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Objective: To determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD)., Methods: We reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG., Results: Thirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0-14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasia (FCD) type IIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17 of 22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging, or histologic abnormalities in the gyral crown. At a median 6.3 (IQR 4.8-9.9) years of follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication., Conclusion: BOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping., Classification of Evidence: This study provides Class IV evidence that 1-stage, limited corticectomy for BOSD is safe and effective for control of seizures., (© 2021 American Academy of Neurology.)

Background : non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), which is considered as low-risk cancer, should be distinguished from the malignant invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). Improved discrimination of NIFTPs from invasive EFVPTCs using a molecular biomarker test could provide useful insights into pre- and post-surgical management of the indeterminate thyroid nodule. Galectin-3 (Gal-3), a β-galactosyl-binding molecule in the lectin group, is involved in different biological functions in well differentiated thyroid carcinomas. The aim of this study was to determine whether Gal-3 expression as a diagnostic marker could distinguish indolent NIFTP from invasive EFVPTC on tissue specimens from surgical thyroid nodules. Methods : immunohistochemical (IHC) analysis of cytoplasmic and nuclear Gal-3 expression was performed in formalin-fixed paraffin-embedded (FFPE) surgical tissues in four specific diagnostic subgroups- benign nodules, NIFTPs, EFVPTCs and lymphocytic/Hashimoto's thyroiditis (LTs). Results : cytoplasmic Gal-3 expression (mean ± SD) was significantly increased in invasive EFVPTCs (4.80 ± 1.60) compared to NIFTPs (2.75 ± 1.58, p < 0.001) and benign neoplasms (2.09 ± 1.19, p < 0.001) with no significant difference between NIFTPs and benign lesions ( p = 0.064). The presence of LT enhanced cytoplasmic Gal-3 expression (3.80 ± 1.32) compared to NIFTPs ( p = 0.016) and benign nodules ( p < 0.001). Nuclear Gal-3 expression in invasive EFVPTCs (1.84 ± 1.30) was significantly higher than in NIFTPs (1.00 ± 0.72, p = 0.001), but similar to benign nodules (1.44 ± 1.77, p = 0.215), thereby obviating its potential clinical application. Conclusions : our observations have indicated that increased cytoplasmic Gal-3 expression shows diagnostic potential in distinguishing NIFTP among encapsulated follicular variant nodules thereby serving as a possible ancillary test to H&E histopathological diagnostic criteria when LT interference is absent, to assist in the detection of the invasive EFVPTC among such nodules.

Atrazine (ATZ), a commonly used pesticide linked to endocrine disruption, cancer, and altered neurochemistry, frequently contaminates water sources at levels above the US Environmental Protection Agency's 3 parts per billion (ppb; μg/L) maximum contaminant level. Adult male zebrafish behavior, brain transcriptome, brain methylation status, and neuropathology were examined to test the hypothesis that embryonic ATZ exposure causes delayed neurotoxicity, according to the developmental origins of health and disease paradigm. Zebrafish (Danio rerio) embryos were exposed to 0 ppb, 0.3 ppb, 3 ppb, or 30 ppb ATZ during embryogenesis (1-72 h post fertilization (hpf)), then rinsed and raised to maturity. At 9 months post fertilization (mpf), males had decreased locomotor parameters during a battery of behavioral tests. Transcriptomic analysis identified altered gene expression in organismal development, cancer, and nervous and reproductive system development and function pathways and networks. The brain was evaluated histopathologically for morphometric differences, and decreased numbers of cells were identified in raphe populations. Global methylation levels were evaluated at 12 mpf, and the body length, body weight, and brain weight were measured at 14 mpf to evaluate effects of ATZ on mature brain size. No significant difference in genome methylation or brain size was observed. The results demonstrate that developmental exposure to ATZ does affect neurodevelopment and neural function in adult male zebrafish and raises concern for possible health effects in humans due to ATZ's environmental presence and persistence. Graphical abstract.

Covering: 2000 to 2020. trans-Bicyclo[4.4.0]decane/decene (such as trans-decalin and trans-octalin)-containing natural products display a wide range of structural diversity and frequently exhibit potent and selective antibacterial activities. With one of the major factors in combatting antibiotic resistance being the discovery of novel scaffolds, the efficient construction of these natural products is an attractive pursuit in the development of novel antibiotics. This highlight aims to provide a critical analysis on how the presence of dense architectural and stereochemical complexity necessitated special strategies in the synthetic pursuits of these natural trans-bicyclo[4.4.0]decane/decene antibiotics.

Atrazine (ATZ) is the second most commonly applied agricultural herbicide in the United States. Due to contamination concerns, the U.S. EPA has set the maximum contaminant level in potable water sources at 3 parts per billion (ppb; μg/l). Depending on the time of year and sampling location, water sources often exceed this limit. ATZ is an endocrine disrupting chemical in multiple species observed to target the neuroendocrine system. In this study the zebrafish vertebrate model was used to test the hypothesis that a developmental ATZ exposure generates metabolites similar to those found in mammals and alters morphology and behavior in developing larvae. Adult AB zebrafish were bred, embryos were collected, and exposed to 0, 0.3, 3, or 30 ppb ATZ from 1 to 120 h post fertilization (hpf). Targeted metabolomic analysis found that zebrafish produce the same major ATZ metabolites as mammals: desethyl atrazine (DEA), deisopropyl atrazine (DIA), and diaminochloroatrazine (DACT). The visual motor response test at 120 hpf detected hyperactivity in larvae in the 0.3 ppb treatment group and hypoactivity in the 30 ppb treatment group (p < 0.05). Further analysis into behavior during the dark and light phases showed zebrafish larvae exposed to 0.3 ppb ATZ had an increase in total distance moved in the first light phase and time spent moving in the first dark and light phases (p < 0.05). Alternatively, a decrease in total distance moved was observed in the second and third dark phases in zebrafish exposed to 30 ppb ATZ (p < 0.05). No significant differences were observed for any of the morphological measurements following ATZ exposure from 1 to 120 hpf (p > 0.05). These findings suggest that a ATZ exposure during early development generates metabolite profiles similar to mammals and leads to behavioral alterations supporting ATZ as a neurodevelopmental toxicant., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Exposures to organic pesticides, particularly during a developmental window, have been associated with various neurodegenerative diseases later in life. Atrazine (ATZ), one of the most used pesticides in the U.S., is suspected to be associated with increased neurodegeneration later in life but few studies assessed the neurotoxicity of developmental ATZ exposure using human neuronal cells. Here, we exposed human SH-SY5Y cells to 0.3, 3, and 30 ppb of ATZ prior to differentiating them into dopaminergic-like neurons in ATZ-free medium to mimic developmental exposure. The differentiated neurons exhibit altered neurite outgrowth and SNCA pathology depending on the ATZ treatment doses. Epigenome changes, such as decreases in 5mC (for 0.3 ppb only), H3K9me3, and H3K27me3 were observed immediately after exposure. These alterations persist in a compensatory manner in differentiated neurons. Specifically, we observed significant reductions in 5mC and H3K9me3, as well as, an increase in H3K27me3 in ATZ-exposed cells after differentiation, suggesting substantial chromatin rearrangements after developmental ATZ exposure. Transcriptional changes of relevant epigenetic enzymes were also quantified but found to only partially explain the observed epigenome alteration. Our results thus collectively suggest that exposure to low-dose of ATZ prior to differentiation can result in long-lasting changes in epigenome and increase risks of SNCA-related 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 © 2020 Elsevier Ltd. All rights reserved.)

