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Background:Catheter ablation is a safe and effective therapy for the treatment of supraventricular tachycardia in children. Current improvements in technology have allowed progressive reduction in radiation exposure associated with the procedure. To assess the impact of three-dimensional mapping, we compared acute procedural results collected from the Catheter Ablation with Reduction or Elimination of Fluoroscopy registry to published results from the Prospective Assessment after Pediatric Cardiac Ablation study.Methods:Inclusion and exclusion criteria from the Prospective Assessment after Pediatric Cardiac Ablation study were used as guidelines to select patient data from the Catheter Ablation with Reduction or Elimination of Fluoroscopy registry to compare acute procedural outcomes between cohorts. Outcomes assessed include procedural and fluoroscopy exposure times, success rates of procedure, and complications.Results:In 786 ablation procedures, targeting 498 accessory pathways and 288 atrioventricular nodal reentrant tachycardia substrates, average procedural time (156.5 versus 206.7 minutes, p < 0.01), and fluoroscopy time (1.2 versus 38.3 minutes, p < 0.01) were significantly shorter in the study group. Success rates for the various substrates were similar except for manifest accessory pathways which had a significantly higher success rate in the study group (96.4% versus 93.0%, p < 0.01). Major complication rates were significantly lower in the study group (0.3% versus 1.6%, p < 0.01).Conclusions:In a large, multicentre study, three-dimensional systems show favourable improvements in clinical outcomes in children undergoing catheter ablation of supraventricular tachycardia compared to the traditional fluoroscopic approach. Further improvements are anticipated as technology advances.

Per- and poly-fluoroalkyl substances, especially perfluorooctanesulfonic acid, have been extensively used for over 50 years. A growing body of evidence has emerged demonstrating the potential adverse effects of these substances, including its effect on the development of non-alcoholic fatty liver disease, as one of the most prevalent chronic liver diseases. Nonetheless, there is no report of effects of perfluorobutanesulfonic acid, the major replacement for perfluorooctanesulfonic acid, on non-alcoholic fatty liver disease. Therefore, the effects of perfluorobutanesulfonic acid exposure on fat accumulation in a human hepatoma cell line were examined. Cells were exposed to perfluorobutanesulfonic acid with or without 300 μmol/L fatty acid mixture (oleic acid:palmitic acid = 2:1) conjugated by bovine serum albumin as an inducer of steatosis for 48 hours. Perfluorobutanesulfonic acid at 200 μmol/L significantly increased the triglyceride level in the presence of fatty acid compared to the control, but not without fatty acid, which was abolished by a specific peroxisome proliferator-activated receptor gamma antagonist. Perfluorobutanesulfonic acid upregulated key genes controlling lipogenesis and fatty acid uptake. Perfluorobutanesulfonic acid treatment also promoted the production of reactive oxygen species, an endoplasmic reticulum stress marker and cytosolic calcium. In conclusion, perfluorobutanesulfonic acid increased fat accumulation, in part, via peroxisome proliferator-activated receptor gamma-mediated pathway in hepatoma cells.

Background:Patients with CHD can be exposed to high levels of cumulative ionising radiation. Utilisation of electroanatomic mapping during catheter ablation leads to reduced radiation exposure in the general population but has not been well studied in patients with CHD. This study evaluated the radiation sparing benefit of using three-dimensional mapping in patients with CHD.Methods:Data were retrospectively collected from the Catheter Ablation with Reduction or Elimination of Fluoroscopy multi-institutional registry. Patients with CHD were selected. Those with previous ablations, concurrent diagnostic or interventional catheterisation and unknown arrhythmogenic foci were excluded. The control cohort was matched for operating physician, arrhythmia mechanism, arrhythmia location, weight and age. The procedure time, rate of fluoroscopy use, fluoroscopy time, procedural success, complications, and distribution of procedures per year were compared between the two groups.Results:Fifty-six patients with congenital heart disease and 56 matched patients without CHD were included. The mean total procedure time was significantly higher in patients with CHD (212.6 versus 169.5 minutes, p = 0.003). Their median total fluoroscopy time was 4.4 minutes (compared to 1.8 minutes), and their rate of fluoroscopy use was 23% (compared to 13%). The acute success and minor complication rates were similar and no major complications occurred.Conclusions:With the use of electroanatomic mapping during catheter ablation, fluoroscopy use can be reduced in patients with CHD. The majority of patients with CHD received zero fluoroscopy.

Microtransplantation of neurolemma tissue fragments from mammalian brain into the plasma membrane of Xenopus laevis oocytes is a tool to examine the endogenous structure and function of various ion channels and receptors associated with the central nervous system. Microtransplanted neurolemma can originate from a variety of sources, contain ion channels and receptors in their native configuration, and are applicable to examine diseases associated with different channelopathies. Here, we examined potential age-related differences in voltage-sensitive sodium channel (VSSC) expression and concentration-dependent responses to pyrethroids following the microtransplantation of juvenile or adult rat brain tissue (neurolemma) into X. laevis oocytes. Using automated western blotting, adult neurolemma exhibited a 2.5-fold higher level of expression of VSSCs compared with juvenile neurolemma. The predominant isoform expressed in both tissues was Na

