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The E6 oncoprotein from high-risk genus alpha human papillomaviruses (α-HPVs), such as HPV 16, has been well characterized with respect to the host-cell proteins it interacts with and corresponding signaling pathways that are disrupted due to these interactions. Less is known regarding the interacting partners of E6 from the genus beta papillomaviruses (β-HPVs); however, it is generally thought that β-HPV E6 proteins do not interact with many of the proteins known to bind to α-HPV E6. Here we identify p300 as a protein that interacts directly with E6 from both α- and β-HPV types. Importantly, this association appears much stronger with β-HPV types 5 and 8-E6 than with α-HPV type 16-E6 or β-HPV type 38-E6. We demonstrate that the enhanced association between 5/8-E6 and p300 leads to p300 degradation in a proteasomal-dependent but E6AP-independent manner. Rather, 5/8-E6 inhibit the association of AKT with p300, an event necessary to ensure p300 stability within the cell. Finally, we demonstrate that the decreased p300 protein levels concomitantly affect downstream signaling events, such as the expression of differentiation markers K1, K10 and Involucrin. Together, these results demonstrate a unique way in which β-HPV E6 proteins are able to affect host-cell signaling in a manner distinct from that of the α-HPVs.

Objective:Early childhood is recognized as a critical window of rapid cognitive development. Unfortunately, many risk factors for atypical cognitive development may occur during this period, including genetic syndromes, congenital neuroanatomical malformations, pre- or perinatal injury, and neurological and medical disorders. The impact of these risk factors on cognitive functioning may not always map onto patterns typically observed in adults. Limited literature exists on the presentation of cognitive profiles within clinical populations in the preschool developmental period. The present study aimed to evaluate whether discrete a priori cognitive profiles consistent with common neurobehavioral syndromes emerge and are distinguishable on testing in early childhood in a mixed clinical sample. We also aimed to determine if there was a consistent association between known medical risk factors and resultant cognitive profiles.Participants and Methods:Participants included 163 children aged 1-5 years (M=48.5 months, SD=12.8 months) referred for neuropsychological evaluation. The sample was predominantly male (67.5%) and White (72.9%), followed by other/mixed race (11.6%), Black (9.7%), and Latino/Hispanic (5.8%). Cognitive abilities assessed included broad intellectual abilities, verbal abilities, nonverbal abilities, attention, and executive functioning. Continuous test scores were transformed into categorical ranges of performance, with scores classified as “above average,” “average,” “below average,” or “extremely low” to allow for profile classification. Theoretical clinical profiles consistent with common neurobehavioral syndromes were determined a priori by consensus among three authors (JK, AH, LM). Chi square tests of independence were conducted to compare membership across neurobehavioral diagnostic groups, clinical profile groups, and medical groups.Results:Based on cognitive data, 55.2% of the sample (n=90) was classified as Global Developmental Delay/Intellectual Disability, 19.6% (GDD/ID; n=32) was classified asLanguage Disorder, and 18.4% (n=30) was classified as Typical Cognitive Development. 4.3% (n=7) of the sample was classified as Attention-Deficit/Hyperactivity Disorder (ADHD), and 2.5% (n=4) was classified as Nondominant Hemisphere Dysfunction. As hypothesized, cognitive profile group membership was consistent with diagnostic impressions, as actual clinical diagnoses of Language Disorder, ADHD, GDD/ID, or a classification of typical cognitive development were significantly associated with theorized cognitive profile based on test performance alone (x2 (1,20) = 147.29, p < .001). Cognitive profile group membership was also significantly associated with referral source (1,28) = 62.88, p < .001) and the presence of a neurological disorder (1,4) = 14.64, p =.006).Conclusions:Findings support the presence of specific theorized cognitive profiles in preschoolers in a mixed clinical sample. Specifically, GDD/ID, Language Disorder, and typical cognitive development are discrete and consistently distinguishable cognitive profiles in this age range. Early life neurological risk factors are also significantly related to cognitive profile membership, suggesting that these factors may be useful in predicting cognitive development even in very young children. Future work is needed to examine the consistency of these profiles over time and their predictive value in estimating subsequent development, and the possibility of discriminating unique cognitive profiles for specific medical conditions in preschoolers.