Background: Superficial parotidectomy has a potential to be performed as an outpatient procedure. The objective of the study is to evaluate the safety and selection profile of outpatient superficial parotidectomy compared to inpatient parotidectomy., Methods: A retrospective review of individuals who underwent superficial parotidectomy between 2006 and 2016 at a tertiary care center was conducted. Primary outcomes included surgical complications, including transient/permanent facial nerve palsy, wound infection, hematoma, seroma, and fistula formation, as well as medical complications in the postoperative period. Secondary outcome measures included unplanned emergency room visits and readmissions within 30 days of operation due to postoperative complications., Results: There were 238 patients included (124 in outpatient and 114 in inpatient group). There was no significant difference between the groups in terms of gender, co-morbidities, tumor pathology or tumor size. There was a trend towards longer distance to the hospital from home address (111 Km in inpatient vs. 27 in outpatient, mean difference 83 km [95% CI,- 1 to 162 km], p = 0.053). The overall complication rates were comparable between the groups (24.2% in outpatient group vs. 21.1% in inpatient, p = 0.56). There was no difference in the rate of return to the emergency department (3.5% vs 5.6%, p = 0.433) or readmission within 30 days (0.9% vs 0.8%, p = 0.952)., Conclusion: Superficial parotidectomy can be performed safely as an outpatient procedure without elevated risk of complications.

Aims: Severe behavioural problems (SBP) are a major contributor to morbidity in children with intellectual disability (ID). Medications used to treat SBP in ID are associated with a high risk of side effects. Cannabidiol has potential therapeutic effects in SBP. This pilot study aimed to investigate the feasibility of conducting a randomised placebo-controlled trial of cannabidiol to reduce SBP in children with ID., Methods: This is a double-blind, placebo-controlled, two-armed, parallel-design, randomised controlled trial of cannabidiol in children aged 8-16 years with ID and SBP. Participants were randomised 1:1 to receive either 98% cannabidiol in oil (Tilray, Canada) or placebo orally for 8 weeks. The dose was up-titrated over 9 days to 20 mg/kg/day in two divided doses, with a maximum dose of 500 mg twice/day. The feasibility and acceptability of all study components were assessed., Results: Eight children were randomised, and all completed the full study protocol. There were no serious adverse events or drop-outs. Protocol adherence for key study components was excellent: study visits 100%, medication adherence 100%, blood tests 92% and questionnaire completion 88%. Parents reported a high degree of acceptability with the study design. All parents reported they would recommend the study to other families with children with similar problems. There was an efficacy signal in favour of active drug., Conclusions: The findings suggest that the study protocol is feasible and acceptable to patients with ID and SBP and their families., (© 2020 The British Pharmacological Society.)

Objective: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes., Methods: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined., Results: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased., Significance: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication., (© 2021 International League Against Epilepsy.)

Lead (Pb) is a commonly found heavy metal due to its historical applications. Recent studies have associated early-life Pb exposure with the onset of various neurodegenerative disease. The molecular mechanisms of Pb conferring long-term neurotoxicity, however, is yet to be elucidated. In this study, we explored the persistency of alteration in epigenetic marks that arise from exposure to low dose of Pb using a combination of image-based and gene expression analysis. Using SH-SY5Y as a model cell line, we observed significant alterations in global 5-methycytosine (5 mC) and histone 3 lysine 27 tri-methylation (H3K27me3) and histone 3 lysine 9 tri-methylation (H3K9me3) levels in a dose-dependent manner immediately after Pb exposure. The changes are partially associated with alterations in epigenetic enzyme expression levels. Long term culturing (14 days) after cease of exposure revealed persistent changes in 5 mC, partial recovery in H3K9me3 and overcompensation in H3K27me3 levels. The observed alterations in H3K9me3 and H3K27me3 are reversed after neuronal differentiation, while reduction in 5 mC levels are amplified with significant changes in patterns as identified via texture clustering analysis. Moreover, correlation analysis demonstrates a strong positive correlation between trends of 5 mC alteration after differentiation and neuronal morphology. Collectively, our results suggest that exposure to low dose of Pb prior to differentiation can result in persistent epigenome alterations that can potentially be responsible for the observed phenotypic changes. Our work reveals that Pb induced changes in epigenetic repressive marks can persist through neuron differentiation, which provides a plausible mechanism underlying long-term neurotoxicity associated with developmental Pb-exposure., 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 © 2020 Elsevier Ltd. All rights reserved.)

Perfluoroalkyl acids (PFAAs) are persistent environmental contaminants that are associated with various adverse health outcomes. Perfluorooctanoic acid (PFOA) is one of the most prominently detected PFAAs in the environment, which is now replaced with shorter chain carbon compounds including perfluorohexanoic acid (PFHxA) and perfluorobutyric acid (PFBA). The aim of this study was to compare the toxicity of four PFAAs as a function of chain length and head group (carboxylate versus sulfonate) with in vitro and in vivo zebrafish assessments, which were subsequently compared to other cell and aquatic models. Mortality rate increased with chain length (PFOA > PFHxA ≫ PFBA) in both whole embryo/larvae and embryonic cell models. The sulfonate group enhanced toxicity with perfluorobutane sulfonate (PFBS) showing higher toxicity than PFBA and PFHxA in both larvae and cells. Toxicity trends were similar among different aquatic models, but sensitivities varied. Discrepancies with other zebrafish studies were confirmed to be associated with a lack of neutralization of acidic pH of dosing solutions in these other investigations, demonstrating the need for rigor in reporting pH of exposure solutions in all experiments. The zebrafish embryonic cell line was also found to be similar to most other cell lines regardless of exposure length. Overall, results agree with findings in other cell lines and organisms where longer chain length and sulfonate group increase toxicity, except in investigations not neutralizing the exposure solutions for these acidic compounds.

