The ISR downstream target ATF4 represses long-term memory in a cell type-specific manner.

The integrated stress response (ISR), a pivotal protein homeostasis network, plays a critical role in the formation of long-term memory (LTM). The precise mechanism by which the ISR controls LTM is not well understood. Here, we report insights into how the ISR modulates the mnemonic process by using targeted deletion of the activating transcription factor 4 (ATF4), a key downstream effector of the ISR, in various neuronal and non-neuronal cell types. We found that the removal of ATF4 from forebrain excitatory neurons (but not from inhibitory neurons, cholinergic neurons, or astrocytes) enhances LTM formation. Furthermore, the deletion of ATF4 in excitatory neurons lowers the threshold for the induction of long-term potentiation, a cellular model for LTM. Transcriptomic and proteomic analyses revealed that ATF4 deletion in excitatory neurons leads to upregulation of components of oxidative phosphorylation pathways, which are critical for ATP production. Thus, we conclude that ATF4 functions as a memory repressor selectively within excitatory neurons.

Diffusion and distal linkages govern interchromosomal dynamics during meiotic prophase.

SignificanceEssential for sexual reproduction, meiosis is a specialized cell division required for the production of haploid gametes. Critical to this process are the pairing, recombination, and segregation of homologous chromosomes (homologs). While pairing and recombination are linked, it is not known how many linkages are sufficient to hold homologs in proximity. Here, we reveal that random diffusion and the placement of a small number of linkages are sufficient to establish the apparent "pairing" of homologs. We also show that colocalization between any two loci is more dynamic than anticipated. Our study provides observations of live interchromosomal dynamics during meiosis and illustrates the power of combining single-cell measurements with theoretical polymer modeling.

Chemogenetic neuronal silencing decouples c-Jun activation from cell death in the temporal cortex.

Initial symptoms of neurodegenerative diseases are often defined by the loss of the most vulnerable neural populations specific to each disorder. In the early stages of Alzheimer's disease, vulnerable circuits in the temporal lobe exhibit diminished activity prior to overt degeneration. It remains unclear whether these functional changes contribute to regional vulnerability or are simply a consequence of pathology. We previously found that entorhinal neurons in the temporal cortex undergo cell death following transient suppression of electrical activity, suggesting a causal role for activity disruption in neurodegeneration. Here we demonstrate that electrical arrest of this circuit stimulates the injury-response transcription factor c-Jun. Entorhinal silencing induces transcriptional changes consistent with c-Jun activation that share characteristics of gene signatures in other neuronal populations vulnerable to Alzheimer's disease. Despite its established role in the neuronal injury response, inhibiting c-Jun failed to ameliorate entorhinal degeneration following activity disruption. Finally, we present preliminary evidence of integrated stress response activity that may serve as an alternative hypothesis to what drives entorhinal degeneration after silencing. Our data demonstrate that c-Jun is activated in response to neuronal silencing in the entorhinal cortex but is decoupled from subsequent neurodegeneration.

Marsupials have monoallelic MEST expression with a conserved antisense lncRNA but MEST is not imprinted.

The imprinted isoform of the Mest gene in mice is involved in key mammalian traits such as placental and fetal growth, maternal care and mammary gland maturation. The imprinted isoform has a distinct differentially methylated region (DMR) at its promoter in eutherian mammals but in marsupials, there are no differentially methylated CpG islands between the parental alleles. Here, we examined similarities and differences in the MEST gene locus across mammals using a marsupial, the tammar wallaby, a monotreme, the platypus, and a eutherian, the mouse, to investigate how imprinting of this gene evolved in mammals. By confirming the presence of the short isoform in all mammalian groups (which is imprinted in eutherians), this study suggests that an alternative promoter for the short isoform evolved at the MEST gene locus in the common ancestor of mammals. In the tammar, the short isoform of MEST shared the putative promoter CpG island with an antisense lncRNA previously identified in humans and an isoform of a neighbouring gene CEP41. The antisense lncRNA was expressed in tammar sperm, as seen in humans. This suggested that the conserved lncRNA might be important in the establishment of MEST imprinting in therian mammals, but it was not imprinted in the tammar. In contrast to previous studies, this study shows that MEST is not imprinted in marsupials. MEST imprinting in eutherians, therefore must have occurred after the marsupial-eutherian split with the acquisition of a key epigenetic imprinting control region, the differentially methylated CpG islands between the parental alleles.