Since the voluntary phaseout of perfluorooctanesulfonic acid (PFOS), smaller congeners, such as perfluorobutanesulfonic acid (PFBS) have served as industrial replacements and been detected in contaminated aquifers. This study sought to examine the effects of a maternal preconception PFBS exposure on the development of eggs and healthy offspring. Adult female zebrafish received a one-week waterborne exposure of 0.08, 0.14, and 0.25 mg/L PFBS. After which, females were bred with non-exposed males and embryos collected over 5 successful breeding events. PFBS concentrations were detected in levels ranging from 99 to 253 pg/embryo in the first collection but were below the limit of quantitation by fourth and fifth clutches. Therefore, data were subsequently binned into early collection embryos in which PFBS was detected and late collections, in which PFBS was below quantitation. In the early collection, embryo 24 h survival was significantly reduced. In the late collection, embryo development was impacted with unique patterns emerging between Nrf2a wildtype and mutant larvae. Additionally, the impact of nutrient loading into the embryos was assessed through measurement of fatty acid profiles, total cholesterol, and triglyceride content. There were no clear dose-dependent effects, but again unique patterns were observed between the genotypes. Preconception PFBS exposures were found to alter egg and embryo development, which is mediated by direct toxicant loading in the eggs, nutrient loading into eggs, and the function of Nrf2a. These findings provide insight into the reproductive and developmental effects of PFBS and identify maternal preconception as a novel critical window of exposure.

Catheter ablation procedures involve fluoroscopy and can result in significant radiation exposure to the patient and staff. From the early 1980s to 2006, there was a 600% increase in the average medical radiation dose per person per year in the USA. Toward the end of this time frame, three-dimensional (3D) mapping systems, which use magnetic or electrical fields to track catheter location and movement, became clinically available. This has allowed reduction in fluoroscopy use. The goal of this manuscript is to review the current state of zero fluoroscopy ablations. In the early 2000s, the first report of a 3D mapping system, used to replace fluoroscopy, emerged. By 2015, centers were routinely performing fluoroless ablations. Today, most centers use these systems to decrease radiation exposure. Multi-center registries now exist to quantify the changes in patient care. Increased radiation exposure is associated with increased long-term risk of cancer. Today’s 3D mapping systems allow most ablation procedures to be performed without the use of fluoroscopy. With further refinements in the available tools, coupled with increasing operator experience, radiation exposure will be eliminated for all routine ablation procedures.

While insecticide resistance presents a challenge for those intent on controlling insect populations, these challenges have also generated a set of tools that can be used to ask fundamental biological questions about that resistance. Numerous species of insects have evolved resistance to multiple classes of insecticides. Each one of these species and their respective resistant populations represent a potential tool for understanding the molecular basis of the evolution of resistance. However, in-laboratory maintenance of resistant insect populations (and their comparative susceptible populations) suitable for asking the needed set of questions around the molecular consequences of long-term pesticide exposure requires a significant, in places prohibitive, level of resources. Drosophila melanogaster (hereafter referred to as Drosophila) is a model insect system with populations easily selected with pesticides and readily maintainable over decades. Even within Drosophila, however, few populations exist where long-term pesticide selection has occurred along with contrasting non-selected population. As such, the Drosophila 91-C and 91-R populations, which exhibit insecticide resistance to DDT (91-R), compared to a non-selection population (91-C), represent a unique resource for the study of high level DDT resistance. Moreover, with the availability of “omics” technologies over the past several decades, this paired population has emerged as a useful tool for understanding both the molecular basis of pesticide resistance and the molecular consequences of long-term pesticide exposure. In this review, we summarize the studies with these aforementioned populations over the past several decades, addressing what has been learned from these efforts.

Background Increasing resistance of head lice against neurotoxic agents and safety concerns have led to the search for treatment alternatives. Dimeticones with a physical mode of action are safe, and bear a reduced risk for the development of resistance. Methods We performed in vitro bioassays to assess pediculicidal and ovicidal activities of a new dimeticone-based product, and a randomized controlled clinical trial to assess efficacy, following 10 min application. Of 153 individuals screened, 100 participants with active head louse infestations were randomly assigned to treatment with either a dimeticone-based test product, or a 0.5% permethrin-based reference product (50 participants per group). Participants received two topical applications of either the test (10 min) or reference products (45 min) at days 0 and 7 or 8. Outcome measures included the efficacies of treatment and their safety, as well as global and local tolerability at baseline, and days 1, 7, and 10. Results After 10 min exposure, all lice treated with the dimeticone test product were classified as non-viable in the in vitro assay. Ovicidal activity after treatment of eggs with the dimeticone test product was 96.8%. In the clinical trial, 96 patients completed all study visits. In the full analysis set (FAS) population, on day 1 after one application, 98% of patients were cured in the test group, as compared to 84% cured in the reference group. All participants in both groups were free of head lice on day 10, following two applications (100% cure rate). In total, 42 adverse events (AEs) in 23 patients of both treatment groups were recorded, with the majority of AEs classified as mild. Conclusions We have shown a high level of pediculicidal and ovicidal activity, and clinical efficacy and safety, of a brief application of a new dimeticone-based product. The short application time and reduced risk for the development of resistance are key drivers for improved patients’ compliance. Trial registration EU Clinical Trials Register EudraCT 2016–004635-20. Registered 14 November 2016.