BACKGROUND:Techniques for achieving hemispheric disconnection in patients with epilepsy continue to evolve. OBJECTIVE:To review the outcomes of the first 50 hemispherectomy surgeries performed by a single surgeon with an emphasis on outcomes, complications, and how these results led to changes in practice. METHODS:The first 50 hemispherectomy cases performed by the lead author were identified from a prospectively maintained database. Patient demographics, surgical details, clinical outcomes, and complications were critically reviewed. RESULTS:From 2004 to 2012, 50 patients underwent hemispherectomy surgery (mean follow-up time, 3.5 years). Modified lateral hemispherotomy became the preferred technique and was performed on 44 patients. Forty patients (80%) achieved complete seizure freedom (Engel I). Presurgical and postsurgical neuropsychological evaluations demonstrated cognitive stability. Two cases were performed for palliation only. Previous hemispherectomy surgery was associated with worsened seizure outcome (2 of 6 seizure free; P .005). The use of Avitene was associated with a higher incidence of postoperative hydrocephalus (56% vs 18%; P = .03). In modified lateral hemispherotomy patients without the use of Avitene, the incidence of hydrocephalus was 13%. Complications included infection (n = 3), incomplete disconnection requiring reoperation (n = 1), reversible ischemic neurological deficit (n = 1), and craniosynostosis (n = 1). There were no (unanticipated) permanent neurological deficits or deaths. Minor technique modifications were made in response to specific complications. CONCLUSION:The modified lateral hemispherotomy is effective and safe for both initial and revision hemispherectomy surgery. Avitene use appears to result in a greater incidence of postoperative hydrocephalus. ABBREVIATIONS:EEG, electroencephalographyFSIQ, Full Scale Intelligence QuotientMCA, middle cerebral arteryMLH, modified lateral hemispherotomy

Objective:Children with epilepsy are at greater risk of lower academic achievement than their typically developing peers (Reilly and Neville, 2015). Demographic, social, and neuropsychological factors, such as executive functioning (EF), mediate this relation. While research emphasizes the importance of EF skills for academic achievement among typically developing children (e.g., Best et al., 2011; Spiegel et al., 2021) less is known among children with epilepsy (Ng et al., 2020). The purpose of this study is to examine the influence of EF skills on academic achievement in a nationwide sample of children with epilepsy.Participants and Methods:Participants included 427 children with epilepsy (52% male; MAge= 10.71), enrolled in the Pediatric Epilepsy Research Consortium (PERC) Epilepsy Surgery Database who had been referred for surgery and underwent neuropsychological testing. Academic achievement was assessed by performance measures (word reading, reading comprehension, spelling, and calculation and word-based mathematics) and parent-rating measures (Adaptive Behavior Assessment System (ABAS) Functional Academics and Child Behavior Checklist (CBCL) School Performance). EF was assessed by verbal fluency measures, sequencing, and planning measures from the Delis Kaplan Executive Function System (DKEFS), NEPSY, and Tower of London test. Rating-based measures of EF included the 'Attention Problems’ subscale from the CBCL and 'Cognitive Regulation’ index from the Behavior Rating Inventory of Executive Function (BRIEF-2). Partial correlations assessed associations between EF predictors and academic achievement, controlling for fullscale IQ (FSIQ; A composite across intelligence tests). Significant predictors of each academic skill or rating were entered into a two-step regression that included FSIQ, demographics, and seizure variables (age of onset, current medications) in the first step with EF predictors in the second step.Results:Although zero-order correlations were significant between EF predictors and academic achievement (.29 < r’s < .63 for performance; -.63 < r’s < -.50 for rating measures), partial correlations controlling for FSIQ showed fewer significant relations. For performance-based EF, only letter fluency (DKEFS Letter Fluency) and cognitive flexibility (DKEFS Trails Condition 4) demonstrated significant associations with performance-based academic achievement (r’s > .29). Regression models for performance-based academic achievement indicated that letter fluency (ß = .22, p = .017) and CBCL attention problems (ß = -.21, p =.002) were significant predictors of sight-word reading. Only letter fluency (ß = .23, p =.006) was significant for math calculation. CBCL Attention Problems were a significant predictor of spelling performance (ß = -.21, p = .009) and reading comprehension (ß = -.18, p =.039). CBCL Attention Problems (ß = -.38, p <.001 for ABAS; ß = -.34, p =.002 for CBCL School) and BRIEF-2 Cognitive Regulation difficulties (ß = -.46, p < .001 for ABAS; ß = -.46, p =.013 for CBCL School) were significant predictors of parent-rated ABAS Functional Academics and CBCL School Performance.Conclusions:Among a national pediatric epilepsy dataset, performance-based and ratings-based measures of EF predicted performance academic achievement, whereas only ratings-based EF predicted parent-rated academic achievement, due at least in part to shared method variance. These findings suggest that interventions that increase cognitive regulation, reduce symptoms of attention dysfunction, and promote self-generative, flexible thinking, may promote academic achievement among children with epilepsy.