Barriers and enablers of active surveillance for prostate cancer: a qualitive study of clinicians.

OBJECTIVES: To identify and explore barriers to, and enablers of, active surveillance (AS) in men with low-risk prostate cancer (LRPCa), as perceived by PCa clinicians. PATIENTS AND METHODS: Urologists and radiation oncologists in Australia and New Zealand were purposively sampled for a cross-section on gender and practice setting (metropolitan/regional; public/private). Using a grounded theory approach, semi-structed interviews were conducted with participants. Interviews were coded independently by two researchers using open, axial, and selective coding. A constant comparative approach was used to analyse data as it was collected. Thematic saturation was reached after 18 interviews, and a detailed model of barriers to, and enablers of, AS for LRPCa, as perceived by clinicians was developed. RESULTS: A model explaining what affects clinician decision making regarding AS in LRPCa emerged. It was underpinned by three broad themes: (i) clinician perception of patients' barriers and enablers; (ii) clinician perception of their own barriers and enablers; and (iii) engagement with healthcare team and resource availability. CONCLUSIONS: Clinicians unanimously agree that AS is an evidence-based approach for managing LRPCa. Despite this many men do not undergo AS for LRPCa, which is due to the interplay of patient and clinician factors, and their interaction with the wider healthcare system. This study identifies strategies to mitigate barriers and enhance enablers, which could increase access to AS by patients with LRPCa.

Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination.

The transcriptional control of CNS myelin gene expression is poorly understood. Here we identify gene model 98, which we have named myelin gene regulatory factor (MRF), as a transcriptional regulator required for CNS myelination. Within the CNS, MRF is specifically expressed by postmitotic oligodendrocytes. MRF is a nuclear protein containing an evolutionarily conserved DNA binding domain homologous to a yeast transcription factor. Knockdown of MRF in oligodendrocytes by RNA interference prevents expression of most CNS myelin genes; conversely, overexpression of MRF within cultured oligodendrocyte progenitors or the chick spinal cord promotes expression of myelin genes. In mice lacking MRF within the oligodendrocyte lineage, premyelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities and die because of seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination.

Peptidylarginine deiminase 2 regulates expression of DGCR8 affecting miRNA biogenesis in gonadotrope cells.

In brief: DGCR8 microprocessor complex, which is important for miRNA biogenesis, is regulated by peptidylarginine deiminase 2 and expression fluctuates in gonadotrope cells across the mouse estrous cycle. Abstract: Canonical miRNA biogenesis requires DGCR8 microprocessor complex subunit, which helps cleave pri-miRNAs into pre-miRNAs. Previous studies found that inhibiting peptidylarginine deiminase (PAD) enzyme activity results in increased DGCR8 expression. PADs are expressed in mouse gonadotrope cells, which play a central role in reproduction by synthesizing and secreting the luteinizing and follicle stimulating hormones. Given this, we tested whether inhibiting PADs alters expression of DGCR8, DROSHA, and DICER in the gonadotrope-derived LßT2 cell line. To test this, LßT2 cells were treated with vehicle or 1 µM pan-PAD inhibitor for 12 h. Our results show that PAD inhibition leads to an increase in DGCR8 mRNA and protein. To corroborate our results, dispersed mouse pituitaries were also treated with 1 µM pan-PAD inhibitor for 12 h which increases DGCR8 expression in gonadotropes. Since PADs epigenetically regulate gene expression, we hypothesized that histone citrullination alters Dgcr8 expression thereby affecting miRNA biogenesis. LßT2 samples were subjected to ChIP using an antibody to citrullinated histone H3, which shows that citrullinated histones are directly associated with Dgcr8. Next, we found that when DGCR8 expression is elevated in LßT2 cells, pri-miR-132 and -212 are reduced, while mature miR-132 and -212 are increased suggesting heightened miRNA biogenesis. In mouse gonadotropes, DGCR8 expression is higher in diestrus as compared to estrus, which is the inverse of PAD2 expression. Supporting this idea, treatment of ovariectomized mice with 17ß-estradiol results in an increase in PAD2 expression in gonadotropes with a corresponding decrease in DGCR8. Collectively, our work suggests that PADs regulate DGCR8 expression leading to changes in miRNA biogenesis in gonadotropes.