BackgroundHead louse females secrete liquid glue during oviposition, which is solidified to form the nit sheath over the egg. Recently, two homologous proteins, named louse nit sheath protein (LNSP) 1 and LNSP 2, were identified as adhesive proteins but the precise mechanism of nit sheath solidification is unknown.MethodsWe determined the temporal transcriptome profiles of the head louse accessory glands plus oviduct, from which putative major structural proteins and those with functional importance were deduced. A series of RNA interference (RNAi) experiments and treatment of an inhibitor were conducted to elucidate the function and action mechanism of each component.ResultsBy transcriptome profiling of genes expressed in the louse accessory glands plus uterus, the LNSP1 and LNSP2 along with two hypothetical proteins were confirmed to be the major structural proteins. In addition, several proteins with functional importance, including transglutaminase (TG), defensin 1 and defensin 2, were identified. WhenLNSP1was knocked down via RNA interference, most eggs became nonviable via desiccation, suggesting its role in desiccation resistance. Knockdown ofLNSP2, however, resulted in oviposition failure, which suggests that LNSP2 may serve as the basic platform to form the nit sheath and may have an additional function of lubrication. Knockdown ofTGalso impaired egg hatching, demonstrating its role in the cross-linking of nit sheath proteins. The role of TG in cross-linking was further confirmed by injecting or hair coating of GGsTop, a TG inhibitor.ConclusionsBoth LNSP1 and LNSP2 are essential for maintaining egg viability besides their function as glue. The TG-mediated cross-linking plays critical roles in water preservation that are essential for ensuring normal embryogenesis. TG-mediated cross-linking mechanism can be employed as a therapeutic target to control human louse eggs, and any topically applied TG inhibitors can be exploited as potential ovicidal agents.Graphical abstract

Previously, deltamethrin (a Type-II pyrethroid) has been reported to increase triglyceride (fat) accumulation in adipocytes, while its underlying molecular mechanism is not fully determined. The aim of this study was to further investigate the molecular mechanisms of deltamethrin induced fat accumulation in murine 3T3-L1 adipocytes. Consistent to previous reports, deltamethrin (10 μM) significantly promoted adipogenesis in 3T3-L1 adipocytes. RNA sequencing (RNA-seq) results showed that 721 differentially expressed genes (DEGs) were identified after deltamethrin treatment, involving in 58 Functional groups of Gene Ontology (GO) and 255 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Several key functional groups regulating adipogenesis, such as fat cell differentiation (Igf1, Snai2, Fgf10, and Enpp1) and cytosolic calcium ion concentration (Nos1, Cxcl1, and Ngf) were significantly enriched. Collectively, these results suggest that the promotion of adipogenesis by deltamethrin was attributed to an obesogenic global transcriptomic response, which provides further understanding of the underlying mechanisms of deltamethrin-induced fat accumulation.

Perfluorooctanesulfonic acid (PFOS) is a persistent synthetic surfactant widely detected in the environment. Developmental PFOS exposures are associated with low birth weight and chronic exposures increase risk for obesity and type 2 diabetes. As an obesogen, PFOS poses a major public health exposure risk and much remains to be understood about the critical windows of exposure and mechanisms impacted, especially during preconception. Here, we leverage evolutionarily conserved pathways and processes in the fruit fly Drosophila melanogaster (wild-type Canton-S and megalin-UAS RNAi transgenic fly lines) to investigate the window of maternal preconception exposure to PFOS on reproductive and developmental toxicity, and examine receptor (megalin)-mediated endocytosis of nutrients and PFOS into the oocyte as a potential mechanism. Preconception exposure to 2 ng PFOS/female resulted in an internal concentration of 0.081 ng/fly over two days post exposure, no mortality and reduced megalin transcription. The number of eggs laid 1–3 days post exposure was reduced and contained 0.018 ng PFOS/egg. Following heat shock, PFOS was significantly reduced in eggs from megalin-knockdown transgenic females. Cholesterol and triglycerides were increased in eggs laid immediately following PFOS exposure by non-heat shocked transgenic females whereas decreased cholesterol and increased protein levels were found in eggs laid by heat shocked transgenic females. Preconception exposure likewise increased cholesterol in early emerging wildtype F1 adults and also resulted in progeny with a substantial developmental delay, a reduction in adult weights, and altered transcription of Drosophila insulin-like peptide genes. These findings support an interaction between PFOS and megalin that interferes with normal nutrient transport during oocyte maturation and embryogenesis, which may be associated with later in life developmental delay and reduced weight.

Introduction: Health disparities due to race and socioeconomic status persist among congestive heart failure (CHF) patients. Our hospital in the Philadelphia area is uniquely situated to study disparities as it sits on the border of a diverse inner city and suburban population. The area west of our hospital is known to have a drastically higher median income than the area to the east. We aimed to evaluate differences in rates of CHF admissions, readmissions, and length of stay (LOS) for patients based on race and socioeconomic status. Methods: From 3/1/2018 to 3/31/2020, 6,785 total patients were admitted to our hospital due to acute decompensated CHF. To compare rates of admission, readmission and a LOS > 5 days based on race and socioeconomic status, we used the SlicerDicer function of the EPIC electronic record platform. For race, we compared data for white and black patients. For socioeconomic status, we included a 10-mile radius around our hospital and used public records to collect median household income for 11 zip codes to the east and 11 to the west. The average yearly median household income for the east and west zip codes were USD $27,171 and $134,390, respectively. Outcomes are expressed as percentages and compared using a Chi-square test of independence and 95% confidence interval (CI) for differences. Significance was assessed at the 0.05 level. Results: Admission rates were significantly higher among Black patients at 67% compared to White patients at 58% (95% CI 7-11%, p 5 days (56% for Black vs. 55% for White patients, 95% CI 0-3%, p=0.42). Admission rates were significantly higher among patients from low income areas at 70% compared to high income areas at 56% (95% CI 11-17%, p 5 days at 57% compared to patients from high income areas at 53% (95% CI 0.8-8%, p Conclusions: Race and socioeconomic status continue to impact CHF patients’ health outcomes including rates of admissions, readmissions, and length of stay.

