for their antibiofilm activity against S. Heidelberg at 25 °C and 37 °C after 10 and 20 min of contact with stainless steel and polyethylene. Potentiostatic polarization tests were performed to compare the corrosive capacity of both compounds. Both compounds were effective in removing S. Heidelberg biofilms. Bacterial counts were significantly lower with ECAW than with disinfectant in polyethylene, regardless the time of contact. The time of contact and the surface significantly influenced the bacterial counts of S. Heidelberg. Temperature was not an important factor affecting the antibiofilm activities of the compounds. ECAW was less corrosive than the disinfectant. ECAW demonstrated a similar or even superior effect in the control of S. Heidelberg biofilms, when compared to disinfectants, reducing bacterial counts by up to 5 log 10 CFU cm -2 . The corrosion of stainless steel with ECAW was similar to that of commercial disinfectants. This technology is a possible alternative for controlling S. Heidelberg in the food production chain., (© 2023. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Mitochondria play a crucial role in cellular respiration, ATP production, and the regulation of various cellular processes. Mitochondrial dysfunctions have been directly linked to pathophysiological conditions, making them a significant target of interest in toxicological research. In recent years, there has been a growing need to understand the intricate effects of xenobiotics on human health, necessitating the use of effective scientific research tools. Caenorhabditis elegans ( C. elegans ), a nonpathogenic nematode, has emerged as a powerful tool for investigating toxic mechanisms and mitochondrial dysfunction. With remarkable genetic homology to mammals, C. elegans has been used in studies to elucidate the impact of contaminants and drugs on mitochondrial function. This review focuses on the effects of several toxic metals and metalloids, drugs of abuse and pesticides on mitochondria, highlighting the utility of C. elegans as a model organism to investigate mitochondrial dysfunction induced by xenobiotics. Mitochondrial structure, function, and dynamics are discussed, emphasizing their essential role in cellular viability and the regulation of processes such as autophagy, apoptosis, and calcium homeostasis. Additionally, specific toxins and toxicants, such as arsenic, cadmium, and manganese are examined in the context of their impact on mitochondrial function and the utility of C. elegans in elucidating the underlying mechanisms. Furthermore, we demonstrate the utilization of C. elegans as an experimental model providing a promising platform for investigating the intricate relationships between xenobiotics and mitochondrial dysfunction. This knowledge could contribute to the development of strategies to mitigate the adverse effects of contaminants and drugs of abuse, ultimately enhancing our understanding of these complex processes and promoting human health.

Introduction: The emergence of continuous glucose monitoring devices revolutionized the monitoring of diabetes, allowing real-time measurement of interstitial glucose levels. These devices are especially important for people with diabetes treated with insulin therapy and have been extensively studied in outpatient settings. In hospitalized patients, studies using continuous glucose monitoring have focused mainly on evaluating its accuracy and feasibility, but the results were unclear on whether continuous glucose monitoring was superior to capillary blood glucose in improving glycemic control and further research is needed to support the use of these devices in hospitalized patients with diabetes., Objective: The primary endpoint of this study was to assess the increase in time-in-range (glycemic readings between 100-180 mg/dL) in hospitalized patients with continuous glucose monitoring, compared to capillary blood glucose. The secondary endpoints included the assessment of reductions in hypoglycemia incidence, mean glucose levels, and glucose coefficient of variation. Additionally, we assessed the intervention's impact on reducing the length of hospital stay, mortality rates, and incidence of inpatient infections., Research Design and Methods: This was a retrospective, cohort study of 60 hospitalized patients with type 2 diabetes, divided into two groups of 30 individuals each: an intervention group monitored through continuous glucose monitoring and a control group using capillary blood glucose., Results: Both groups were comparable in terms of demographic and clinical characteristics. Continuous glucose monitoring users had a higher number of readings per day (six vs. four, p < 0.001), in-range readings (53.5% vs. 35%, p = 0.027), fewer above-range readings (25.5% vs. 56.5%, p = 0.003), particularly above 250 mg/dL (5% vs. 27.5%, p = 0.001), with no difference in the percentage of hypoglycemia occurence (1% vs. 0%, p = 0.107). Lower mean glucose (161.9 mg/dL vs. 206.5 mg/dL, p < 0.001) was also observed in this group. No difference was observed in mortality, length of stay, or in infection rate ( p = 1.000, p = 0.455, and p = 0.606, respectively)., Conclusions: This retrospective study supports the use of continuous glucose monitoring in optimizing glycemic control in hospitalized patients with type 2 diabetes on intensive insulin therapy. These findings suggest that continuous glucose monitoring can improve time-in-range and prevent hyperglycemia., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Veríssimo et al.)