Sleep disturbances and depression are bidirectionally associated among college student athletes across COVID-19 pandemic exposure classes.

College athletes may be vulnerable to sleep disturbances and depression during the COVID-19 pandemic as a result of large shifts in social and athletic obligations. In a national sample of college athletes, we examined the associations between sleep disturbances and depression across two timepoints, using COVID-19 exposure as a moderator. Data were collected from 2098 NCAA Division I, II, and III college athletes during two timepoints, from April 10 to May 23, and from August 4 to September 15, 2020. First, a latent class analysis was conducted with five indicators of levels of COVID-19 exposure to determine different exposure profiles. Second, to examine the directionality of associations between sleep disturbance and depression, a cross-lagged panel model was added to the latent class membership structural equation model; this allowed for testing of moderation by COVID exposure class membership. Four highly homogeneous, well-separated classes of COVID-19 exposure were enumerated: Low Exposure (57%); Quarantine Only (21%); High Other, Low Self Exposure (14%); and High Exposure (8%). COVID-19 exposure class membership did not significantly moderate associations between sleep disturbances and depression. However, student athletes significantly differed in T2 depression by their COVID-19 exposure class membership. Depression and sleep disturbances were positively correlated at both timepoints (r T1 = 0.39; r T2 = 0.30). Additionally, cross-lagged associations were found such that T2 depression was associated with T1 sleep disturbances (ß = 0.14) and vice versa (ß = 0.11). These cross-lagged associations were not significantly affected by athletes' level of COVID-19 exposure during the beginning of the pandemic.

The Relationship of Resilience, Self-Compassion, and Social Support to Psychological Distress in Women Collegiate Athletes During COVID-19.

Given how COVID-19 had caused significant increases in collegiate athletes' psychological distress, we examined the extent to which such distress may have been ameliorated by the athletes' psychosocial resources (e.g., resilience). We used structural equation modeling to examine the direct and indirect relationships of resilience, self-compassion, and social support to women collegiate athletes' (N = 3,924; 81.2% White) psychological distress; athletes completed measures of these constructs from mid-April to mid-May 2020. Analyses revealed significant direct effects: More supported (ß = -0.12 to -0.19), self-compassionate (ß = -0.48 to -0.53), and resilient (ß = -0.21 to -0.35) athletes experienced less psychological distress (R2 = .61-.65). Further, self-compassion and social support were related indirectly (and inversely) to psychological distress through higher levels of resilience. These psychosocial resources appear to have played a positive role in how athletes coped with the pandemic, being associated with less psychological distress. These findings have application beyond the pandemic, providing direction for how sport psychology professionals may assist athletes in maintaining their well-being.

Dehalogenation of Chlorinated Ethenes to Ethene by a Novel Isolate, "Candidatus Dehalogenimonas etheniformans".

Dehalococcoides mccartyi strains harboring vinyl chloride (VC) reductive dehalogenase (RDase) genes are keystone bacteria for VC detoxification in groundwater aquifers, and bioremediation monitoring regimens focus on D. mccartyi biomarkers. We isolated a novel anaerobic bacterium, "Candidatus Dehalogenimonas etheniformans" strain GP, capable of respiratory dechlorination of VC to ethene. This bacterium couples formate and hydrogen (H2) oxidation to the reduction of trichloro-ethene (TCE), all dichloroethene (DCE) isomers, and VC with acetate as the carbon source. Cultures that received formate and H2 consumed the two electron donors concomitantly at similar rates. A 16S rRNA gene-targeted quantitative PCR (qPCR) assay measured growth yields of (1.2 ± 0.2) × 108 and (1.9 ± 0.2) × 108 cells per µmol of VC dechlorinated in cultures with H2 or formate as electron donor, respectively. About 1.5-fold higher cell numbers were measured with qPCR targeting cerA, a single-copy gene encoding a putative VC RDase. A VC dechlorination rate of 215 ± 40 µmol L-1 day-1 was measured at 30°C, with about 25% of this activity occurring at 15°C. Increasing NaCl concentrations progressively impacted VC dechlorination rates, and dechlorination ceased at 15 g NaCl L-1. During growth with TCE, all DCE isomers were intermediates. Tetrachloroethene was not dechlorinated and inhibited dechlorination of other chlorinated ethenes. Carbon monoxide formed and accumulated as a metabolic by-product in dechlorinating cultures and impacted reductive dechlorination activity. The isolation of a new Dehalogenimonas species able to effectively dechlorinate toxic chlorinated ethenes to benign ethene expands our understanding of the reductive dechlorination process, with implications for bioremediation and environmental monitoring. IMPORTANCE Chlorinated ethenes are risk drivers at many contaminated sites, and current bioremediation efforts focus on organohalide-respiring Dehalococcoides mccartyi strains to achieve detoxification. We isolated and characterized the first non-Dehalococcoides bacterium, "Candidatus Dehalogenimonas etheniformans" strain GP, capable of metabolic reductive dechlorination of TCE, all DCE isomers, and VC to environmentally benign ethene. In addition to hydrogen, the new isolate utilizes formate as electron donor for reductive dechlorination, providing opportunities for more effective electron donor delivery to the contaminated subsurface. The discovery that a broader microbial diversity can achieve detoxification of toxic chlorinated ethenes in anoxic aquifers illustrates the potential of naturally occurring microbes for biotechnological applications.