This paper examines the daily abnormal stock price returns of a sample of 154 publicly-traded hospitality firms from 23 different countries representing over $400 billion in combined market capitalization around the time that COVID-19 was first viewed by stock market participants as a major—possibly even existential—threat. The findings of the study suggest that, financially, hotels performed better than restaurants, which themselves performed better than casinos. These findings are consistent with medical recommendations concerning the relative safety of various hospitality-related activities and, therefore, also with the tenets of financial market efficiency in the hospitality sector. Additional findings suggest that hospitality firms with strong balance sheets and income statements characterized by relatively low leverage ratios, high market value (consistent with a “too big to fail” mentality), and higher price/earnings ratios (implying higher relative profitability) all fared better than smaller, weaker firms. Although, in no case, did Bloomberg's proprietary environmental, social, and governance (ESG) variable possess any predictive power, variables reflecting cross-country cultural differences support Huynh’s (2020) finding that “individualism” was an important factor in explaining the economic impact of the COVID-19 pandemic on hospitality firms.

Background: Drinking water contamination related to the use of aqueous film-forming foam (AFFF) has been documented at hundreds of military bases, airports, and firefighter training facilities. AFFF has historically contained high levels of long-chain per- and polyfluoroalkyl substances (PFAS), which pose serious health concerns. However, the composition and toxicity of legacy AFFF mixtures are unknown, presenting great uncertainties in risk assessment and affected communities. Objectives: This study aimed to determine the fluorinated and nonfluorinated chemical composition of a legacy AFFF sample and its toxicity in zebrafish embryos. Methods: A sample of legacy AFFF (3% application formulation, manufactured before 2001) was provided by the Massachusetts Department of Environmental Protection. High resolution mass spectrometry (HRMS) was used to identify PFAS and nonfluorinated compounds, and a commercial laboratory measured 24 PFAS by a modified U.S. EPA Method 537.1. AFFF toxicity was assessed in zebrafish embryos in comparison with four major constituents: perfluorooctanesulfonic acid (PFOS); perfluorohexanesulfonic acid (PFHxS); sodium dodecyl sulfate (SDS); and sodium tetradecyl sulfate (TDS). End points included LC50 values, and sublethal effects on growth, yolk utilization, and pancreas and liver development. Results: We identified more than 100 PFAS. Of the PFAS detected, PFOS was measured at the highest concentration (9,410mg/L) followed by PFHxS (1,500mg/L). Fourteen nonfluorinated compounds were identified with dodecyl sulfate and tetradecyl sulfate the most abundant at 547.8 and 496.4mg/L, respectively. An LC50 of 7.41×10−4% AFFF was calculated, representing a dilution of the 3% formulation. TDS was the most toxic of the constituents tested but could not predict the AFFF phenotype in larval zebrafish. PFOS exposure recapitulated the reduction in length but could not predict effects on development of the liver, which was the tissue most sensitive to AFFF. Discussion: To our knowledge, this research is the first characterization of the chemical composition and toxicity of legacy AFFF, which has important implications for regulatory toxicology. https://doi.org/10.1289/EHP6470

This article examines the link between corporate social responsibility (CSR), as measured by the Kinder, Lydenberg, and Domini Research and Analytics Inc. (KLD) data, and the likelihood that a firm experiences an extreme return in a given year. An extreme-return firm is defined as one that has a return either in the top or bottom 3% of all firms with CSR data. The authors find CSR is negatively related to the likelihood of a firm experiencing an extreme return. Accounting for this negative relationship significantly improves a model used to predict future extreme returns. Finally, they form two portfolios: one with all firms with CSR data and one with all firms with CSR data except those firms with the highest predicted probability of extreme returns in the following year. Our results indicate that the returns for the two portfolios are nearly identical. However, the standard deviation of the portfolio excluding likely extreme movers is 3% lower than the portfolio with all firms. Thus, this simple portfolio strategy incorporating CSR has the potential to lower risk without impacting return.

Understanding the behavior of pesticide translocation is significant for effectively applying pesticides and reducing pesticide exposures from treated plants. Herein, we applied surface enhanced Raman spectroscopy (SERS) for real-time monitoring of pesticide translocation in tomato plant tissues, including leaves and flowers, following root exposure in hydroponic and soil systems. Various concentrations of the systemic pesticide, thiabendazole, was introduced into hydroponic systems used for growing tomato plants. At selected time intervals, tomato leaves and flowers were picked and thiabendazole was measured directly under a Raman microscope after pipetting gold nanoparticle-containing solution onto the plant tissue. We found that the pesticide signals first appeared along the midrib in the lowest leaves and moved distally to the edge of the leaves. As the concentration of pesticide applied to the root was increased, the time necessary to detect the signal was decreased. The SERS surface mapping method was also able to detect thiabendazole in the trichomes of the leaves. In addition, we found a unique SERS peak at 737 cm-1 on both leaves and flowers at 4 and 6 days following the application of 200 mg/L thiabendazole to the hydroponic system. This peak appears to be coming from adenine-containing materials and may be related to the plant's response to pesticide toxicity, which could be used as a potential marker for monitoring plant responses to stresses. These results demonstrate a successful application of SERS as a rapid and effective way to study the real-time translocation behavior of pesticides in a plant system.