Metabolic syndrome (MetS) is an important public health issue that affects millions of people around the world and is growing to pandemic-like proportions. This syndrome is defined by the World Health Organization (WHO) as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Moreover, the etiology of MetS is multifactorial, involving many environmental factors, including toxicant exposures. Several studies have associated MetS with heavy metals exposure, which is the focus of this review. Environmental and/or occupational exposure to heavy metals are a major risk, contributing to the development of chronic diseases. Of particular note, toxic metals such as mercury, lead, and cadmium may contribute to the development of MetS by altering oxidative stress, IL-6 signaling, apoptosis, altered lipoprotein metabolism, fluid shear stress and atherosclerosis, and other mechanisms. In this review, we discuss the known and potential roles of heavy metals in MetS etiology as well as potential targeted pathways that are associated with MetS. Furthermore, we describe how new approaches involving proteomic and transcriptome analysis, as well as bioinformatic tools, may help bring about an understanding of the involvement of heavy metals and metalloids in MetS.

BACKGROUND Primary aldosteronism and pheochromocytoma are endocrine causes of secondary arterial hypertension. The association of primary aldosteronism and pheochromocytoma is rare and the involved mechanisms are poorly understood. Either there is a coexistence of both diseases or the pheochromocytoma stimulates the production of aldosterone. Since management approaches may differ significantly, it is important to properly diagnose the 2 conditions. We describe concomitant pheochromocytoma and primary aldosteronism in a patient with resistant hypertension, which demanded a challenging and individualized approach. CASE REPORT A 64-year-old man was sent for observation in our department for type 2 diabetes and resistant hypertension. Laboratory work-up suggested a primary aldosteronism and a pheochromocytoma. The abdominal CT (before and after intravenous contrast, with portal and delayed phase acquisitions) revealed an indeterminate right adrenal lesion and 3 nodules in the left adrenal gland: 1 indeterminate and 2 compatible with adenomas. A 18F-FDOPA PET-CT showed increased uptake in the right adrenal gland. The patient underwent a right adrenalectomy and a pheochromocytoma was confirmed. An improvement in glycemic control was observed after surgery but the patient remained hypertensive. A captopril test confirmed the persistence of primary aldosteronism, and he was started on eplerenone, achieving blood pressure control. CONCLUSIONS This case highlights the challenges in diagnosing and treating the simultaneous occurrence of pheochromocytoma and primary aldosteronism. Our main goal was surgical removal of the pheochromocytoma due to the risk of an adrenergic crisis.

Background: In acute coronary syndromes (ACS), the optimal revascularization strategy for unprotected left main coronary artery (ULMCA) culprit lesion has been under-investigated. Therefore, we compared clinical characteristics and short- and medium-term outcomes of percutaneous and surgical revascularization in ACS., Methods and Results: Of 31886 patients enrolled in a multicenter, national, prospective registry study between October 2010 and December 2020, 246 (0.8%) had ULMCA as a culprit lesion and underwent percutaneous coronary intervention (PCI) alone (n=133, 54%) or coronary artery bypass grafting (CABG) alone (n=113, 46%). Patients undergoing PCI presented more frequently ongoing chest pain (68% versus 41%, p<0.001) and cardiogenic shock (25% versus 1%, p<0.001). Time from admission to revascularization was higher in surgical group with a median time to CABG of 4.5 days compared to 0 days to PCI (p<0.001). Angiographic success rate was 93.2% in patients who underwent PCI. Primary endpoint (all-cause death, non-fatal reinfarction and/or non-fatal stroke during hospitalization) occurred in 15.9% of patients and was more frequent in the PCI group (p<0.001). After adjustment, surgical revascularization was associated with better in-hospital prognosis (odds ratio (OR) 0.164; 95% confidence interval (CI), 0.04-0.64; p=0.009). Similar results were achieved after propensity score matching. No difference was found at one-year all-cause death., Conclusion: Percutaneous coronary intervention was the most common revascularization strategy in the ACS with ULMCA culprit lesion. PCI was preferred in unstable patients and presented a high angiographic success. CABG was often delayed and preferred in low-risk patients. At one-year follow-up, PCI and CABG conferred a similar prognosis. The two approaches appear complementary in this high risk cohort., (Copyright © 2023 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