Aim: This paper describes the use of the single patient therapy plan (SPTP). The SPTP has been designed to assess the efficacy at an individual level of a commercially available cannabinoid product, cannabidiol, in reducing seizure frequency in paediatric patients with intractable epilepsy., Methods: The SPTP is a randomised, double-blind, placebo-controlled N-of-1 trial designed to assess the efficacy of treatment in a neurology outpatient setting. The primary objective of the SPTP is to assess the efficacy of cannabidiol in reducing seizure frequency in each patient with intractable epilepsy, with change in seizure frequency being the primary outcome of interest. The analysis adopts a Bayesian approach, which provides results in the form of posterior probabilities that various levels of benefit (based on the primary outcome measure, seizure frequency) have been achieved under active treatment compared to placebo, accompanied by decision rules that provide thresholds for deciding whether treatment has been successful in the individual patient. The SPTP arrangement is most accurately considered part of clinical practice rather than research, since it is aimed at making clinical treatment decisions for individual patients and is not testing a hypothesis or collecting aggregate data. Therefore, Human Research Ethics Committee approval was considered not to be required, although it is recommended that hospital Clinical Ethics Committees provide ethical oversight., Conclusion: These SPTP resources are made available so that they may inform clinical practice in the treatment of severe epilepsy or adapted for use in other conditions., (© 2020, Commonwealth of Australia. Journal of Paediatrics and Child Health © 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy., Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature., Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants., Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis., (© 2020 International League Against Epilepsy.)

Slightly brackish groundwater contaminated by polycyclic aromatic hydrocarbons (PAHs) at a Superfund site in the Central Valley of California was pumped from 250 feet below land surface to a water storage tank using solar power and then gravity-fed into 18, 330-gallon intermediate bulk containers (totes) as follows: (1) Five totes contained planting medium with three salt-tolerant hybrid poplar trees per tote ( n = 15); (2) Seven totes contained planting medium with three salt-tolerant hybrid poplar trees per tote and inoculated with the naturally occurring, PAH-degrading endophyte Pseudomonas putida PD1 ( n = 21); (3) Three totes contained planting medium only ( n = 0); (4) One tote contained groundwater with three PD1-inoculated trees ( n = 3) and one tote contained groundwater with three regular trees ( n = 3); and (5) One tote contained groundwater only ( n = 0). All trees grew well during the 7-month growing season in spite of the area's hot, dry air temperature, little precipitation, tote-influent chloride concentrations of 290 mg/L, and tote-influent naphthalene concentrations that ranged from 650 to 5,100 mg/L. PD1-inoculated trees initially had 56% larger tree area (tree height × tree width) than regular trees and up to 69% larger tree area by the end of the growing season, indicating some conferred phytoprotection to the PAH contamination. All trees had similar trunk caliper (diameter) and leaf chlorophyll content by the end of the growing season. Total naphthalene removal ranged from 88% to 100% across all totes. The lowest naphthalene removal of 88% was observed in a tote that contained only planting medium and indicates substantial adsorption of naphthalene onto the high organic content of the planting medium. Contaminant removal due to uptake by the hybrid poplar trees was confirmed by the detection of naphthalene in in vivo passive samplers placed in tree trunks. Benzene, toluene, ethylbenzene, total xylenes, 2-methylnaphthalene, 1,2,4-trimethylbenzene, and isopropylbenzene were also detected. These results from the pilot-scale study indicate that a full-scale application of using salt-tolerant hybrid poplar trees at this site could effectively decrease naphthalene concentrations in groundwater pumped from the deep aquifer. These initial results provide hope for similar application at other contaminated sites characterized by groundwater at considerable depths, especially at Superfund sites where costly pump-and-treat systems have been used long-term to treat low levels of groundwater contamination.

The zebrafish ( Danio rerio ) is routinely used in biological studies as a vertebrate model system that provides unique strengths allowing applications in studies of neurodevelopmental and neurodegenerative diseases. One specific advantage is that the neurotransmitter systems are highly conserved throughout vertebrate evolution, including between zebrafish and humans. Disruption of the dopaminergic signaling pathway is linked to multiple neurological disorders. One of the most common is Parkinson's disease, a neurodegenerative disease associated with the loss of dopaminergic neurons, among other neuropathological characteristics. In this review, the development of the zebrafish's dopaminergic system, focusing on genetic control of the dopaminergic system, is detailed. Second, neurotoxicant models used to study dopaminergic neuronal loss, including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the pesticides paraquat and rotenone, and 6-hydroxydopamine (6-OHDA), are described. Next, zebrafish genetic knockdown models of dj1 , pink1 , and prkn established for investigating mechanisms of Parkinson's disease are discussed. Chemical modulators of the dopaminergic system are also highlighted to showcase the applicability of the zebrafish to identify mechanisms and treatments for neurodegenerative diseases such as Parkinson's disease associated with the dopaminergic system.

DNA copy number variants are associated with the development of complex neurological diseases and disorders including autism spectrum disorder, schizophrenia, Alzheimer's disease, and Parkinson's disease. Exposure to multiple environmental chemicals including various heavy metals is suggested as a risk factor in these neurological diseases and disorders, but few studies have addressed if heavy-metal exposure can result in de novo DNA copy number changes as a genetic mechanism contributing to these disease outcomes. In this study to further investigate the relationship between heavy-metal exposure and de novo copy number alterations (CNAs), zebrafish fibroblast cells were exposed to the neurotoxicant lead (Pb). A crystal violet assay was first used to determine exposure concentrations with >80% cell confluency. Then a zebrafish-specific array comparative genomic hybridization platform was used to detect CNAs following a 72 h Pb exposure (0.24, 2.4, or 24 μM). The Pb exposure resulted in 72 CNA amplifications ranging in size from 5 to 329 kb. No deletions were detected. CNAs resulted in 15 CNA regions (CNARs), leaving 7 singlet CNAs. Two of the singlets were within high repeat genomic locations. The number of CNAs tended to increase in a concentration-dependent manner. Several CNARs encompassed genes previously reported to have altered expression with Pb exposure, suggesting a mechanistic link. In addition, almost all genes are associated within a molecular network with amyloid precursor protein, a key molecular target associated with the pathophysiology of Alzheimer's disease. Overall, these findings show that Pb exposure results in de novo CNAs that could serve as a mechanism driving adverse health outcomes associated with Pb toxicity including neurological disease pathogenesis for further study.

The first total synthesis of the potent antibiotic anthracimycin was achieved in 20 steps. The synthesis features an intramolecular Diels-Alder reaction to forge the trans -decalin moiety, and an unprecedented aldol reaction using a complex β-ketoester to provide the tricarbonyl motif. A Stork-Zhao olefination and Grubbs ring closing metathesis delivered the E / Z -diene and forged the macrocycle. The C2 configuration was set with a base-mediated epimerization, providing access to (-)-anthracimycin.