Herbivorous insects encounter a variety of toxic environmental substances ranging from ingested plant defensive compounds to human-introduced insecticidal agents. Dietary antioxidants are known to reduce the negative physiological impacts of toxins in mammalian systems through amelioration of reactive oxygen-related cellular damage. The analogous impacts to insects caused by multigenerational exposure to pesticides and the effects on adaptive responses within insect populations, however, are currently unknown. To address these research gaps, we used Drosophila as a model system to explore adaptive phenotypic responses to acute dichlorodiphenyltrichloroethane (DDT) exposure in the presence of the dietary antioxidant vitamin C and to examine the structural genomic consequences of this exposure. DDT resistance increased significantly among four replicates exposed to a low concentration of DDT for 10 generations. In contrast, dietary intake of vitamin C significantly reduced DDT resistance after mutigenerational exposure to the same concentration of DDT. As to the genomic consequences, no significant differences were predicted in overall nucleotide substitution rates across the genome between any of the treatments. Despite this, replicates exposed to a low concentration of DDT without vitamin C showed the highest number of synonymous and non-synonymous variants (3196 in total), followed by the DDT plus vitamin C (1174 in total), and vitamin C alone (728 in total) treatments. This study demonstrates the potential role of diet (specifically, antioxidant intake) on adaptive genome responses, and thus on the evolution of pesticide resistance within insect populations.

A significant rise in the incidence of obesity and type 2 diabetes has occurred worldwide in the last two decades. Concurrently, a growing body of evidence suggests a connection between exposure to environmental pollutants, particularly insecticides, and the development of obesity and type 2 diabetes. This review summarizes key evidence of (1) the presence of different types of neuronal receptors - target sites for neurotoxic insecticides - in non-neuronal cells, (2) the activation of these receptors in non-neuronal cells by membrane-depolarizing insecticides, and (3) changes in metabolic functions, including lipid and glucose accumulation, associated with changes in membrane potential. Based on these findings, we propose that changes in membrane potential (V

Permethrin is a pyrethroid insecticide that acts thru membrane depolarization and is known to disrupt calcium levels in neurons. Disrupted calcium homeostasis is linked to oxidative stress as well as many other cellular mis-functions and permethrin has been reported to disrupt lipid and glucose metabolism in animals and mammalian cell models. It is not known, however, if permethrin influences calcium levels and its associated cellular mechanisms in liver cells. Thus, the goal of the current study was to investigate the mechanisms of permethrin on calcium-mediated cellular signaling pathway, particularly on activation of extracellular signal-related kinase (ERK1/2 or p42/p44) using human hepatocytes, HepG2. The current results showed that permethrin treatment induced oxidative stress and phosphorylation of ERK1/2, which were dependent upon voltage-sensitive sodium channels (VSSC). It was further determined that permethrin-induced ERK1/2 activation was mediated by the metabotropic glutamate receptors (mGluRs)-phosphoinositide phospholipase C (PLC)-protein kinase C (PKC) pathway, but not by changes of intracellular calcium or ER stress-mediated mechanisms.

Previously, we observed increased transcription levels of specific cytochrome P450 monooxygenase (P450) and adenosine triphosphate binding cassette (ABC) transporter genes in human body lice, Pediculus humanus humanus, following exposure to ivermectin using the non-invasive induction assay, which resulted in tolerance. To confirm the roles of these genes in induction and tolerance, the robust genetic model insect Drosophila melanogaster was chosen. Orthologous genes corresponding to the body louse P450 (Cyp9f2, Cyp6g2 and Cyp9h1) and ABC transporter (Mrp1, GC1824 as an ABCB type and CG3327 as an ABCG type) genes were selected for in vivo bioassay. Following a brief treatment with a sublethal dose of ivermectin, the mortality response was significantly slower, indicating the presence of tolerance. Concurrently, the transcription levels of Cyp9f2 and Mrp1 at 3 h and those of Cyp6g2, Cyp9h1, Mrp1, CG1824 and CG3327 at 6 h post-treatment were upregulated, indicating gene induction. In behavioural bioassay using GAL4/UAS-RNA interference transgenic fly lines, increased susceptibility to ivermectin was observed following heat shock in the Cyp9f2 , Cyp6g2 , Cyp9h1 , Mrp1 or CG3327-knockdown flies. Considering that these five genes are orthologous to those which had the largest over-expression level following ivermectin-induced tolerance in the body louse, the current results suggest that they are also associated with ivermectin detoxification in D. melanogaster and that body lice and D. melanogaster are likely to share, in part, similar mechanisms of tolerance to ivermectin.

Background Cytochrome P450 monooxygenases (P450s) are involved in the biosynthesis of endogenous intracellular compounds and the metabolism of xenobiotics, including chemical insecticides. We investigated the structural and expression level variance across all P450 genes with respect to the evolution of insecticide resistance under multigenerational dichlorodiphenyltrichloroethane (DDT) selection. Results RNA-sequencing (RNA-seq) and reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) indicated that the transcript levels of seven P450 genes were significantly up-regulated and three P450 genes were down-regulated in the DDT-resistant strain 91-R, as compared to the control strain 91-C. The overexpression of Cyp6g1 was associated with the presence of an Accord and an HMS-Beagle element insertion in the 5' upstream region in conjunction with copy number variation in the 91-R strain, but not in the 91-C strain. A total of 122 (50.2%) fixed nonsynonymous (amino acid-changing) mutations were found between 91-C and 91-R, and 20 (8.2%) resulted in amino acid changes within functional domains. Three P450 proteins were truncated as a result of premature stop codons and fixed between strains. Conclusion Our results demonstrate that a combination of changes in P450 protein-coding regions and transcript levels are possibly associated with DDT resistance, and thereby suggest that selection for variant function may occur within this gene family in response to chronic DDT exposure. © 2018 Society of Chemical Industry.