The scope of the study was to typify the violence suffered by the homeless population and analyze the associated factors in a medium-sized municipality in Minas Gerais. A cross-sectional study was conducted and data about sociodemographic status, health, risk behaviors and occurrence of violence among the homeless was collected. Multivariate logistic regression was performed to verify the association between exposure and outcomes. Of the 85 respondents, the majority were male (75.3%), aged between 40 and 59 years (59.5%), non-white (86.3%), smokers (69.4%), alcoholics (80.7%) and drug users (53.6%). The overall prevalence of violence was 62.3%. The types of violence most reported were verbal and physical aggression and threats. Being a woman (OR 42.1; 95%CI 27.8-638.0) and being non-white (OR 9.02; 95%CI 1.33-61.1) were associated with a higher risk of experiencing violence. Having no morbidity (OR 0.14; 95%CI 0.03-0.62) and living on the streets for up to five years (OR 0.17; 95%CI 0.04-0.71) revealed a negative association. It was observed how violence is present in the urban context associated with sex, race, self-reported morbidity and time living on the streets.

The year 2022 witnessed the control of the COVID-19 pandemic in most countries through social and hygiene measures and also vaccination campaigns. It also saw a decrease in total approvals by the U.S. Food and Drug Administration (FDA). Nevertheless, there was no fall in the Biologics class, which was boosted through the authorization of 15 novel molecules, thus maintaining the figures achieved in previous years. Indeed, the decrease in approvals was only for the category of small molecules. Monoclonal antibodies (mAbs) continued to be the drug class with the most approvals, and cancer remained the most targeted disease, followed by autoimmune conditions, as in previous years. Interestingly, the FDA gave the green light to a remarkable number of bispecific Biologics (four), the highest number in recent years. Indeed, 2022 was another year without the approval of an antimicrobial Biologic, although important advancements were made in targeting new diseases, which are discussed herein. In this work, we only analyze the Biologics authorized in 2022. Furthermore, we also consider the orphan drugs authorized. We not only apply a quantitative analysis to this year's harvest, but also compare the efficacy of the Biologics with those authorized in previous years. On the basis of their chemical structure, the Biologics addressed fall into the following classes: monoclonal antibodies; antibody-drug conjugates; and proteins/enzymes.

Parkinson's disease (PD) is a multifactorial neurodegenerative pathology characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the brain. Aging is considered the main risk factor for the development of idiopathic PD. However, immunity and inflammation play a crucial role in the pathogenesis of this disorder. In mice, we showed that pro-inflammatory priming of the brain sensitizes to severe PD development, regardless of animal age. Age-related sub-acute inflammation, as well as the activation of the immune response upon exposure to harmful stimuli, enhances PD manifestations. The severity of PD is influenced by the engagement of host resistance mechanisms against infection based on the removal of iron (Fe) from the circulation. The sequestration of Fe by immune cells prevents pathogens from proliferating. However, it leads to the formation of a Fe-loaded circulating compartment. When entering the brain through a compromised blood-brain barrier, Fe-loaded immune cells contribute to enhancing neuroinflammation and brain Fe overload. Thus, pro-inflammatory priming of the brain exacerbates neuronal damage and represents a risk factor for the development of severe PD symptoms. Further investigations are now required to better understand whether therapeutic interventions inhibiting this phenomenon might protect against PD.