The widespread use of polystyrene (PS) products in a myriad of consumer products has resulted in widespread contamination of PS nanoplastics (PSNPs) in aquatic ecosystems. Fish early life stages are exposed to nanoplastics dermally and via gills. Additional routes of exposure include oral via the ingestion of contaminated prey and maternal transfer. However, there is limited amount of work studying the impact of exposure route in the toxicokinetics and toxicodynamics of PSNPs. The objective of this study was to compare the effects of exposure routes (aqueous and microinjection) on the organ distribution and toxicity of PSNPs. We "mimicked" the maternal exposure of PSNPs to zebrafish by injecting a known concentration of fluorescent particles directly into 2-cell stage embryos. Endpoints were collected starting at 96 h post-fertilization until several weeks post-hatch to evaluate depuration. Although both exposure routes led to the accumulation of PSNPs in the yolk sac followed by brain, eyes, gut and swim bladder, the aqueous exposure caused higher PSNP concentrations in the brain and eyes and the injection exposure caused PSNP accumulation mainly in the trunk area. A waterborne exposure also reduced antioxidant gene expression; increased frequency of developmental abnormalities such as bent tails, jaw deformities and pericardial edema; and resulted in lower growth rates and hypoactivity. Overall, a waterborne exposure to PSNPs resulted in higher transfer to the brain and caused greater toxic effects to zebrafish compared to an injection exposure and highlights the key role of exposure routes in the uptake, localization and subsequent distribution of nanoparticles., 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 © 2020 Elsevier B.V. All rights reserved.)

Objective: To assess the role of trust when adolescents search for and appraise online health information., Study Design: A systematic search of online databases (MEDLINE, EMBASE, PsycINFO, and ERIC) was performed. Google Scholar and reference lists for included studies were manually searched for additional articles. Studies were included if they examined the role of trust when adolescents (in the 13- to 18-year-old age range) searched for and/or appraised online health information. Findings were synthesized using thematic analysis., Results: There were 22 studies that met the inclusion criteria. Four key themes were identified: adolescents generally distrust the Internet but use it anyway (subthemes were why adolescents distrust online health information; why adolescents still use online health information), adolescents use heuristics to appraise the trustworthiness of online health information (subthemes were different heuristics used by different adolescents, range of heuristics used by adolescents), adolescents trust websites more than social media or social networking sites, and adolescents' level of trust in online health information guides their actions and responses., Conclusions: Adolescents often distrust health information from the Internet, but continue to use it. Adolescents are aware of the need to evaluate the trustworthiness of online health information; however, their approaches vary in sophistication. As the reach and content of the Internet expands, it is important to equip adolescents with effective eHealth literacy to assess the trustworthiness of online health information., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Children with epilepsy report lower health-related quality of life (QOL) compared with healthy children and those with other chronic disorders. This study piloted the recently published Pediatric Quality of Life Inventory (PedsQL) Epilepsy Module (PedsQL-EM) in an ambulatory setting and studied epilepsy-related factors contributing to QOL in children with epilepsy., Methods: Children with epilepsy aged 8-18 years who were ambulant and verbal were recruited from pediatric neurology clinics. Children and their caregivers completed age-appropriate versions of the PedsQL-EM (8-12 or 13-18 years) in the clinic waiting area. Treating neurologists completed medical questionnaires about their patients' epilepsy., Results: We collected 151 parent-report and 127 self-report PedsQL-EMs. Administration time was 5-10 min with some children receiving assistance from the researcher. Mean age of children was 12.9+/-3.0, with 77 females (51%). Parents reported lower mean QOL scores across all subdomains compared with their children. Parents reported significantly lower QOL for children with earlier age at epilepsy onset, longer epilepsy duration, presence of seizures during the last month, more severe epilepsy, increased number of antiepileptic drugs (AEDs), and cognitive comorbidity. The same factors impacted on child self-reporting, but with more variability across subdomains., Conclusions: The PedsQL-EM is an epilepsy-specific measure of QOL that is quick and easy to administer and is sensitive to the clinical factors reported to impact on QOL in pediatric epilepsy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Zebrafish ( Danio rerio ) are an integrative vertebrate model ideal for toxicity studies. The zebrafish genome is sequenced with detailed characterization of all life stages. With their genetic similarity to humans, zebrafish models are established to study biological processes including development and disease mechanisms for translation to human health. The zebrafish genome, similar to other eukaryotic organisms, contains microRNAs (miRNAs) which function along with other epigenetic mechanisms to regulate gene expression. Studies have now established that exposure to toxins and xenobiotics can change miRNA expression profiles resulting in various physiological and behavioral alterations. In this review, we cover the intersection of miRNA alterations from toxin or xenobiotic exposure with a focus on studies using the zebrafish model system to identify miRNA mechanisms regulating toxicity. Studies to date have addressed exposures to toxins, particulate matter and nanoparticles, various environmental contaminants including pesticides, ethanol, and pharmaceuticals. Current limitations of the completed studies and future directions for this research area are discussed., 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., (© 2020 The Authors.)

Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- β1) and anchors it on the cell surface; this anchoring is required for activation of TGF-β1 in macrophages and microglia. We report six individuals from four families with bi-allelic variants in NRROS. All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination. The clinical course in affected individuals began with normal development or mild developmental delay, and the onset of seizures occurred within the first year of life, followed by developmental regression. Intracranial calcification was detected in three individuals. The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-β1 deficiency. The disease-causing NRROS variants involve two significant functional NRROS domains. These variants result in aberrant NRROS proteins with impaired ability to anchor latent TGF-β1 on the cell surface. Using confocal microscopy in HEK293T cells, we demonstrate that wild-type and mutant NRROS proteins co-localize with latent TGF-β1 intracellularly. However, using flow cytometry, we show that our mutant NRROS proteins fail to anchor latent TGF-β1 at the cell surface in comparison to wild-type NRROS. Moreover, wild-type NRROS rescues the defect of our disease-associated mutants in presenting latent TGF-β1 to the cell surface. Taken together, our findings suggest that loss of NRROS function causes a severe childhood-onset neurodegenerative condition with features suggestive of a disordered response to inflammation., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Introduction: Severe behavioural problems (SBPs) are a common contributor to morbidity and reduced quality of life in children with intellectual disability (ID). Current medication treatment for SBP is associated with a high risk of side effects. Innovative and safe interventions are urgently needed. Anecdotal reports and preliminary research suggest that medicinal cannabis may be effective in managing SBP in children with developmental disabilities. In particular, cannabidiol (CBD) may be a plausible and safe alternative to current medications. Families who are in urgent need of solutions are seeking cannabis for their ID children with SBP. However there is no evidence from randomised controlled trials to support the use of CBD for SBP. This pilot study aims to investigate the feasibility of conducting a randomised placebo-controlled trial of CBD to improve SBP in children with ID., Methods and Analysis: This is a single-site, double-blind, parallel-group, randomised, placebo-controlled pilot study of 10 participants comparing 98% CBD oil with placebo in reducing SBP in children aged 8-16 years with ID. Eligible participants will be randomised 1:1 to receive either CBD 20 mg/kg/day or placebo for 8 weeks. Data will be collected regarding the feasibility and acceptability of all study components, including recruitment, drop-out rate, study visit attendance, protocol adherence and the time burden of parent questionnaires. Safety outcomes and adverse events will be recorded. All data will be reported using descriptive statistics. These data will inform the design of a full scale randomised controlled trial to evaluate the efficacy of CBD in this patient group., Ethics and Dissemination: This protocol has received ethics approval from the Royal Children's Hospital ethics committee (Human Research Ethics Committee no. 38236). Results will be disseminated through peer-reviewed journals, professional networks, conferences and social media., Trial Registration Number: ACTRN12618001852246., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Trichloroethylene (TCE), an industrial solvent and degreaser, is an environmental toxicant that contaminates over half of Superfund sites, is a known carcinogen, and is linked to congenital defects and neurodegenerative disease. The developmental toxicity of TCE near ecologically relevant levels needs further characterization in order to better assess health risks of exposure. In this study, the toxicodynamics of TCE in the zebrafish (Danio rerio) model was investigated through the establishment of a LC50 concentration and by monitoring the acute developmental toxicity of ecologically relevant concentrations (0, 5, 50, and 500 parts per billion; ppb) of TCE during two different exposure lengths (1-72 hours post fertilization (hpf) and 1-120 hpf). Acute developmental toxicity was assessed by monitoring survival and hatching, larval morphology, larval heart rate, and behavioral responses during an embryonic photomotor response test and a larval visual motor response test. Embryonic exposure to TCE was associated with decreased percent hatch at 48 hpf, altered larval morphology, increased heart rate, and altered behavioral responses during the photomotor response test and visual motor response test. Larval morphology and behavioral alterations were more pronounced in the 1-120 hpf exposure length trials. The observed alterations suggest developmental TCE toxicity is still a concern at regulatory concentrations and that timing of exposure influences developmental toxicity.