Managing a student-managed investment fund course populated with part-time students that have full-time jobs presents some unique challenges. This article discusses these challenges and makes suggestions related to course structure and the role of the faculty advisor. Combating the problem of overly distracted (or overly burdened) students requires a course structure that provides periodic deadlines to hold students accountable for learning in an active learning environment. Faculty advisors should be cognizant of potential distractions that might exist for students who have worked all day and create an environment that helps students stay engaged in the student fund activities.

The incidence of diabetes has increased dramatically in recent decades and become one of the leading health problems worldwide. Lifestyle and dietary changes alone cannot account for the dramatic rise of diabetes, while an increasing number of publications have reported the possible relationships between exposure to environmental pollutants and risk of diabetes. In the present review, our objective was to summarize the human studies on environmental pollutants, which includes persistent organic pollutants, pesticides (not on the Stockholm Convention list), bisphenol A, and phthalates, and the risk of diabetes. Currently published results suggest a positive relationship between certain persistent organic pollutants (dichlorodiphenyldichloroethene, dichlorodiphenyltrichloroethane, hexachlorobenzene, and polychlorinated biphenyls) and bisphenol A exposure and risk of diabetes. For pyrethroids, organophosphates, carbamates, and phthalates, there are insufficient studies to reach conclusions and theref...

Permethrin, a pyrethroid insecticide, was previously reported to promote adipogenesis in vitro and weight gain in vivo. The mechanism by which permethrin promotes adipogenesis/obesity, however, has not been fully explored. Intracellular calcium and endoplasmic reticulum (ER) stress have been reported to be linked with adipogenesis and obesity. Because pyrethroid insecticides have been determined to influence intracellular calcium and ER stress in vitro, the purpose of this current study was to investigate whether permethrin potentiates adipogenesis via a change in intracellular calcium, leading to endoplasmic reticulum (ER) stress in 3T3-L1 adipocytes. 3T3-L1 cells were exposed to four different concentrations of permethrin (0.01, 0.1, 1 & 10 μM) for 6 days during differentiation. Treatment of permethrin increased intracellular calcium level in a concentration-dependent manner. Similarly, permethrin treatment increased protein levels of ER stress markers in a concentration-dependent manner. These data suggest that intracellular calcium and ER stress may be involved in permethrin-induced adipogenesis of 3T3-L1 cells.

Permethrin, a type 1 pyrethroid insecticide, was previously reported to promote adipogenesis in 3T3-L1 adipocytes and insulin resistance in C2C12 muscle cells; however, the effects of permethrin exposure on glucose and lipid metabolisms in vivo remain unknown. The purpose of this study was to investigate the effects of permethrin exposure on glucose and lipid homeostasis as well as voluntary movement in female mice in response to dietary fat. We tested three doses of permethrin (50, 500, & 5000 μg/kg body weight/day) in low fat diet-fed (4% w/w of diet) and high fat diet-fed (20% w/w of diet) female C57BL/6 J mice for twelve weeks. Our results demonstrated that permethrin treatment potentiated high fat diet-induced insulin resistance as indicated by insulin tolerance tests, glucose tolerance tests, and homeostasis model assessment - insulin resistance (HOMA-IR) without altering weight or fat mass. Permethrin treatment significantly decreased voluntary movement and elevated blood glucose and insulin levels. Western blot results further showed that permethrin impaired insulin signaling via the Akt signaling pathway in the gastrocnemius muscle. Taken together, these results suggest that oral administration of permethrin potentiated high fat diet-induced insulin resistance, possibly increasing the risk of type 2 diabetes without altering weight gain in female C57BL/6 J mice.

We previously observed that ivermectin-induced detoxification genes, including ATP binding cassette transporter C4 (PhABCC4) and cytochrome P450 6CJ1 (CYP6CJ1) were identified from body lice following a brief exposure to a sublethal dose of ivermectin using a non-invasive induction assay. In this current study, the functional properties of PhABCC4 and CYP6CJ1 were investigated after expression in either X. laevis oocytes or using a baculovirus expression system, respectively. Efflux of [3 H]-9-(2-phosphonomethoxyethyl) adenine ([3 H]-PMEA), a known ABCC4 substrate in humans, was detected from PhABCC4 cRNA-injected oocytes by liquid scintillation spectrophotometric analysis and PhABCC4 expression in oocytes was confirmed using ABC transporter inhibitors. Efflux was also determined to be ATP-dependent. Using a variety of insecticides in a competition assay, only co-injection of ivermectin and dichlorodiphenyltrichloroethane led to decreased efflux of [3 H]-PMEA. PhABCC4-expressing oocytes also directly effluxed [3 H]-ivermectin, which increased over time. In addition, ivermectin appeared to be oxidatively metabolized and/or sequestered, although at low levels, following functional expression of CYP6CJ1 along with cytochrome P450 reductase in Sf9 cells. Our study suggests that PhABCC4 and perhaps CYP6CJ1 are involved in the Phase III and Phase I xenobiotic metabolism of ivermectin, respectively, and may play an important role in the evolution of ivermectin resistance in lice and other insects as field selection occurs.