Sub-chronic inflammation, caused by age-related dysbiosis, primes the brain to neuroinflammation and neurodegenerative diseases. Evidence revealed that Parkinson's disease (PD) might originate in the gut, demonstrating gastro-intestinal disturbances, as reported by PD patients long before developing motor symptoms. In this study, we conducted comparative analyses in relatively young and old mice maintained in conventional or gnotobiotic conditions. We aimed to confirm that the effects induced by age-related dysbiosis, rather than aging itself, sensitize to PD onset. This hypothesis was confirmed in germ-free (GF) mice, which proved resistant to the pharmacological induction of PD, regardless of their age. Contrary to conventional animals, old GF mice did not develop an inflammatory phenotype or an accumulation of iron in the brain, two catalysts sensitizing to disease onset. The resistance of GF mice to PD is reverted when colonized with stool collected from conventional old animals, but not if receiving bacterial content from young mice. Hence, changes in gut microbiota composition are a risk factor for PD development and can be targeted preventively by iron chelators, shown to protect the brain from pro-inflammatory intestinal priming that sensitizes to neuroinflammation and the development of severe PD.

Cancer incidence is increasing, and the drugs are not very selective. These drugs cause adverse effects, and the cells become resistant. Therefore, new drugs are needed. Here, we evaluated the effects of ZIM , a candidate for chemotherapy, and 4-AA alone and in association with commercial chemotherapeutic agents. Subsequently, the results of ZIM and 4-AA were compared. Male Swiss mice were treated with doses of 12, 24, or 48 mg/kg ZIM or 4-AA alone or in association with cisplatin (6 mg/kg), doxorubicin (16 mg/kg), and cyclophosphamide (100 mg/kg). Biometric parameters, DNA damage (comet and micronuclei), cell death, and splenic phagocytosis were evaluated. DNA docking was also performed to confirm the possible interactions of ZIM and 4-AA with DNA. 4-AA has been shown to have low genotoxic potential, increase the frequency of cell death, and activate phagocytosis. ZIM causes genomic and chromosomal damage in addition to causing cell death and activating phagocytosis. In association with chemotherapeutical agents, both 4-AA and ZIM have a chemopreventive effect and, therefore, reduce the frequency of DNA damage, cell death, and splenic phagocytosis. The association of 4-AA and ZIM with commercial chemotherapeutic agents increased the frequency of lymphocytes compared to chemotherapeutic agents alone. Molecular docking demonstrated that ZIM has more affinity for DNA than 4-AA and its precursors ( 1 and 2 ). This was confirmed by the lower interaction energy of the complex (-119.83 kcal/mol). ZIM can break the DNA molecule and, therefore, its chemotherapeutic effect can be related to DNA damage. It is considered that ZIM has chemotherapeutic potential. However, it should not be used in combination with cisplatin, doxorubicin, and cyclophosphamide as it reduces the effects of these drugs.