How environmental chemicals can affect and exert their toxic effect at a molecular level has gained significant interest in recent years, not only for understanding their immediate health implications over exposed individuals, but also for their subsequent progeny. Atrazine (ATZ) is a commonly used herbicide in the U.S. and a long-suspected endocrine disrupting chemical. The molecular mechanism conferring long-term adverse health outcomes, however, remain elusive. Here, we explored changes in epigenetic marks that arise after exposure to ATZ at selected doses using image-based analysis coupled with data clustering. Significant decreases in methylated CpG ( me CpG) and histone 3 lysine 9 tri-methylated (H3K9me3) were observed in the selected human cell line with a clear spatial preference. Treating cells with ATZ leads to the loss of a subpopulation of cells with high me CpG levels as identified in our clustering and histogram analysis. A similar trend was observed in H3K9me3 potentially attributing to the cross-talking between me CpG and H3K9me3. Changes in me CpG are likely to be associated with alterations in epigenetic enzyme expression levels regulating me CpG and persist after the removal of ATZ source which collectively provide a plausible mechanism for long-term ATZ-induced toxicity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Unpredicted human safety events in clinical trials for new drugs are costly in terms of human health and money. The drug discovery industry attempts to minimize those events with diligent preclinical safety testing. Current standard practices are good at preventing toxic compounds from being tested in the clinic; however, false negative preclinical toxicity results are still a reality. Continual improvement must be pursued in the preclinical realm. Higher-quality therapies can be brought forward with more information about potential toxicities and associated mechanisms. The zebrafish model is a bridge between in vitro assays and mammalian in vivo studies. This model is powerful in its breadth of application and tractability for research. In the past two decades, our understanding of disease biology and drug toxicity has grown significantly owing to thousands of studies on this tiny vertebrate. This Review summarizes challenges and strengths of the model, discusses the 3Rs value that it can deliver, highlights translatable and untranslatable biology, and brings together reports from recent studies with zebrafish focusing on new drug discovery toxicology.

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel K v 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of K v 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less-severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms., (© 2019 Wiley Periodicals, Inc.)

We report two unrelated patients with infantile onset leukoencephalopathy with vanishing white matter (VWM) and hyperinsulinaemic hypoglycaemia. To our knowledge, this association has not been described previously. Both patients had compound heterozygous pathogenic variants in EIF2B4 detected on exome sequencing and absence of other variants which might explain the hyperinsulinism. Hypoglycaemia became apparent at 6 and 8 months, respectively, although in one patient, transient neonatal hypoglycaemia was also documented. One patient responded to diazoxide and the other was managed with continuous nasogastric feeding. We hypothesise that the pathophysiology of hyperinsulinism in VWM may involve dysregulation of transcription of genes related to insulin secretion., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

We sought to determine incidence, etiologies, and yield of genetic testing in infantile onset developmental and epileptic encephalopathies (DEEs) in a population isolate, with an intensive multistage approach. Infants born in Tasmania between 2011 and 2016, with seizure onset <2 years of age, epileptiform EEG, frequent seizures, and developmental impairment, were included. Following review of EEG databases, medical records, brain MRIs, and other investigations, clinical genetic testing was undertaken with subsequent research interrogation of whole exome sequencing (WES) in unsolved cases. The incidence of infantile DEEs was 0.44/1000 per year (95% confidence interval 0.25 to 0.71), with 16 cases ascertained. The etiology was structural in 5/16 cases. A genetic basis was identified in 6 of the remaining 11 cases (3 gene panel, 3 WES). In two further cases, WES identified novel variants with strong in silico data; however, paternal DNA was not available to support pathogenicity. The etiology was not determined in 3/16 (19%) cases, with a candidate gene identified in one of these. Pursuing clinical imaging and genetic testing followed by WES at an intensive research level can give a high diagnostic yield in the infantile DEEs, providing a solid base for prognostic and genetic counseling., Competing Interests: None of the authors have any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Most neurodegenerative diseases are currently incurable, with large social and economic impacts. Recently, there has been renewed interest in investigating natural products in the modern drug discovery paradigm as novel, bioactive small molecules. Moreover, the discovery of potential therapies for neurological disorders is challenging and involves developing optimized animal models for drug screening. In contemporary biomedicine, the growing need to develop experimental models to obtain a detailed understanding of malady conditions and to portray pioneering treatments has resulted in the application of zebrafish to close the gap between in vitro and in vivo assays. Zebrafish in pharmacogenetics and neuropharmacology are rapidly becoming a widely used organism. Brain function, dysfunction, genetic, and pharmacological modulation considerations are enhanced by both larval and adult zebrafish. Bioassay-guided identification of natural products using zebrafish presents as an attractive strategy for generating new lead compounds. Here, we see evidence that the zebrafish's central nervous system is suitable for modeling human neurological disease and we review and evaluate natural product research using zebrafish as a vertebrate model platform to systematically identify bioactive natural products. Finally, we review recently developed zebrafish models of neurological disorders that have the potential to be applied in this field of research.