The introduction of insecticides has greatly improved agricultural productivity and human nutrition; however, the wide use of insecticides has also sparked growing concern over their health impacts. Increased rate of cancers, neurodegenerative disorders, reproductive dysfunction, birth defects, respiratory diseases, cardiovascular diseases and aging have been linked with insecticide exposure. Meanwhile, a growing body of evidence is suggesting that exposure to insecticides can also potentiate the risk of obesity and type 2 diabetes. This review summarizes the relationship between insecticide exposure and development of obesity and type 2 diabetes using epidemiological and rodent animal studies, including potential mechanisms. The evidence as a whole suggests that exposure to insecticides is linked to increased risk of obesity and type 2 diabetes.

Imidacloprid, a neonicotinoid insecticide, was previously reported to enhance adipogenesis and resulted in insulin resistance in cell culture models. It was also reported to promote high fat diet-induced obesity and insulin resistance in male C57BL/6J mice. Thus, the goal of the present study was to determine the effects of imidacloprid and dietary fat interaction on the development of adiposity and insulin resistance in female C57BL/6J mice. Mice were fed with a low (4% w/w) or high fat (20% w/w) diet containing imidacloprid (0.06, 0.6, or 6 mg/kg bw/day) for 12 weeks. Mice fed with imidacloprid (0.6 mg/kg bw/day) significantly enhanced high fat diet-induced weight gain and adiposity. Treatment with imidacloprid significantly increased serum insulin levels with high fat diet without effects on other markers of glucose homeostasis. AMPKα activation was significantly inhibited by 0.6 and 6 mg imidacloprid/kg bw/day in white adipose tissue. Moreover, AMPKα activation with 5-aminoimidazole-4-carboxamide ribonucleotide abolished the effects of imidacloprid (10 μM) on enhanced adipogenesis in 3T3-L1 adipocytes. N-Acetyl cysteine also partially reversed the effects of imidacloprid on reduced phosphorylation of protein kinase B (AKT) in C2C12 myotubes. These results indicate that imidacloprid may potentiate high fat diet-induced adiposity in female C57BL/6J mice and enhance adipogenesis in 3T3-L1 adipocytes via the AMPKα-mediated pathway. Imidacloprid might also influence glucose homeostasis partially by inducing cellular oxidative stress in C2C12 myotubes.

Most countries have banned the use of 4,4'-dichlorodiphenyltrichloroethane (DDT). However, owing to its extremely high lipophilic characteristics, DDT and its metabolite 4,4'-dichlorodiphenyldichloroethylene (DDE) are ubiquitous in the environment and in many types of food. The positive correlation between exposure to insecticides, including DDT and DDE, and weight gain, resulting in impaired energy metabolism in offspring following perinatal DDT and DDE exposure, was previously reported. Therefore the influence of DDT and DDE on myogenesis using C2C12 myoblasts was investigated in this study.; Results: DDT and DDE decreased myotube formation dose- and time-dependently. Among myogenic regulatory factors, DDT and DDE mainly decreased MyoD1 and Myf5 expression. DDT and DDE treatment also altered Myostatin expression, phosphorylation of protein kinase B, p70 ribosomal protein S6 kinase, forkhead box O protein 3 and mammalian target of rapamycin, resulting in attenuation of myotube formation.; Conclusion: These results may have significant implications for understanding the effects of developmental exposure of DDT and DDE on myogenesis and development of obesity and type 2 diabetes later in life. © 2017 Society of Chemical Industry.; © 2017 Society of Chemical Industry.

Microtransplantation of mammalian brain neurolemma into the plasma membrane of Xenopus oocytes is used to study ion channels in their native form as they appear in the central nervous system. Use of microtransplanted neurolemma is advantageous for various reasons: tissue can be obtained from various sources and at different developmental stages; ion channels and receptors are present in their native configuration in their proper lipid environment along with appropriate auxiliary subunits; allowing the evaluation of numerous channelpathies caused by neurotoxicants in an ex vivo state. Here we show that Xenopus oocytes injected with post-natal day 90 (PND90) rat brain neurolemma fragments successfully express functional ion channels. Using a high throughput two electrode voltage clamp (TEVC) electrophysiological system, currents that were sensitive to tetrodotoxin, ω-conotoxin MVIIC, and tetraethylammonium were detected, indicating the presence of multiple voltage-sensitive ion channels (voltage-sensitive sodium (VSSC), calcium and potassium channels, respectively). The protein expression pattern for nine different VSSC isoforms (Nav1.1-Nav1.9) was determined in neurolemma using automated western blotting, with the predominant isoforms expressed being Nav1.2 and Nav1.6. VSSC were also successfully detected in the plasma membrane of Xenopus oocytes microtransplanted with neurolemma. Using this approach, a "proof-of-principle" experiment was conducted where a well-established structure-activity relationship between the neurotoxicant, 1,1,1-trichloro-2,2-di(4-chlorophenyl)ethane (DDT) and its non-neurotoxic metabolite, 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (DDE) was examined. A differential sensitivity of DDT and DDE on neurolemma-injected oocytes was determined where DDT elicited a concentration-dependent increase in TTX-sensitive inward sodium current upon pulse-depolarization whereas DDE resulted in no significant effect. Additionally, DDT resulted in a slowing of sodium channel inactivation kinetics whereas DDE was without effect. These results are consistent with the findings obtained using heterologous expression of single isoforms of rat brain VSSCs in Xenopus oocytes and with many other electrophysiological approaches, validating the use of the microtransplantation procedure as a toxicologically-relevant ex vivo assay. Once fully characterized, it is likely that this approach could be expanded to study the role of environmental toxicants and contaminants on various target tissues (e.g. neural, reproductive, developmental) from many species.