The evaluation of the environmental impacts of chestnut production in the Beira Interior region (Portugal) is accessed. The comparative life cycle assessment (LCA) was performed with the use of openLCA software with 16 Environmental Footprint (EF) impact categories retrieved from the AGRIBALYSE database. The system boundary was from "cradle-to-farm gate" and the functional unit was 1 ton of chestnut delivered to consumers (only wholesale buyers). The processes model for the production of agricultural machinery, pesticides, fertilizers, and materials was modeled based on surveys and existing literature. The data was gathered from four different production areas: Serra da Estrela, Malcata, Gardunha, and Plateau area. Each site has two selected representative producers inner 250 km 2 square radius environment. The results showed that the average GHG emissions in the low-input group (Estrela and Gardunha) were 1.83 kg CO 2 -eq/ton with the energy burden (80-89%) as main contribution emissions and in the intensive-input group (Malcata and Plateau) were 2.61 kg CO 2 -eq/ton with the main contribution source of emissions are fertilizer (76-83%). Sensitivity analysis results indicate shift input material and cultivation activities in chestnut production systems can be possible for all study areas without reducing yield production. The suggestions in this article can be used by farmers, policymakers, and other stakeholders to adopt new alternative production scenarios., Competing Interests: The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: The risk of falling increases with neuromusculoskeletal and cognitive changes resulting from aging. Physical exercise shows beneficial effects on the risk of falling, but the results are unknown when associated with cognitive activity dual-task (DT)., Objective: The objective of the study was to evaluate the impacts of the Otago Exercise Program (OEP) plus DT cognitive activity on the risk of falling in older adults., Methods: 36 older adults (83.5 ± 5.7 years) participated in a quasi-experimental study, distributed in two experimental groups and a control group: 1) OEP (OEPG; n=12), 2) OEP plus DT (OEPDTG; n = 12), and a control group (CG; n=12). Older adults were evaluated at pre- and post- 12 weeks of intervention. The thresholds for the risk of falling were considered as multiparameter scores of the 10 Meter Walking Test (10MWT), evocative 10MWT, Timed Up and Go (TUG), Sit to Stand Test (STS), and The Four-Stage Balance Test (Four-Stage), and the Montreal Cognitive Assessment (MoCA), to test the cognitive impairment., Results: At baseline, all groups were homogeneous. Post-intervention, the experimental groups presented significant functional differences, in comparison to the CG, for 10MWT (OEPDTG: p= 0.002; OEPG: p= 0.002); evocative 10MWT (OEPDTG: p=0.001; OEPG: p=0.001); TUG (OEPDTG: p=0.034); STS (OEPDTG: p<0.001; OEPG: p<0.001) and cognitive for MoCA (OEPDTG: p<0.019). Significant intra-group differences (pre-post) were observed in all intervention groups, but none in CG. The risk of falling (Four-Stage) in experimental groups (OEPDTG: 33.3%; OEPG: 41.7%) was considerably lower than CG (83.3%)., Conclusion: Otago Exercise Program alone can reduce the risk of falling due to improved functionality, but adding the dual task also improves cognitive capacity in older adults. The clinical significance of these interventions goes beyond statistics., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The toxicity of diuron herbicide and its metabolites has been extensively investigated; however, their precise toxic mechanisms have yet to be fully appreciated. In this context, we evaluated the toxic mechanism of diuron, 3,4-dichloroaniline (DCA) and 3-(3,4-dichlorophenyl)-1-methylurea (DCPMU), using Caenorhabditis elegans (C. elegans) in the L1 larval stage. For this purpose, worms were acutely exposed to the test chemicals with a preliminary concentration range of 0.5 to 500 μM and first analyzed for lethality (%). Next, the highest concentration (500 μM) was considered for survival (%), reactive oxygen and nitrogen species (RONS), glutathione (GSH) and ATP levels, autophagy index, behavior, and dopaminergic neurodegeneration parameters. Interestingly, increased lethality (%) was found for all chemicals at the higher concentrations tested (100 and 500 μM), with significant differences at 500 μM DCA (p < 0.05). A decrease in the median survival was observed mainly for DCA. Although no changes were observed in RONS production, GSH levels were significantly increased upon diuron and DCA treatment, likely reflecting an attempt to restore the redox status. Moreover, diuron and its metabolites impaired ATP levels, suggesting an alteration in mitochondrial function. The latter may trigger autophagy as an adaptive survival mechanism, but this was not observed in C. elegans. Dopaminergic neurotoxicity was observed upon treatment with all the tested chemicals, but only diuron induced alterations in the worms' locomotor behavior. Combined, these results indicate that exposure to high concentrations of diuron and its metabolites elicit distinct adverse outcomes in C. elegans, and DCA in particular, plays an important role in the overall toxicity observed in this experimental model., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Strategies to minimize dynamic hyperinflation (DH) and dyspnea, such as slow chest compression (SCC), are relevant in people with chronic obstructive pulmonary disease (COPD)., Objectives: To analyze the acute effects of SCC after exercise on DH and dyspnea in people with COPD and to identify responders to the technique., Methods: This is a cross-over study with 40 patients. Two six-minute step tests (6MSTs) were performed followed by a one-minute application of SCC (6MST SCC ) or rest (6MST CONTROL ), at random. End-expiratory lung volume (EELV) and dyspnea were assessed. A difference ≥76 ml in ΔEELV between SCC and control characterized the responders., Results: The performance in 6MST SCC and 6MST CONTROL were similar. There was a greater reduction in EELV after 6MST SCC compared to 6MST CONTROL (124 ± 193 ml vs. 174 ± 183 ml; p = .049), while there was no difference in change in dyspnea between the SCC and control groups. Twenty-one participants were SCC responders and had higher functional residual capacity [FRC: 5.36 ± 1.09 vs. 4.58 ± 0.94; p = .02; cutoff point: 4.56; sensitivity = 76%; specificity = 53%; AUC = 0.71 (95%CI: 0.54 to 0.87); p = .02]., Conclusion: SCC applied immediately after exercise reduced DH, but did not reduce dyspnea in people with COPD. The technique is beneficial only for some patients and FRC can help to identify them.