Increased sedentary time and decreased physical activity increases lipoprotein associated phospholipase A2 in obese individuals.

BACKGROUND AND AIMS: Lipoprotein-associated Phospholipase A2 (Lp-PLA2) is a protein produced by inflammatory cells in circulation and is associated with cardiovascular disease (CVD) risk. Physical activity (PA) is known to reduce inflammation and risk for CVD. However, Lp-PLA2 has yet to be examined in relation to PA and sedentary time. The purpose of this study was to determine if PA and sedentary time impacts Lp-PLA2 mass. A total of 25 subjects with an average BMI of 30.6 ± 5.7 were included in the data analysis. METHODS AND RESULTS: Data collected included anthropometric data, Lp-PLA2 mass, peak oxygen uptake (VO2peak), resting heart rate and blood pressure, obstructive sleep apnea (OSA) risk, and assessment of PA using an accelerometer. Sedentary minutes per day was positively associated with Lp-PLA2 (r = 0.41, P < 0.05). Light intensity PA was negatively associated (r = -0.51. P = 0.01) with Lp-PLA2. When subjects were divided into 2-quantiles by Lp-PLA2, the group with the higher Lp-PLA2 mass accumulated more sedentary time per day (P < 0.001) and less light intensity PA per day (P = 0.001). OSA risk and Lp-PLA2 showed no relationship. Sedentary behavior was higher, and light intensity PA was lower in subjects with hiLp-PLA2 mass. No difference was seen in moderate-to-vigorous intensity PA or steps per day. CONCLUSIONS: This suggests that, total PA habits, including time spent sedentary and lower intensity PA, impacts the levels of Lp-PLA2, an important inflammatory marker and marker of CVD risk.

Selective Optimization and Compensation, Skilled Golf Performance, and Age.

The present study tests predictions regarding skilled golf performance and age-based upon Selection, Optimization, and Compensation (SOC) theory. Participants were 1,324 adults (17-85 years old) who competed in a three-day major amateur golf tournament. Findings indicated that older golfers were most likely to identify difficulties in their games worthy of remediation, relied on performance-enhancing equipment to the greatest degree, and scored higher on SOC selection. For such players, SOC selection and remaining competitive predicted better tournament performance. Older players were also less likely to rate a variety of game improvement techniques as effective, less likely to engage in preround preparation, and were less likely than younger players to engage in SOC optimization and compensation strategies. This pattern of findings to a large extent also characterized middle-aged players. Despite a mixed picture of support for SOC theory, these findings provide valuable insights into its application to aging and the competitive sport domain.

Endocytosis of flavivirus NS1 is required for NS1-mediated endothelial hyperpermeability and is abolished by a single N-glycosylation site mutation.

