Toxicity profile of high-dose methotrexate in young children with central nervous system tumors.

High-dose methotrexate (HD-MTX) is used in the treatment of children with central nervous system (CNS) tumors; however, toxicity information is limited. We characterized toxicities following 102 administrations of HD-MTX (4.6-13.5 g/m2) infused over 4 or 24 h in 38 children with a CNS tumor before 6 years of age (2010-2020). Delayed clearance of methotrexate occurred following 24% of infusions. Common Terminology Criteria for Adverse Events v5 grade 2-3 mucositis was observed in 47% of individuals, Grade 4 neutropenia in 76%, and grade 3-4 thrombocytopenia in 58%. No neurotoxicity was observed. HD-MTX can be safely used with supportive care and monitoring.

The temporal dynamics of visual object priming.

Priming reflects an important means of learning that is mediated by implicit memory. Importantly, priming occurs for previously viewed objects (item-specific priming) and their category relatives (category-wide priming). Two distinct neural mechanisms are known to mediate priming, including the sharpening of a neural object representation and the retrieval of stimulus-response mappings. Here, we investigated whether the relationship between these neural mechanisms could help explain why item-specific priming generates faster responses than category-wide priming. Participants studied pictures of everyday objects, and then performed a difficult picture identification task while we recorded event-related potentials (ERP). The identification task gradually revealed random line segments of previously viewed items (Studied), category exemplars of previously viewed items (Exemplar), and items that were not previously viewed (Unstudied). Studied items were identified sooner than Unstudied items, showing evidence of item-specific priming, and importantly Exemplar items were also identified sooner than Unstudied items, showing evidence of category-wide priming. Early activity showed sustained neural suppression of parietal activity for both types of priming. However, these neural suppression effects may have stemmed from distinct processes because while category-wide neural suppression was correlated with priming behavior, item-specific neural suppression was not. Late activity, examined with response-locked ERPs, showed additional processes related to item-specific priming including neural suppression in occipital areas and parietal activity that was correlated with behavior. Together, we conclude that item-specific and category-wide priming are mediated by separate, parallel neural mechanisms in the context of the current paradigm. Temporal differences in behavior are determined by the timecourses of these distinct processes.

Stress, Dependence, and COVID-19-related Changes in Past 30-day Marijuana, Electronic Cigarette, and Cigarette Use among Youth and Young Adults.

BACKGROUND: Studies show smoking and vaping behaviors increase risk of contracting and worse symptoms of COVID-19. This study examines whether past 30-day youth and young adult users of marijuana, e-cigarettes, and cigarettes self-reported changes in their use of these substances due to the COVID-19 pandemic; and cross-sectional associations between perceived stress, nicotine or marijuana dependence, and COVID-19-related changes in use. METHODS: Participants were 709 past 30-day self-reported substance users from the Texas Adolescent Tobacco and Marketing Surveillance study (TATAMS; mean age = 19; 58% female; 38% Hispanic, 35% white). Multiple logistic regression models assessed cross-sectional associations between perceived stress and dependence and increased, decreased, or sustained past 30-day use of marijuana, e-cigarettes, and cigarettes due to COVID-19 (e.g., "Has your marijuana use changed due to the COVID-19 outbreak?"). Covariates included age, race/ethnicity, socio-economic status (SES), dependence (exposure: stress), and stress (exposure: dependence). RESULTS: Most participants reported sustained (41%, 43%, 49%) or increased (37%, 34%, 25%) use of marijuana, e-cigarettes, and cigarettes due to COVID-19, respectively. Participants who reported symptoms of dependence were significantly more likely than their non-dependent peers to report increasing their marijuana (AOR: 1.66; 95% CI: 1.15-2.39) and e-cigarette (AOR: 2.57; 95% CI: 1.38-4.77) use. Those who reported higher perceived stress were significantly more likely to report increasing their marijuana use (AOR: 1.55; 95% CI: 1.01-2.42). CONCLUSIONS: Most youth and young adults did not decrease their substance use amid a global, respiratory disease pandemic. Health messaging and interventions that address the health effects of smoking and vaping as well as factors like stress and dependence that may be barriers to decreasing use are vital in curbing the COVID-19 pandemic.

Exposing an "Intangible" Cognitive Skill among Collegiate Football Players: Enhanced Interference Control.

American football is played in a chaotic visual environment filled with relevant and distracting information. We investigated the hypothesis that collegiate football players show exceptional skill at shielding their response execution from the interfering effects of distraction (interference control). The performances of 280 football players from National Collegiate Athletic Association Division I football programs were compared to age-matched controls in a variant of the Eriksen flanker task (Eriksen and Eriksen, 1974). This task quantifies the magnitude of interference produced by visual distraction on split-second response execution. Overall, football athletes and age controls showed similar mean reaction times (RTs) and accuracy rates. However, football athletes were more proficient at shielding their response execution speed from the interfering effects of distraction (i.e., smaller flanker effect costs on RT). Offensive and defensive players showed smaller interference costs compared to controls, but defensive players showed the smallest costs. All defensive positions and one offensive position showed statistically smaller interference effects when compared directly to age controls. These data reveal a clear cognitive advantage among football athletes at executing motor responses in the face of distraction, the existence and magnitude of which vary by position. Individual differences in cognitive control may have important implications for both player selection and development to improve interference control capabilities during play.