Per- and polyfluoroalkyl substances, a group of fluoro-surfactants widely detected in the environment, wildlife and humans, have been linked to adverse health effects. A growing body of literature has addressed their effects on obesity, diabetes and non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis. This review summarizes the brief historical use and chemistry of per- and polyfluoroalkyl substances, routes of human exposure, as well as the epidemiologic evidence for associations between exposure to per- and polyfluoroalkyl substances and the development of obesity, diabetes and non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis. We identified 22 studies on obesity and 32 studies on diabetes, while only 1 study was found for non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis by searching PubMed for human studies. Approximately 2/3 of studies reported positive associations between per- and polyfluoroalkyl substances exposure and the prevalence of obesity and/or type 2 diabetes. Causal links between per- and polyfluoroalkyl substances and obesity, diabetes and non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis, however, require further large-scale prospective cohort studies combined with mechanistic laboratory studies to better assess these associations.

Previous research has shown that deltamethrin, a Type-II pyrethroid, increases fat accumulation in adipocytes and Caenorhabditis elegans. The underlying mechanisms on how deltamethrin promotes fat accumulation, however, are unknown. The aim of the current study was therefore to determine the possible mechanisms through which deltamethrin increases fat accumulation in mouse 3T3-L1 adipocytes and C. elegans. Deltamethrin (10 μM) significantly increased fat accumulation, and the expression of adipogenic regulators, such as CCAAT/enhancer-binding protein (C/EBPα) and fatty acid synthase (FAS). Deltamethrin significantly decreased the phosphorylation of AMP-activated kinase α (AMPKα), while it increased protein expression of endoplasmic reticulum (ER) stress markers in 3T3-L1 adipocytes and C. elegans. The activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or the inhibition of ER stress with 4-phenylbutyrate (4-PBA) abolished the effects of deltamethrin on adipogenesis. Further study reveals that 4-PBA recovered the decreased AMPK phosphorylation induced by deltamethrin. These results suggest that deltamethrin promotes adipogenesis through an ER stress-AMPKα mediated pathway.

There is increasing interest in the potential role of epigallocatechin gallate (EGCG) in changing body composition to lower body fat with increased lean mass. In this study, we examined the sex-dependent effect of EGCG on body composition, locomotion, feeding behaviour, sugar levels, and transcription levels of key regulators in lipid, carbohydrate, and energy metabolisms in

Recent studies have reported the positive association between exposure to insecticides and increased risk of obesity and type 2 diabetes, which are closely associated with non-alcoholic fatty liver disease (NAFLD). However, it is not known if insecticide exposure can contribute to NAFLD. Thus, the goal of the current study was to determine if insecticide exposures can exacerbate the physiological conditions of NAFLD by modulating hepatic lipid metabolism. The effects of 12 insecticides on triglycerides (TG) accumulation were tested using palmitic acid (PA)-induced HepG2 hepatoma steatosis model. Results showed that among tested insecticides, permethrin and ivermectin significant interacted with palmitic acid to potentiate (permethrin) or decrease (ivermectin) TG accumulation. Further study showed that permethrin significantly promoted fatty acid synthesis, while suppressed lipid oxidation-related genes only under steatosis conditions. In comparison, ivermectin inhibited lipogenesis-related genes and promoted farnesoid X receptor, which upregulates fatty acid oxidation. Results in this study suggested that hepatic lipid metabolism may be more susceptible to insecticide exposure in the presence of excessive fatty acids, which can be associated with the development of NAFLD.

Human body and head lice are highly related haematophagous ectoparasites but only the body louse has been shown to transmit Bartonella quintana, the causative agent of trench fever. The mechanisms by which body lice became a vector for B. quintana, however, are poorly understood. Following oral challenge, green fluorescent protein-expressing B. quintana proliferated over 9 days postchallenge with the number of bacteria being significantly higher in whole body vs. head lice. The numbers of B. quintana detected in faeces from infected lice, however, were approximately the same in both lice. Nevertheless, the viability of B. quintana was significantly higher in body louse faeces. Comparison of immune responses in alimentary tract tissues revealed that basal transcription levels of peptidoglycan recognition protein and defensins were lower in body lice and the transcription of defensin 1 was up-regulated by oral challenge with wild-type B. quintana in head but not in body lice. In addition, the level of cytotoxic reactive oxygen species generated by epithelial cells was significantly lower in body lice. Although speculative at this time, the reduced immune response is consistent with the higher vector competence seen in body vs. head lice in terms of B. quintana infection.

Imidacloprid, a neonicotinoid insecticide widely used in agriculture worldwide, has been reported to promote adipogenesis and cause insulin resistance in vitro. The purpose of the current study was to determine the effects of imidacloprid and its interaction with dietary fat in the development of adiposity and insulin resistance using male C57BL/6J mice. Imidacloprid (0.06, 0.6, or 6 mg/kg bw/day) was mixed in a low-fat (4% w/w) or high-fat (20% w/w) diet and given to mice ad libitum for 12 weeks. Imidacloprid significantly promoted high fat diet-induced body weight gain and adiposity. In addition, imidacloprid treatment with the high fat diet resulted in impaired glucose metabolism. Consistently, there were significant effects of imidacloprid on genes regulating lipid and glucose metabolisms, including the AMP-activated protein kinase-α (AMPKα) pathway in white adipose tissue and liver. These results suggest that imidacloprid may potentiate high fat diet-induced adiposity and insulin resistance in male C57BL/6J mice.