Arthropod-borne flaviviruses cause life-threatening diseases associated with endothelial hyperpermeability and vascular leak. We recently found that vascular leak can be triggered by dengue virus (DENV) non-structural protein 1 (NS1) via the disruption of the endothelial glycocalyx-like layer (EGL). However, the molecular determinants of NS1 required to trigger EGL disruption and the cellular pathway(s) involved remain unknown. Here we report that mutation of a single glycosylated residue of NS1 (N207Q) abolishes the ability of NS1 to trigger EGL disruption and induce endothelial hyperpermeability. Intriguingly, while this mutant bound to the surface of endothelial cells comparably to wild-type NS1, it was no longer internalized, suggesting that NS1 binding and internalization are distinct steps. Using endocytic pathway inhibitors and gene-specific siRNAs, we determined that NS1 was endocytosed into endothelial cells in a dynamin- and clathrin-dependent manner, which was required to trigger endothelial dysfunction in vitro and vascular leak in vivo. Finally, we found that the N207 glycosylation site is highly conserved among flaviviruses and is also essential for West Nile and Zika virus NS1 to trigger endothelial hyperpermeability via clathrin-mediated endocytosis. These data provide critical mechanistic insight into flavivirus NS1-induced pathogenesis, presenting novel therapeutic and vaccine targets for flaviviral diseases.

Markers of poor sleep quality increase sedentary behavior in college students as derived from accelerometry.

PURPOSE: Sleep is essential for overall health and can impact academic performance. Prior research reports reduced sleep time in college students. Poor sleep may impact physical activity (PA) and sedentary behavior, or vice versa, but has not been examined extensively in this population. Therefore, the purpose of this study was to examine markers of sleep quality, PA, and sedentary behavior in college students using objective means. METHODS: A convenience sample of college students underwent body composition analysis and 7-day objective PA and sleep assessment via accelerometry. RESULTS: Among 81 college students (53 women), there was no association between total sleep time (TST) and weekly average PA. TST was negatively associated with sedentary minutes per day, sedentary bouts per day, and total time in sedentary bouts per day. Greater sedentary bouts per day and average sedentary minutes per day were seen in those with a TST < 6 h, with no difference in body composition. Further, TST was negatively associated with sedentary minutes accumulated on the subsequent day, for all 7 days. CONCLUSION: In a primarily residential college student cohort, poor sleep is associated with sedentary behavior more than PA. These students, who require a high amount of transport PA to and from campus during the week, are compensating by sleeping more and moving less on the weekend.

Insomnia, Psychosocial Well-Being, and Weight Control Behaviors Among Healthy-Weight Adolescent Females: Brief Report.

BACKGROUND: Weight control behaviors (WCBs) typically involve appearance- or health-driven behaviors that may be influenced by physiological, psychological, or social factors. Sleep disturbances like insomnia are an important area of research for adolescent populations, as early intervention may result in improvements in other physical and mental health domains. The purpose of this study was to investigate the relationship of insomnia, psychosocial well-being, and current WCBs in healthy-weight female adolescents. METHOD: Female adolescents (N = 323; Mage = 12.33 ± .04) who had healthy body mass index (BMI) levels completed self-report items on insomnia, depression, self-esteem, and physical self-concept. Multivariate analysis of covariance (MANCOVA), controlling for age, was conducted to further examine differences in insomnia and psychosocial variables among the WCB groups. RESULTS: Compared to those who were trying to stay the same weight or not trying to do anything about their weight, the girls who were trying to lose weight had significantly greater insomnia and depression symptoms, and lower self-esteem, with small to medium effect sizes. CONCLUSIONS: Clinicians working with adolescent girls should include assessments of WCBs in addition to measures of insomnia symptoms, even for adolescent girls within a normal BMI range, as these are common and frequently co-occurring phenomena. Additional research is needed to further disentangle these complicated relationships.

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier.

As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system include neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-CoV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. The spike protein, which plays a key role in receptor recognition, is formed by the S1 subunit containing a receptor binding domain (RBD) and the S2 subunit. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is ubiquitously expressed throughout various vessel calibers in the frontal cortex. Moreover, ACE2 expression was upregulated in cases of hypertension and dementia. ACE2 was also detectable in primary hBMVECs maintained under cell culture conditions. Analysis of cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48 h exposure window. Introduction of spike proteins to invitro models of the blood-brain barrier (BBB) showed significant changes to barrier properties. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluidic model of the human BBB, a platform that more closely resembles the physiological conditions at this CNS interface. Evidence provided suggests that the SARS-CoV-2 spike proteins trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients.