Objective:The COVID-19 pandemic significantly disrupted schools and learning formats. Children with epilepsy are at-risk for generalized academic difficulties. We investigated the potential impact of COVID-19 on learning in those with epilepsy by comparing achievement on well-established academic measures among school-age children with epilepsy referred prior to the COVID-19 pandemic and those referred during the COVID-19 pandemic.Participants and Methods:This study included 466 children [52% male, predominately White (76%), MAge=10.75 years] enrolled in the Pediatric Epilepsy Research Consortium Epilepsy (PERC) Surgery database project who were referred for surgery and seen for neuropsychological testing. Patients were divided into two groups based on a proxy measure of pandemic timing completed by PERC research staff at each site (i.e., “were there any changes to typical in-person administration [of the evaluation] due to COVID?”). 31% of the sample (N = 144) were identified as having testing during the pandemic (i.e., “yes” response), while 69% were identified as having testing done pre-pandemic (i.e., “no” response). Of the 31% who answered yes, 99% of administration changes pertained to in-person testing or other changes, with 1% indicating remote testing. Academic achievement was assessed by performance measures (i.e., word reading, reading comprehension, spelling, math calculations, and math word problems) across several different tests. T-tests compared the two groups on each academic domain. Subsequent analyses examined potential differences in academic achievement among age cohorts that approximately matched grade level [i.e., grade school (ages 5-10), middle school (ages 11-14), and high school (ages 15-18)].Results:No significant differences were found between children who underwent an evaluation before the pandemic compared to those assessed during the pandemic based on age norms across academic achievement subtests (all p’s > .34). Similarly, there were no significant differences among age cohorts. The average performance for each age cohort generally fell in the low average range across academic skills. Performance inconsistently varied between age cohorts. The youngest cohort (ages 5-10) scored lower than the other cohorts for sight-word reading, whereas this cohort scored higher than the middle cohort (ages 11-14) for math word problems and reading comprehension. There were no significant differences between the two pandemic groups on demographic variables, intellectual functioning, or epilepsy variables (i.e., age of onset, number of seizure medications, seizure frequency).Conclusions:Academic functioning was generally equivalent between children with epilepsy who underwent academic testing as part of a pre-surgical evaluation prior to the pandemic compared to those who received testing during the pandemic. Additionally, academic functioning did not significantly differ between age cohorts. Children with epilepsy may have entered the pandemic with effective academic supports and/or were accustomed to school disruptions given their seizure history. Replication is needed as findings are based on a proxy measure of pandemic timing and the extent to which children experienced in-person, remote, and hybrid learning is unknown. Children tested a year into the pandemic, after receiving instruction through varying educational methods, may score differently than those tested earlier. Future research can address these gaps. Although it is encouraging that academic functioning was not disproportionately impacted during the pandemic in this sample, children with epilepsy are at-risk for generalized academic difficulties and continued monitoring of academic functioning is necessary.