In situ generation and reaction of novel 5-membered N-tosyl cyclic α,β-unsaturated iminium ions from readily prepared stable precursors is demonstrated. Formal iminium Diels-Alder cycloaddition proceeded in good yield via a stepwise rather than concerted cycloaddition process, confirmed through the isolation of a Mukaiyama-Michael type intermediate. Relative stereochemistry was determined upon subsequent intramolecular cyclisation under Lewis acid catalysis to afford formal endo 5,6-spirobicyclic adducts, as confirmed by crystallography. Further synthetic elaboration towards complex molecular scaffolds based on the dinoflagellate metabolite portimine, a potent apoptosis inducer, were also developed.

Aim: To assess the effectiveness and tolerability of lacosamide in paediatric clinical practice., Methods: A search of our hospital's pharmacy database yielded all children <16 years old dispensed lacosamide for drug-resistant epilepsy between January 2011 and June 2016. Medical records were reviewed for clinical and drug details. Continued treatment for ≥12 months was considered an indicator of effectiveness and tolerability., Results: A total of 107 children (61 boys) satisfied inclusion criteria. Median age at lacosamide commencement was 9.9 years (interquartile range 6.7-13.7). Of those children, 57 (53%) children had focal epilepsy, with focal motor or impaired awareness seizures most commonly reported; 50 (47%) children had generalised epilepsy, most with tonic-clonic seizures, tonic seizures or epileptic spasms; 83 (78%) children had an intellectual disability, 24 (22%) had a physical disability and 22 (21%) had an autism spectrum disorder; 69 (65%) children continued lacosamide for ≥12 months. Reasons for discontinuation before 12 months in 38 (35%) children included ineffectiveness in 25 (66%), adverse events in 7 (18%) and worsening of seizures in 2 (5%). The most common adverse events were drowsiness, behavioural changes, unsteadiness, nausea and vomiting. Epilepsy type and comorbidities were not associated with continuation or reasons for discontinuation., Conclusions: Most children continued treatment with lacosamide, suggesting effectiveness and tolerability. Lacosamide may prove to be a useful, 'broad-spectrum' antiepileptic medication in children for focal and generalised epilepsies and in association with comorbidities., (© 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Background: There are no guidelines regarding post-treatment surveillance specific to skull base chordomas., Objective: To determine an optimal imaging surveillance schedule to detect both local and distant metastatic skull base chordoma recurrences., Methods: A retrospective review of 91 patients who underwent treatment for skull base chordoma between 1993 and 2017 was conducted. Time to and location of local and distant recurrence(s) were cataloged. Existing chordoma surveillance recommendations (National Comprehensive Cancer Network [NCCN], London and South East Sarcoma Network [LSESN], European Society for Medical Oncology [ESMO], Chordoma Global Consensus Group [CGCG]) were applied to our cohort to compare the number of recurrent patients and months of undiagnosed tumor growth between surveillances. These findings were used to inform the creation of a revised imaging surveillance protocol (MD Anderson Cancer Center Chordoma Imaging Protocol [MDACC-CIP]), presented here., Results: Thirty-four patients with 79 local/systemic recurrences met inclusion criteria. Mean age at diagnosis and follow-up time were 45 yr and 79 mo, respectively. The MDACC-CIP imaging protocol significantly reduced the time to diagnosis of recurrence compared with the LSESN and CGCG/ESMO imaging protocols for surveillance of local disease with a cumulative/average of 576/16.9 (LSESN), 336/9.8 (CGCG), and 170/5.0 (MDACC-CIP) months of undetected growth, respectively. The NCCN and MDACC-CIP guidelines for distant metastatic surveillance identified a cumulative/average of 65/6.5 and 51/5.1 mo of undetected growth, respectively, and were not significantly different., Conclusion: The MDACC-CIP for skull base chordoma accounts for recurrence trends unique to this disease, including a higher rate of leptomeningeal spread than sacrococcygeal primaries, resulting in improved sensitivity and prompt diagnosis.

Tungsten is a refractory metal that is used in a wide range of applications. It was initially perceived that tungsten was immobile in the environment, supporting tungsten as an alternative for lead and uranium in munition and military applications. Recent studies report movement and detection of tungsten in soil and potable water sources, increasing the risk of human exposure. In addition, experimental research studies observed adverse health effects associated with exposure to tungsten alloys, raising concerns on tungsten toxicity with questions surrounding the safety of exposure to tungsten alone or in mixtures with other metals. Tungsten is commonly used as an alloy with nickel and cobalt in many applications to adjust hardness and thermal and electrical conductivity. This review addresses the current state of knowledge in regard to the mechanisms of toxicity of tungsten in the absence or presence of other metals with a specific focus on mixtures containing nickel and cobalt, the most common components of tungsten alloy.

This protocol details a method to analyze two tissue samples at the transcriptomic level using microarray analysis, ingenuity pathway analysis (IPA) and gene set enrichment analysis (GSEA). Methods such as these provide insight into the mechanisms underlying biological differences across two samples and thus can be applied to interrogate a variety of processes across different tissue samples, conditions, and the like. The full method detailed below can be applied to determine the effects of muscle-specific Notch1 activation in the mdx mouse model and to analyze previously published microarray data of human liposarcoma cell lines., Competing Interests: Competing interests The authors declare no conflicts of interest or competing interests.

Introduction: Surgery and radiation therapy are the standard treatment options for meningiomas, but these treatments are not always feasible. Expression profiling was performed to determine the presence of therapeutic actionable biomarkers for prioritization and selection of agents., Methods: Meningiomas (n = 115) were profiled using a variety of strategies including next-generation sequencing (592-gene panel: n = 14; 47-gene panel: n = 94), immunohistochemistry (n = 8-110), and fluorescent and chromogenic in situ hybridization (n = 5-70) to determine mutational and expression status., Results: The median age of patients in the cohort was 60 years, with a range spanning 6-90 years; 52% were female. The most frequently expressed protein markers were EGFR (93%; n = 44), followed by PTEN (77%; n = 110), BCRP (75%; n = 8), MRP1 (65%, n = 23), PGP (62%; n = 84), and MGMT (55%; n = 97). The most frequent mutation among all meningioma grades occurred in the NF2 gene at 85% (11/13). Recurring mutations in SMO and AKT1 were also occasionally detected. PD-L1 was expressed in 25% of grade III cases (2/8) but not in grade I or II tumors. PD-1 + T cells were present in 46% (24/52) of meningiomas. TOP2A and thymidylate synthase expression increased with grade (I = 5%, II = 22%, III = 62% and I = 5%, II = 23%, III = 47%, respectively), whereas progesterone receptor expression decreased with grade (I = 79%, II = 41%, III = 29%)., Conclusion: If predicated on tumor expression, our data suggest that therapeutics directed toward NF2 and TOP2A could be considered for most meningioma patients.

