Detecting and Quantifying pADPr In Vivo.

Poly(ADP-ribose) polymerases (PARP) participate in diverse biological processes contributing to cellular homeostasis or exacerbating injury. PARP catalyzes the addition of ADP-ribose molecules (pADPr) to the target proteins, a process termed poly-ADP-ribosylation. Overactivation of PARP - reflected by increased poly-ADP-ribosylation and accumulation of pADPr-modified proteins or free pADPr - contributes to depletion of NAD+ and mitochondrial dysfunction, potentially leading to cell death. Thus, PARP overactivation and increases in free pADPr have been identified as key contributors to the pathobiology of many diseases. In stark contrast, PARP inhibitors are in clinical use in cancer patients where they potentiate cell death induced by chemotherapeutic agents. Accordingly, monitoring PARP-1 activation - responsible for up to 80-90% of cellular pADPr synthesis - by detecting and quantifying pADPr may provide valuable mechanistic insights as well as facilitating therapeutic drug monitoring for PARP inhibitors.Several non-isotopic immunodetection methods for quantifying pADPr are discussed: Western blotting of poly-ADP-ribosylated proteins, cellular localization of pADPr by immunohistochemistry, quantification of pADPr by enzyme-linked immunoassay, and small-scale two-dimensional gel electrophoresis.

Addressing the Challenge of COVID-19: One Health Care Site's Leadership Response to the Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic created an extremely disruptive challenge for health care leaders that required a rapid, dynamic, and innovative response. The purpose of this manuscript is to share the leadership actions and decisions at Mayo Clinic in Florida during the first 6 months of the pandemic (February to July 2020). We note 4 strategies that contributed to an effective response: (1) leverage experience with disaster preparedness and mobilize regional and national networks; (2) use surge models to anticipate and to address supply chain issues as well as practical and financial effects of the pandemic; (3) adapt creatively to establish new safety and procedural protocols in various areas for various populations; and (4) communicate timely information effectively and be the common source of truth. Mayo Clinic in Florida was able to address the surges of patients with COVID-19, to provide ongoing tertiary care, and to restore function within the first 6 months with new, strengthened practices and protocols.

Oral narratives in monolingual and bilingual preschoolers with SLI.

BACKGROUND: The body of literature on narratives of bilingual children with and without specific language impairment (SLI) is growing. However, little is known about the narrative abilities of bilingual preschool children with SLI and their patterns of growth. AIMS: To determine the similarities and differences in narrative abilities between preschoolers with and without SLI who are either monolingual or bilingual at two time points. METHODS & PROCEDURES: Forty children completed a narrative retell task in English at two test points. The mean ages were 52 and 58 months at Times 1 and 2, respectively. We examined performance on measures of narrative macrostructure (narrative information) and microstructure (sentence length, number of different words, verb accuracy, first mentions) in monolingual and bilingual children with and without SLI. The bilingual children were from diverse first-language backgrounds and all spoke English most of the time. OUTCOMES & RESULTS: A series of repeated-measures analyses of variance was used with language ability (typical development or SLI) and bilingual status (monolingual versus bilingual) as the between-subjects factors and time (Times 1 or 2) as the within-subjects factor. Results indicated a significant main effect of time for four measures (i.e., Information Score, lexical diversity, sentence length and verb accuracy). The between-subjects analyses indicated a significant difference between the typically developing children and the children with SLI in all measures and a significant difference between monolingual and bilingual children for verb accuracy only. CONCLUSIONS & IMPLICATIONS: This study showed that all four groups of children showed growth over a 6-month period and that bilingual children exposed predominantly to English in the home performed similarly to their monolingual peers in measures of narrative information, sentence length, number of different words and first mentions.

Narrative abilities in monolingual and dual language learning children with specific language impairment.