Caenorhabditis elegans ( C. elegans ) is a nematode present worldwide. The worm shows homology to mammalian systems and expresses approximately 40% of human disease-related genes. Since Dr. Sydney Brenner first proposed C. elegans as an advantageous experimental worm-model system for genetic approaches, increasing numbers of studies using C. elegans as a tool to investigate topics in several fields of biochemistry, neuroscience, pharmacology, and toxicology have been performed. In this regard, C. elegans has been used to characterize the molecular mechanisms and affected pathways caused by metals that lead to neurotoxicity, as well as the pathophysiological interrelationship between metal exposure and ongoing neurodegenerative disorders. Several toxic metals, such as lead, cadmium, and mercury, are recognized as important environmental contaminants, and their exposure is associated with toxic effects on the human body. Essential elements that are required to maintain cellular homeostasis and normal physiological functions may also be toxic when accumulated at higher concentrations. For instance, manganese (Mn) is a trace essential element that participates in numerous biological processes, such as enzymatic activities, energy metabolism, and maintenance of cell functions. However, Mn overexposure is associated with behavioral changes in C. elegans , which are consistent with the dopaminergic system being the primary target of Mn neurotoxicity. Caenorhabditis elegans has been shown to be an important tool that allows for studies on neuron morphology using fluorescent transgenic worms. Moreover, behavioral tests may be conducted using worms, and neurotransmitter determination and related gene expression are likely to change after Mn exposure. Likewise, mutant worms may be used to study molecular mechanisms in Mn toxicity, as well as the expression of proteins responsible for the biosynthesis, transport, storage, and uptake of dopamine. Furthermore, this review highlights some advantages and limitations of using the experimental model of C. elegans and provides guidance for potential future applications of this model in studies directed toward assessing for Mn neurotoxicity and related mechanisms., Competing Interests: The authors declare no conflict of interest.

Water solubility enhancement is a long-standing challenge in a multitude of chemistry-related fields. Hydrotropy is a simple and efficient method to improve the solubility of hydrophobic molecules in aqueous media. However, the mechanism behind this phenomenon remains controversial. Herein the impact of salt doping on the hydrotropy phenomenon is determined experimentally using the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride ([C 4 mim]Cl) as a hydrotope and vanillin as a solute. Hydrophobic interactions were found to be central to the aggregation of the hydrotrope around the solute, and seem to drive hydrotropy. Furthermore, 1 H-NMR analysis indicates that hydrotrope-solute interactions present a degree of site-specificity. The addition of chloride salts in the presence of higher IL concentrations promotes a greater relative decrease of the vanillin solubility than in the corresponding system without the IL. This was assigned to the negative impact of increased hydrotrope pre-aggregation in the presence of inorganic salts. The results were rationalised using statistical thermodynamics through which hydrotrope aggregation prior to solute addition is shown to be detrimental to the hydrotropic effect, seemingly confirming solute-induced clustering of the hydrotrope to be the predominant mechanism of hydrotropy.