Family History of Alzheimer's Disease is Associated with Impaired Perceptual Discrimination of Novel Objects.

Early detection may be the key to developing therapies that will combat Alzheimer's disease (AD). It has been consistently demonstrated that one of the main pathologies of AD, tau, is present in the brain decades before a clinical diagnosis. Tau pathology follows a stereotypical route through the medial temporal lobe beginning in the entorhinal and perirhinal cortices. If early pathology leads to very subtle changes in behavior, it may be possible to detect these changes in subjects years before a clinical diagnosis can currently be made. We aimed to discover if cognitively normal middle-aged adults (40-60 years old) at increased risk for AD due to family history would have impaired performance on a cognitive task known to challenge the perirhinal cortex. Using an oddity detection task, we found that subjects with a family history of AD had lowered accuracy without demonstrating differences in rate of acquisition. There were no differences between subjects' medial temporal lobe volume or cortical thickness, indicating that the changes in behavior were not due to significant atrophy. These results demonstrate that subtle changes in perceptual processing are detectable years before a typical diagnosis even when there are no differences detectable in structural imaging data. Anatomically-targeted cognitive testing may be useful in identifying subjects in the earliest stages of AD.

Motor and memory testing of long-lived pregnancy-associated plasma protein--a knock-out mice.

UNLABELLED: Mice deficient in pregnancy-associated plasma protein-A (PAPP-A), an IGF binding protein protease, have been shown to be resistant to experimentally induced atherosclerosis and diabetic nephropathy, and, in the laboratory environment, live 30-40% longer than wild-type littermates in association with delayed incidence and occurrence of age-related neoplasms and degenerative diseases. OBJECTIVE: PAPP-A is highly expressed in the cerebellum and hippocampus of the mouse brain. Therefore, the studies presented here were aimed at determining motor behavior, learning and retention in PAPP-A knock-out (KO) mice compared to wild-type (WT) littermates with age. DESIGN: Balance and coordination were assessed using an accelerating rotarod; learning and memory were assessed in a Stone T-maze. RESULTS: Time on the rotarod decreased with age but there was no significant difference between PAPP-A KO and WT mice at any of the testing ages. Latency to reach the goal box and number of errors committed in the Stone T-maze did not change with age and there were no significant differences between PAPP-A KO and WT mice. CONCLUSION: Lack of PAPP-A in mice did not impact central regulation of coordination, learning or memory.

Insulin-like growth factor (IGF)-I and IGF-II contribute differentially to the phenotype of pregnancy associated plasma protein-A knock-out mice.

CONTEXT: Insulin-like growth factor (IGF) signaling is essential for achieving optimal body size during fetal development, peak bone mass during puberty, and maximal fecundity in the reproductive period. IGF-II is considered the main fetal IGF, whereas IGF-I is more important postnatally. Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through cleavage of inhibitory IGF binding proteins. Conversely, inhibition of PAPP-A results in reduced local IGF action. Thus, PAPP-A knock-out (KO) mice are born as proportional dwarfs due to the dysregulation of IGF-II signaling during early embryogenesis that impacts body size. Relaxation of IgfII imprinting through mutation of a reciprocally imprinted downstream gene, H19, which allowed transcription of IGF-II from the normally silent maternal allele, rescued the dwarf phenotype of PAPP-A KO mice. OBJECTIVE: To determine the effect of increased IGF-II expression on postnatal phenotypes of PAPP-A KO mice. DESIGN: Young adult wild-type (WT), PAPP-A KO, H19 mutant (ΔH19/WT) and ΔH19/PAPP-A KO mice were characterized for skeletal phenotype (peripheral quantitative computed tomography at the midshaft and distal metaphysis of the femur) and reproductive phenotype (time to first litter, time between litters, pups per litter). RESULTS: Serum IGF-II levels were significantly increased in ΔH19/WT and ΔH19/PAPP-A KO mice compared to WT and PAPP-A KO mice; serum IGF-I levels were not affected by H19 mutation. PAPP-A KO mice had reductions in cortical thickness and in cortical and trabecular area, bone mineral content and bone mineral density compared to WT mice. There were no significant differences between PAPP-A KO and ΔH19/PAPP-A KO mice in any of the bone parameters. PAPP-A KO crossed with (×) PAPP-A KO had a longer time until first litter, normal time between subsequent litters, and significantly reduced number of pups per litter compared to WT×WT. ΔH19/PAPP-A KO×ΔH19/PAPP-A KO had an even longer time to first litter, but also longer time between litters. This phenotype was associated with female ΔH19/PAPP-A KO mice. Furthermore, these ΔH19/PAPP-A KO mouse mothers failed to care for their pups. CONCLUSIONS: An increase in IGF-II expression did not rescue the skeletal and reproductive deficiencies associated with reduced local IGF-I signaling in PAPP-A KO mice. In addition, the data suggest a potential new role for genomic imprinting at the IgfII/H19 locus affecting maternal behavior.