PURPOSE: The aim of this study was to compare narrative abilities in children with specific language impairment (SLI) who are monolingual and those who are dual language learners. METHOD: The participants were 26 children with SLI, 14 monolingual English speakers and 12 dual language learners. The dual language learners were English dominant and spoke a variety of other languages in the home. The two SLI groups were compared using standardized tests and measures from two narrative samples. RESULTS: Compared to the monolingual children, the dual language learners achieved lower scores on standardized tests of morphosyntax but not on measures of language form derived from the narrative samples. Both groups achieved below average scores on productivity, narrative structure, literate language, and language form measures from the narrative samples. CONCLUSION: The data suggest that narrative samples can be a sensitive way to assess the language skills of dual language learners with specific language impairment. Furthermore, the findings are consistent with the position that English standardized tests may be a biased assessment measure when used with dual language learners, particularly for the assessment of expressive morphosyntactic skills. LEARNING OUTCOMES: Readers will be able to (1) describe the narrative abilities of typically developing dual language learners; (2) describe similarities between the narrative abilities of children with SLI who are monolingual and dual language learners; (3) identify ways to analyses narratives at a variety of levels.

The contribution of processing impairments to SLI: insights from attention-deficit/hyperactivity disorder.

UNLABELLED: Slowed speed of processing and impaired rapid temporal processing (RTP) have been proposed to underlie specific language impairment (SLI), but it is not clear that these dysfunctions are unique to SLI. We considered the contribution of attention-deficit/hyperactivity disorder (ADHD), which frequently co-occurs with language impairments, to performances on processing tasks. School-aged children who had SLI without concurrent ADHD (n=14), ADHD without concurrent SLI (n=14), and typical development (TD, n=28) performed two nonverbal speeded tasks and one auditory RTP task. RTP impairments were found in many children with SLI and ADHD, and some children with TD. Children with ADHD demonstrated slower processing speed than children with SLI or TD. Overall, findings questioned the uniqueness of these processing dysfunctions to language impairments and the validity of the behavioural paradigms traditionally used to estimate processing dysfunctions. Accounts of SLI should be further scrutinized by considering the influence of other disorders. LEARNING OUTCOMES: Readers will (1) become familiar with areas of overlap between SLI and ADHD, (2) understand some of the confounds associated with behavioural measures of processing speed in children, and (3) recognize the value in testing models of language disorders by including participants with other types of disorders.

Twenty-year follow-up of children with and without speech-language impairments: family, educational, occupational, and quality of life outcomes.

PURPOSE: Parents, professionals, and policy makers need information on the long-term prognosis for children with communication disorders. Our primary purpose in this report was to help fill this gap by profiling the family, educational, occupational, and quality of life outcomes of young adults at 25 years of age (N = 244) from the Ottawa Language Study, a 20-year, prospective, longitudinal study of a community sample of individuals with (n = 112) and without (n = 132) a history of early speech and/or language impairments. A secondary purpose of this report was to use data from earlier phases of the study to predict important, real-life outcomes at age 25. METHOD: Participants were initially identified at age 5 and subsequently followed at 12, 19, and 25 years of age. Direct assessments were conducted at all 4 time periods in multiple domains (demographic, communicative, cognitive, academic, behavioral, and psychosocial). RESULTS: At age 25, young adults with a history of language impairments showed poorer outcomes in multiple objective domains (communication, cognitive/academic, educational attainment, and occupational status) than their peers without early communication impairments and those with early speech-only impairments. However, those with language impairments did not differ in subjective perceptions of their quality of life from those in the other 2 groups. Objective outcomes at age 25 were predicted differentially by various combinations of multiple, interrelated risk factors, including poor language and reading skills, low family socioeconomic status, low performance IQ, and child behavior problems. Subjective well-being, however, was primarily associated with strong social networks of family, friends, and others. CONCLUSION: This information on the natural history of communication disorders may be useful in answering parents' questions, anticipating challenges that children with language disorders might encounter, and planning services to address those issues.