Antioxidant treatment ameliorates phenotypic features of SMC1A-mutated Cornelia de Lange syndrome in vitro and in vivo.

Cornelia de Lange syndrome (CdLS) is a rare disease characterized by cognitive impairment, multisystemic alterations and premature aging. Furthermore, CdLS cells display gene expression dysregulation and genomic instability. Here, we demonstrated that treatment with antioxidant drugs, such as ascorbic acid and riboceine, reduced the level of genomic instability and extended the in vitro lifespan of CdLS cell lines. We also found that antioxidant treatment partially rescued the phenotype of a zebrafish model of CdLS. Gene expression profiling showed that antioxidant drugs caused dysregulation of gene transcription; notably, a number of genes coding for the zinc finger (ZNF)-containing Krueppel-associated box (KRAB) protein domain (KRAB-ZNF) were found to be downregulated. Taken together, these data suggest that antioxidant drugs have the potential to ameliorate the developmental phenotype of CdLS.

The impact of sevoflurane anesthesia on postoperative renal function: a systematic review and meta-analysis of randomized-controlled trials.

PURPOSE: Renal damage secondary to fluoride ions and compound A (CpdA) after sevoflurane anesthesia remains unclear. For safety reasons, some countries still recommend minimum fresh-gas flows (FGFs) with sevoflurane. We review the evidence regarding the intraoperative use of sevoflurane for anesthesia maintenance and postoperative renal function compared with other anesthetic agents used for anesthetic maintenance. Secondarily, we examine the effects of peak plasma fluoride and CpdA levels and the effect of FGF and duration of anesthesia on these parameters. SOURCE: The databases of MEDLINE (OVID and Pubmed), EMBASE, the Cochrane Library, Health Technology Assessment Database, CINAHL, and Web of Science were searched from inception until 23 April 2020 to identify randomized-controlled trials (RCTs) in humans utilizing sevoflurane or an alternative anesthetic for anesthesia maintenance with subsequent measurements of renal function. Two different paired reviewers independently selected the studies and extracted data. The quality of the evidence was appraised using GRADE recommendations. PRINCIPAL FINDINGS: Of 3,766 publications screened, 41 RCTs in human patients were identified. There was no difference between creatinine at 24 hr (21 studies; n = 1,529), or creatinine clearance (CCR) at 24 hr (12 studies; n = 728) in the sevoflurane vs alternative anesthetic groups. Peak fluoride and fluoride measured at 24 hr were higher with sevoflurane compared with other inhaled anesthetics. Subgroup analyses for sevoflurane usage in various contexts showed no significant difference between sevoflurane and alternative anesthetics for creatinine or CCR at 24 hr at varying FGF, duration of exposure, baseline renal function, or absorbent use. CONCLUSIONS: We did not find any association between the use of sevoflurane and postoperative renal impairment compared with other agents used for anesthesia maintenance. The scientific basis for recommending higher FGF with the use of sevoflurane needs to be revisited.