Atrazine (ATZ), the second most commonly used herbicide in the United States, is an endocrine disrupting chemical linked to cancer and a common drinking water contaminant. This study further investigates ATZ-related developmental toxicity by testing the following hypotheses in zebrafish: the effects of embryonic ATZ exposure are dependent on timing of exposure; embryonic ATZ exposure alters brain development and function; and embryonic ATZ exposure changes protein abundance in carcinogenesis-related pathways. After exposing embryos to 0, 0.3, 3, or 30 parts per billion (ppb) ATZ, we monitored the expression of cytochrome P450 family 17 subfamily A member 1 (cyp17a1), glyoxalase I (glo1), ring finger protein 14 (rnf14), salt inducible kinase 2 (sik2), tetratricopeptide domain 3 (ttc3), and tumor protein D52 like 1 (tpd52l1) at multiple embryonic time points to determine normal expression and if ATZ exposure altered expression. Only cyp17a1 had normal dynamic expression, but ttc3 and tpd52l1 had ATZ-related expression changes before 72 h. Larvae exposed to 0.3 ppb ATZ had increased brain length, while larvae exposed to 30 ppb ATZ were hypoactive. Proteomic analysis identified altered protein abundance in pathways related to cellular function, neurodevelopment, and genital-tract cancer. The results indicate embryonic ATZ toxicity involves interactions of multiple pathways., Significance: This is the first report of proteomic alterations following embryonic exposure to atrazine, an environmentally persistent pesticide and common water contaminant. Although the transcriptomic alterations in larval zebrafish with embryonic atrazine exposure have been reported, neither the time at which gene expression changes occur nor the resulting proteomic changes have been investigated. This study seeks to address these knowledge gaps by evaluating atrazine's effect on gene expression through multiple time points during embryogenesis, and correlating changes in gene expression to pathological alterations in brain length and functional changes in behavior. Finally, pathway analysis of the proteomic alterations identifies connections between the molecular changes and functional outcomes associated with embryonic atrazine exposure., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Limited data exist to guide the management of recurrent chordomas arising in the skull base., Objective: To determine factors affecting tumor control rates and disease-specific survival (DSS) in recurrent disease., Methods: A retrospective review was performed of 29 patients with 55 recurrences treated at our institution. Tumor and treatment factors were assessed for impact on freedom from progression (FFP; primary outcome) and DSS (secondary outcome)., Results: Postradiotherapy disease failure was much more difficult to manage vs progression after surgery alone (15.9 vs 41.4 mo, P = .094). Distant metastases and, specifically, leptomeningeal disease at presentation were associated with poorer DSS and FFP (P < .05). For local progression after surgery alone, repeat resection (P < .05) improved median FFP. With postradiotherapy local failure, repeat resection did not confer any benefit (13.5 vs 17.6 mo, P > .05), while a trend towards improved FFP was seen with stereotactic radiosurgery (28.3 vs 16.2 mo, P = .233). For distant metastases, site-directed therapy (surgery or radiation) allowed for site control (P < .05) but did not affect FFP or DSS. Presentation with early progression <6 mo from previous treatment portended significantly worse DSS (19.3 vs 77.6 mo, P < .05)., Conclusion: There is a need for treatment of recurrent disease to be tailored to the pattern of tumor recurrence and previously received treatments. Postradiotherapy progression poses particular challenges given the apparent limited role of repeat resection alone. Stereotactic radiosurgery may have a role in this setting. While patients with systemic metastases appear to respond well to site-directed therapy, those with leptomeningeal disease have a dismal prognosis.

OBJECTIVE The endoscopic endonasal transmaxillary transpterygoid (TMTP) approach has been the gateway for lateral skull base exposure. Removal of the cartilaginous eustachian tube (ET) and lateral mobilization of the internal carotid artery (ICA) are technically demanding adjunctive steps that are used to access the petroclival region. The gained expansion of the deep working corridor provided by these maneuvers has yet to be quantified. METHODS The TMTP approach with cartilaginous ET removal and ICA mobilization was performed in 5 adult cadaveric heads (10 sides). Accessible portions of the petrous apex were drilled during the following 3 stages: 1) before ET removal, 2) after ET removal but before ICA mobilization, and 3) after ET removal and ICA repositioning. Resection volumes were calculated using 3D reconstructions generated from thin-slice CT scans obtained before and after each step of the dissection. RESULTS The average petrous temporal bone resection volumes at each stage were 0.21 cm 3 , 0.71 cm 3 , and 1.32 cm 3 (p < 0.05, paired t-test). Without ET removal, inferior and superior access to the petrous apex was limited. Furthermore, without ICA mobilization, drilling was confined to the inferior two-thirds of the petrous apex. After mobilization, the resection was extended superiorly through the upper extent of the petrous apex. CONCLUSIONS The transpterygoid corridor to the petroclival region is maximally expanded by the resection of the cartilaginous ET and mobilization of the paraclival ICA. These added maneuvers expanded the deep window almost 6 times and provided more lateral access to the petroclival region with a maximum volume of 1.5 cm 3 . This may result in the ability to resect small-to-moderate sized intradural petroclival lesions up to that volume. Larger lesions may better be approached through an open transcranial approach.

The laboratory zebrafish (Danio rerio) is now an accepted model in toxicologic research. The zebrafish model fills a niche between in vitro models and mammalian biomedical models. The developmental characteristics of the small fish are strategically being used by scientists to study topics ranging from high-throughput toxicity screens to toxicity in multi- and transgenerational studies. High-throughput technology has increased the utility of zebrafish embryonic toxicity assays in screening of chemicals and drugs for toxicity or effect. Additionally, advances in behavioral characterization and experimental methodology allow for observation of recognizable phenotypic changes after xenobiotic exposure. Future directions in zebrafish research are predicted to take advantage of CRISPR-Cas9 genome editing methods in creating models of disease and interrogating mechanisms of action with fluorescent reporters or tagged proteins. Zebrafish can also model developmental origins of health and disease and multi- and transgenerational toxicity. The zebrafish has many advantages as a toxicologic model and new methodologies and areas of study continue to expand the usefulness and application of the zebrafish.

Objective: To determine if early access to multidisciplinary surgical care affects outcomes in patients with skull base chordoma., Method: A retrospective chart review of prospectively collected data was performed on 51 patients treated from 1993 to 2014. The cohort was divided into those presenting (1) for initial management (ID, n = 21) or (2) with persistent/progressive disease after prior biopsy/surgery (PD, n = 30) outside of a multidisciplinary setting. The impact of initial surgical management in a multidisciplinary center on progression-free survival (PFS) was assessed with Kaplan-Meier and log-rank analyses., Results: Mean follow-up, median PFS, median overall survival (OS), and 10-year OS for the entire cohort was 70 months, 47 months, 159 months, and 19%, respectively. Initial management in a multidisciplinary center resulted in a significant improvement in PFS versus initial surgery with or without radiotherapy (XRT) outside of this setting (64 vs 25 months, p = 0.035). Initial surgical resection outside of a multidisciplinary setting increased the risk of recurrence/progression on univariate (HR, 2.276; p = 0.022) and multivariate analysis (HR, 2.831; p = 0.006), respectively., Conclusions: The results from this study emphasize the impact that coordinated multidisciplinary surgical care has on patient outcomes for chordomas of the clivus. Biopsy followed by attempted radical resection at a dedicated center does not affect PFS and, therefore, represents a reasonable first step in management for patients presenting outside of multidisciplinary setting.