Adolescents with spina bifida (SB) vary in their ability to adapt to the disease, and it is likely that numerous risk and protective factors affect adaptation outcomes. The primary aim was to test neuropsychological impairment, exemplified herein by executive dysfunction, as a risk factor in the Ecological Model of Adaptation for Adolescents with SB. Specific hypotheses were that: (1) executive functioning predicts the adaptation outcome of functional independence in adolescents with SB; (2) executive functioning mediates the impact of neurological severity on functional independence; and (3) family and adolescent protective factors are related to functional independence and moderate the relationship between executive functioning and functional independence. Forty-three adolescents aged 12–21 years completed neuropsychological measures and an interview that assessed risk, adolescent and family protective factors, and functional independence. Age, level of lesion, executive functioning, and the protective factor adolescent activities were significantly correlated with the functional independence outcome. In hierarchical regression analysis, the model accounted for 61% of the variance in functional independence outcomes. Executive functioning mediated the impact of neurological severity on functional independence. (JINS, 2008, 14, 793–804.)

Exogenous expression of hTERT, the catalytic component of telomerase, is sufficient for the immortalization of human fibroblasts but insufficient for the immortalization of human foreskin keratinocytes (HFKs) and human mammary epithelial cells (HMECs). These latter cell types can overcome senescence by coexpression of hTERT and human papillomavirus (HPV) E7 or by expression of hTERT and loss of p16 INK4a expression, indicating that the retinoblastoma (Rb. pathway, along with a telomere maintenance pathway, plays a role in determining the life span of epithelial cells. In this study, we further characterize hTERT-immortalized HFKs and human adenoid epithelial cells (HAKs) for genotypic and phenotypic alterations that are associated with immortalization. Of five hTERT-immortalized HFK and HAK cell lines examined, four exhibited repression of p16 INK4a expression by promoter methylation or specific large-scale deletion of chromosome 9p, the location of p16 INK4a. Interestingly, one cell line exhibited complete down-regulation of expression of p14 ARF, with only slight down-regulation of expression of p16 INK4a. Yet, all of the immortal cells lines exhibited hyperphosphorylated Rb. Cytogenetic analysis revealed clonal chromosome aberrations in three of the five cell lines. All of the cell lines retained a growth block response with the expression of mutant ras. When grown on organotypic raft cultures, however, the hTERT-immortalized cells exhibited a maturation delay on terminal differentiation. Our results indicate that immortalization of epithelial cells may require both activation of telomerase and other genetic and/or epigenetic alterations that abrogate normal differentiation.

Progression to advanced-stage cervical carcinomas is characterized by a recurrent pattern of chromosomal rearrangements. Structural chromosome rearrangements are generated through the fusion of broken chromosome ends. These chromosome breaks may be induced by mutagenic agents such as ionizing radiation, or chromosome ends may be exposed through extensive telomere shortening. The human papilloma virus oncogene 16E6 induces telomerase activity in human keratinocytes, a model system for cervical tumor formation. The present study explores the relationship between 16E6 expression, telomerase activity, and chromosomal instability. We show that the frequency of anaphase bridges is dependent on the level of telomerase activity in 16E6/E7-expressing clones, and is the result of telomere shortening. High frequencies of anaphase bridges, associated with low telomerase activity, correlate with increased chromosome instability. Anaphase bridge formation is also associated with the presence of micronuclei, which are shown to contain unstable chromosomes frequently involved in rearrangements. As anaphase bridges are observed in both high and low telomerase 16E6/E7 clones, but not in hTERT-expressing control clones, expression of 16E6 in these immortalized clones is not sufficient to stabilize shortened telomeres completely. We suggest a model in which HPV-induced tumorigenesis may be dependent on persistent bridge–breakage–fusion cycles that allow for continued genomic rearrangements.