RéSUMé: OBJECTIF: Les lésions rénales secondaires aux ions fluorure et au composé A (CpdA) après une anesthésie au sévoflurane demeurent incertaines. Pour des raisons de sécurité, certains pays recommandent encore des débits de gaz frais (DGF) minimaux lors de l'utilisation du sévoflurane. Nous avons passé en revue les données probantes concernant l'utilisation peropératoire de sévoflurane pour le maintien de l'anesthésie sur la fonction rénale postopératoire comparativement à d'autres agents anesthésiques utilisés pour le maintien de l'anesthésie. En analyse secondaire, nous avons examiné les effets des taux plasmatiques maximaux de fluorure et de CpdA et l'effet du DGF et de la durée de l'anesthésie sur ces paramètres. SOURCE: Des recherches ont été menées dans les bases de données de MEDLINE (OVID et Pubmed), EMBASE, the Cochrane Library, Health Technology Assessment Database, CINAHL et Web of Science, de leur création jusqu'au 23 avril 2020. Nous y avons identifié les études randomisées contrôlées (ERC) réalisées sur des sujets humains utilisant du sévoflurane ou un agent anesthésique alternatif pour le maintien de l'anesthésie et présentant des mesures subséquentes de la fonction rénale. Deux différents réviseurs appariés ont sélectionné de manière indépendante les études et extrait les données. La qualité des données probantes a été évaluée à l'aide des recommandations GRADE. CONSTATATIONS PRINCIPALES: Parmi les 3766 publications passées en revue, 41 ERC réalisées chez des patients humains ont été identifiées. Aucune différence n'a été observée en ce qui touchait à la valeur de créatinine à 24 h (21 études; n = 1529) ou de la clairance de la créatinine (CCR) à 24 h (12 études; n = 728) dans les groupes sévoflurane vs autres anesthésiques. Les taux maximaux de fluorure et le fluorure mesuré à 24 h étaient plus élevés lors de l'utilisation de sévoflurane que d'autres agents anesthésiques halogénés. Les analyses de sous-groupe portant sur l'utilisation du sévoflurane dans divers contextes n'ont démontré aucune différence significative entre le sévoflurane et les autres anesthésiques en matière de valeur de créatinine ou de CCR à 24 h selon différents DGF, durées d'exposition, fonctions rénales de base ou absorbants. CONCLUSION: Nous n'avons pas trouvé d'association entre l'utilisation du sévoflurane et des détériorations de la fonction rénale postopératoires par rapport aux autres agents utilisés pour le maintien de l'anesthésie. Les raisons scientifiques sur lesquelles repose la recommandation d'un DGF plus élevé lors de l'utilisation de sévoflurane doivent être réexaminées.

Female Athletes in Retirement: A Test of a Psychosocial Model of Bulimic Symptomatology.

Although researchers have examined eating disorders in female athletes, few such studies have been done with athletes who are retired, and even fewer have been quantitative. Thus, the authors empirically tested an established eating disorder theoretical model with 218 former NCAA Division-I female collegiate athletes who had been retired for 2-6 years. In retirement, participants completed measures of general sociocultural pressures related to body and appearance, thin-ideal internalization, body dissatisfaction, dietary restraint, negative affect, and bulimic symptomatology. Through structural equation modeling, the authors examined the direct and indirect relationships among the latent variables while controlling for body mass index and years since retirement. The model fit the data well, supporting the hypothesized direct and indirect relationships among the variables and explaining 54% of the variance in bulimic symptomatology. Despite no longer being exposed to sport pressures that contribute to eating disorders, female athletes experience such symptoms long into retirement.

Locomotor sensitization in male Sprague-Dawley rats following repeated concurrent treatment with 4-methylmethcathinone and 3,4-methylenedioxymethamphetamine.

Recreational abuse of illicit synthetic cathinones is an ongoing public health concern. Recent studies indicate that the methcathinone derivative 4-methylmethcathinone (4-MMC) produces behavioral and neurochemical effects similar to the entactogen 3,4-methylenedioxymethamphetamine (MDMA). Whereas polysubstance abuse is common, most preclinical studies of drug abuse liability only evaluate the effects of single drugs. Utilizing the locomotor sensitization paradigm, the present study assessed the combined locomotor stimulant effects of 4-MMC and MDMA for induction of sensitization following repeated administration and for expression of sensitization to a challenge dose of either substance alone after a 10-day period of drug abstinence. Male Sprague-Dawley rats received once daily intraperitoneal injections of saline, 4-MMC (1.0 mg/kg or 5.0 mg/kg), MDMA (3.0 mg/kg), or a mixture containing 4-MMC (1.0 mg/kg or 5.0 mg/kg) + MDMA (3.0 mg/kg) for 7 consecutive days. Following a 10-day drug-free period, rats were given a single intraperitoneal injection of either saline, 4-MMC (1.0 or 5.0 mg/kg), or 3.0 mg/kg MDMA. Activity was recorded for 1 h immediately before and 1 h immediately after injections on days 1, 7, and 17. 4-MMC treatment failed to induce locomotor sensitization, but, when combined with MDMA, sensitization was induced to a greater extent than with MDMA alone. Furthermore, the expression of sensitization to a subsequent challenge dose of MDMA was observed only in animals previously exposed to MDMA or a 5.0 mg/kg 4-MMC + MDMA mixture. In consideration of these findings along with the fact that 4-MMC has similar neurochemical actions to MDMA, further research may be warranted to determine the abuse liability of drug mixtures including 4-MMC and MDMA.