Objective: To conduct a systematic review of the evidence concerning whether and how adolescents search for online health information and the extent to which they appraise the credibility of information they retrieve., Study Design: A systematic search of online databases (MEDLINE, EMBASE, PsycINFO, ERIC) was performed. Reference lists of included papers were searched manually for additional articles. Included were studies on whether and how adolescents searched for and appraised online health information, where adolescent participants were aged 13-18 years. Thematic analysis was used to synthesize the findings., Results: Thirty-four studies met the inclusion criteria. In line with the research questions, 2 key concepts were identified within the papers: whether and how adolescents search for online health information, and the extent to which adolescents appraise online health information. Four themes were identified regarding whether and how adolescents search for online health information: use of search engines, difficulties in selecting appropriate search strings, barriers to searching, and absence of searching. Four themes emerged concerning the extent to which adolescents appraise the credibility of online health information: evaluation based on Web site name and reputation, evaluation based on first impression of Web site, evaluation of Web site content, and absence of a sophisticated appraisal strategy., Conclusions: Adolescents are aware of the varying quality of online health information. Strategies used by individuals for searching and appraising online health information differ in their sophistication. It is important to develop resources to enhance search and appraisal skills and to collaborate with adolescents to ensure that such resources are appropriate for them., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Coal mining is one of the economic activities with the greatest impact on environmental quality. At all stages contaminants are released as particulates such as coal dust. The first aim of this study was to obtain an aqueous coal dust extract and characterize its composition in terms of trace elements by ICP-MS. In addition, the developmental toxicity of the aqueous coal extract was evaluated using zebrafish (Danio rerio) after exposure to different concentrations (0-1000 ppm; μg mL -1 ) to establish acute toxicity, morphology and transcriptome changes. Trace elements within the aqueous coal dust extract present at the highest concentrations (>10 ppb) included Sr, Zn, Ba, As, Cu and Se. In addition, Cd and Pb were found in lower concentrations. No significant difference in mortality was observed (p > 0.05), but a delay in hatching was found at 0.1 and 1000 ppm (p < 0.05). No significant differences in morphological characteristics were observed in any of the treatment groups (p > 0.05). Transcriptomic results of zebrafish larvae revealed alterations in 77, 61 and 1376 genes in the 1, 10, and 100 ppm groups, respectively. Gene ontology analysis identified gene alterations associated with the development and function of connective tissue and the hematological system, as well as pathways associated with apoptosis, the cell cycle, transcription, and oxidative stress including the MAPK signaling pathway. In addition, altered genes were associated with cancer; connective tissue, muscular, and skeletal disorders; and immunological and inflammatory diseases. Overall, this is the first study to characterize gene expression alterations in response to developmental exposure to aqueous coal dust residue from coal mining with transcriptome results signifying functions and systems to target in future studies.

MicroRNA-223 is known as a myeloid-enriched anti-inflammatory microRNA that is dysregulated in numerous inflammatory conditions. Here, we report that neutrophilic inflammation (wound response) is augmented in miR-223-deficient zebrafish, due primarily to elevated activation of the canonical nuclear factor κB (NF-κB) pathway. NF-κB over-activation is restricted to the basal layer of the surface epithelium, although miR-223 is detected throughout the epithelium and in phagocytes. Not only phagocytes but also epithelial cells are involved in miR-223-mediated regulation of neutrophils' wound response and NF-κB activation. Cul1a/b, Traf6, and Tab1 are identified as direct targets of miR-223, and their levels rise in injured epithelium lacking miR-223. In addition, miR-223 is expressed in cultured human bronchial epithelial cells, where it also downregulates NF-κB signaling. Together, this direct connection between miR-223 and the canonical NF-κB pathway provides a mechanistic understanding of the multifaceted role of miR-223 and highlights the relevance of epithelial cells in dampening neutrophil activation., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

The hormonally active nature of intracranial meningioma has prompted research examining the risk of tumorigenesis in patients using hormonal contraception. Studies exploring estrogen-only and estrogen/progesterone combination contraceptives have failed to demonstrate a consistent increased risk of meningioma. By contrast, the few trials examining progesterone-only contraceptives have shown higher odds ratios for risk of meningioma. With progesterone-only contraception on the rise, the risk of tumor recurrence with these specific medications warrants closer study. We sought to determine whether progesterone-only contraception increases recurrence rate and decreases progression-free survival in pre-menopausal women with surgically resected WHO Grade I meningioma. Comparative analysis of 67 pre-menopausal women taking hormone-based contraceptives (progesterone-only medication, n = 21; estrogen-only or estrogen/progesterone combination medication, n = 46) who underwent surgical resection of WHO Grade I intracranial meningioma was performed. Differences in demographics, degree of resection, adjuvant therapy and time to recurrence were compared between the two groups. Compared to patients taking combination or estrogen-only contraception, those taking progesterone-only contraception demonstrated a greater recurrence rate (33.3 vs. 19.6%) with a reduced time to recurrence (18 vs. 32 months, p = 0.038) despite a significantly shorter follow-up (p = 0.014). There were no significant demographic or treatment related differences. The results from this study suggest that exogenous progesterone-only medications may represent a specific contraceptive subgroup that should be avoided in patients with meningioma.

Developmental lead (Pb) exposure is linked to neurological health issues. Results from non-human primate and rodent studies suggest detrimental effects of an early life Pb exposure, showing transcriptional disturbances and pathological evidence of Alzheimer's disease in the adult animal brain. To elucidate the impacts of an embryonic Pb exposure on the adult brain, transcriptomic analysis was completed on the brain of zebrafish aged 12months exposed to a control treatment or to an embryonic 100μg/L Pb exposure by sex. In the adult female zebrafish brain, significant changes in expression profiles occurred in a number of genes involved in neurological disease and nervous system development and function. On the other hand, in adult males, a number of genes with significant expression alterations were found to be associated with cancer and tumors. p38 mitogen-activated protein kinase (p38 MAPK) was also indicated as an upstream regulator of observed gene expression changes. Western blot analysis confirmed activation of p38 MAPK in the form of phosphorylated p38 MAPK in the male zebrafish brain. In addition, we compared transcriptomic changes observed in this study to a previous study with an embryonic exposure of 10μg/L Pb by sex, showing unique sets of genes dependent on Pb concentration. Overall, these results show sex-specific and concentration-dependent disturbances of global gene expression patterns in the brain of adult zebrafish exposed to Pb during embryogenesis., (Copyright © 2017 Elsevier Inc. All rights reserved.)