Pregnancy-associated plasma protein-A2 (PAPP-A2): tissue expression and biological consequences of gene knockout in mice.

Pregnancy-associated plasma protein-A2 (PAPP-A2) is a novel homolog of PAPP-A in the metzincin superfamily. However, compared with the accumulating data on PAPP-A, very little is known about PAPP-A2. In this study, we determined the tissue expression pattern of PAPP-A2 mRNA in wild-type (WT) mice and characterized the phenotype of mice with global PAPP-A2 deficiency. Tissues expressing PAPP-A2 in WT mice were more limited than those expressing PAPP-A. The highest PAPP-A2 mRNA expression was found in the placenta, with abundant expression in fetal, skeletal, and reproductive tissues. Heterozygous breeding produced the expected Mendelian distribution for the pappa2 gene and viable homozygous PAPP-A2 knockout (KO) mice that were normal size at birth. The most striking phenotype of the PAPP-A2 KO mouse was postnatal growth retardation. Male and female PAPP-A2 KO mice had 10 and 25-30% lower body weight, respectively, than WT littermates. Adult femur and body length were also reduced in PAPP-A2 KO mice, but without significant effects on bone mineral density. PAPP-A2 KO mice were fertile, but with compromised fecundity. PAPP-A expression was not altered to compensate for the loss of PAPP-A2 expression, and proteolysis of PAPP-A2's primary substrate, IGF-binding protein-5, was not altered in fibroblasts from PAPP-A2 KO embryos. In conclusion, tissue expression patterns and biological consequences of gene KO indicate distinct physiological roles for PAPP-A2 and PAPP-A in mice.

Modafinil and zolpidem use by emergency medicine residents.

OBJECTIVES: The objective was to assess the prevalence and patterns of modafinil and zolpidem use among emergency medicine (EM) residents and describe side effects resulting from use. METHODS: A voluntary, anonymous survey was distributed in February 2006 to EM residents nationally in the context of the national American Board of Emergency Medicine in-training examination. Data regarding frequency and timing of modafinil and zolpidem use were collected, as well as demographic information, reasons for use, side effects, and perceived dependence. RESULTS: A total of 133 of 134 residency programs distributed the surveys (99%). The response rate was 56% of the total number of EM residents who took the in-training examination (2,397/4,281). Past modafinil use was reported by 2.4% (57/2,372) of EM residents, with 66.7% (38/57) of those using modafinil having initiated their use during residency. Past zolpidem use was reported by 21.8% (516/2,367) of EM residents, with 15.3% (362/2,367) reporting use in the past year and 9.3% (221/2,367) in the past month. A total of 324 of 516 (62.8%) of zolpidem users initiated use during residency. Side effects were commonly reported by modafinil users (31.0%)-most frequent were palpitations, insomnia, agitation, and restlessness. Zolpidem users reported side effects (22.6%) including drowsiness, dizziness, headache, hallucinations, depression/mood lability, and amnesia. CONCLUSIONS: Zolpidem use is common among EM residents, with most users initiating use during residency. Modafinil use is relatively uncommon, although most residents using have also initiated use during residency. Side effects are commonly reported for both of these agents, and long-term safety remains unclear.

Substance use in emergency medicine training programs.

OBJECTIVES: To explore the prevalence of substance use among emergency medicine (EM) residents and compare to a prior study conducted in 1992. METHODS: A voluntary, anonymous survey was distributed in February 2006 to EM residents nationally in the context of the national in-service examination. Data regarding 13 substances, demographics, and perceptions of personal patterns of substance use were collected. RESULTS: A total of 133 of 134 residencies distributed the surveys (99%). The response rate was 56% of the total EM residents who took the in-service examination (2,397/4,281). The reported prevalence of most illicit drug use, including cocaine, heroin, amphetamines, and other opioids, among EM residents are low. Although residents reporting past marijuana use has declined (52.3% in 1992 to 45.0% in 2006; p < 0.001), past-year use (8.8%-11.8%; p < 0.001) and past-month use (2.5%-4.0%; p < 0.001) have increased. Alcohol use appears to be increasing, including an increase in reported daily drinkers from 3.3% to 4.9% (p < 0.001) and an increase in number of residents who indicate that their consumption of alcohol has increased during residency (from 4% to 12.6%; p < 0.001). CONCLUSIONS: Self-reported use of most street drugs remains uncommon among EM residents. Marijuana and alcohol use, however, do appear to be increasing. Educators should be aware of these trends, and this may allow them to target resources for impaired and at-risk residents.