Objective:Individuals with Spina Bifida (SB) are at increased risk for difficulties with various aspects of adaptive functioning. Poorer adaptive functioning could delay or prevent an individual from successfully living independently and managing their own condition. Despite the importance of understanding adaptive functioning in SB, currently the literature on predictors of and associated neurocognitive skills with adaptive functioning is sparse. Thus, this retrospective chart review study aimed to explore the extent to which intellectual functioning, predicts adaptive functioning in a clinical sample of children with SB.Participants and Methods:A retrospective chart review of children with SB was conducted at a Midwestern academic medical center. Children were seen in the context of routine neuropsychological evaluations to identify neuropsychological diagnoses and provide treatment recommendations. All measures were administered based on the age of the child and in accordance with administration guidelines. Only children with complete data were included in analyses. The sample included 42 participants (Mage=10.89, SDage=3.15; 18 male, 24 female). Intellectual functioning was evaluated using either the Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V) or Wechsler Intelligence Scale for Children—Fourth Edition (WISC-IV). Adaptive functioning was evaluated using primary caregiver-report scores from the Adaptive Behavior Assessment System - Third Edition (ABAS-3). Hierarchical regressions were conducted to investigate the extent to which intellectual functioning predicts parent-reported adaptive functioning. The unique contribution of each predictor variable was also considered.Results:Model predictors included participant sex, verbal comprehension, working memory, processing speed, and full scale IQ to predict 4 different indices on the ABAS-3. Results showed a significant contribution of participant sex in all models, with males having been rated as having poorer adaptive skills. Intellectual functioning did not significantly contribute to the models. Semipartial correlations revealed that processing speed and working memory often each accounted for a fair amount of variability when controlling for all of the remaining variables in the models. In particular, when accounting for all of the remaining variables, processing speed accounted for 6.3% of variability in global adaptive functioning, 6.1% in Conceptual Skills, and 10.11% in Social Skills. Furthermore, after controlling for all of the other variables, working memory accounted for 4.5% of the variability in global adaptive functioning.Conclusions:The present results suggest that males with SB are at increased risk for poorer adaptive functioning, and there may be some preliminary evidence of processing speed and working memory playing contributory roles as well. This may suggest at least in childhood, the verbal and global cognitive capacities of individuals with SB are not as contributory to adaptive functioning as more basic cognitive skills, such as processing speed and working memory. It is recommended that males with SB in particular should be closely monitored with regard to their development of adaptive skills, as they may be at risk of poorer adaptive abilities. Additionally, our findings provide preliminary evidence of processing speed and working memory impacting adaptive functioning. Thus, interventions and accommodations targeting both of these domains may be appropriate to implement to help with poorer adaptive skills in this population.

Despite growing interest in assessment of program implementation, little is known about the best way to evaluate whether a particular program has implemented the intended service to a level that is minimally acceptable to a funding source, such as a state mental health authority. Such is the case for assertive community treatment (ACT), an evidence-based practice being widely disseminated. Using an exploratory, actuarial approach to defining program standards, this study applies different statistical criteria for determining whether or not a program meets ACT standards using the 28-item Dartmouth Assertive Community Treatment Scale. The sample consists of 51 ACT programs, 25 intensive case management programs, and 11 brokered case management programs which were compared to identify levels of fidelity that discriminated between programs, but were still attainable by the majority of ACT programs. A grading system based on mean total score for a reduced set of 21 items appeared to be most attainable, but still discriminated ACT programs from other forms of case management. Implications for setting and evaluating ACT program standards are discussed.