The Met protooncogene is a transcriptional target of NF kappaB: implications for cell survival.

NF kappaB transcription factor regulates gene expression in response to extracellular stimuli such as TNF alpha. The genes regulated by NF kappaB encode for proteins which control cell growth and survival. Met is the tyrosine kinase receptor for hepatocyte growth factor, and it too promotes cell mitogenesis and survival. Previously, we showed that Met gene expression is regulated by TNF alpha. In this report, we identify and characterize a TNF alpha response element in the Met promoter. This element contains tandem C/EBP sites adjacent to an NF kappaB site. Binding of the NF kappaB p65 subunit and C/EBP beta to this element is induced by TNF alpha. To examine the interplay of NF kappaB and Met in vivo, we determined that Met mRNA and protein levels are reduced in the livers of p65-/- mice as compared to controls. In p65-/- mouse embryonic fibroblasts (MEFs), Met induction by TNF alpha is abrogated while Met's basal gene expression is reduced by half as compared to controls. When overexpressed in p65-/- MEFs, Met confers resistance to TNF-alpha-mediated cell death. Conversely, expression of dominant negative Met in wild-type MEFs renders them sensitive to cell death induced by TNF alpha. A similar response following TNF alpha challenge was observed in hepatocytic cells treated with siRNA to knockdown endogenous Met. Together, these results indicate that the Met gene is a direct target of NF kappaB and that Met participates in NF kappaB-mediated cell survival.

Emerging adult outcomes of adolescent psychiatric and substance use disorders.

This study investigates the age 25 outcomes of late adolescent mental health and substance use disorders. A hierarchical cluster analysis of age 19 DSM-III-R mental health and substance diagnoses placed participants into one of 9 clusters: Anxious, Depressed, Antisocial, Drug Abuser, Problem Drinker, Anxious Drinker, Depressed Drug Abuser and Antisocial Drinker, and No Diagnosis. Diagnoses were generated from the University of Michigan Composite International Diagnostic Interview. Repeated measures multivariate analyses of variance revealed distinct trajectories of improvement and decline among the 9 clusters. Clusters with co-occurring substance and mental health disorders improved over adolescent levels, but continued to have higher levels of depression symptoms, poorer global functioning, and higher levels of substance use than the No Diagnosis cluster. Members of the The Problem Drinkers cluster, who tended to have alcohol use disorders only at age 19, did not differ from their peers with no diagnoses. Drug use disorders in adolescence, with or without a co-occurring mental health disorders, were associated with a poor prognosis in emerging adulthood. Clinical interventions should distinguish among these diverse clinical presentations.

Models and determinants of vocabulary growth from kindergarten to adulthood.

BACKGROUND: Increasing evidence suggests that childhood language problems persist into early adulthood. Nevertheless, little is known about how individual and environmental characteristics influence the language growth of individuals identified with speech/language problems. METHOD: Individual growth curve models were utilised to examine how speech/language impairment and environmental variables (socioeconomic status, family separation, and maternal factors) influence vocabulary development from age 5 to 25. Participants were taken from a community sample of children initially diagnosed with speech/language problems at age 5 and their sex- and age-matched controls. RESULTS: The language impaired group had significantly poorer receptive vocabulary than the speech impaired and control groups throughout the 20-year period. Family income was a significant predictor of vocabulary growth when considered separately, but ceased to be a predictor when language impairment status was taken into account. Maternal education and family separation were determinants of vocabulary at age 5, over and above language impairment status. CONCLUSION: Language impairment is a significant risk factor for vocabulary development from childhood to adulthood. Individuals with speech impairment were less impaired on receptive vocabulary than individuals with language impairment. Further investigation into maternal and familial risk factors may provide targets for early intervention with children at risk for language impairment.

Lack of Fas antagonism by Met in human fatty liver disease.

Hepatocytes in fatty livers are hypersensitive to apoptosis and undergo escalated apoptotic activity via death receptor-mediated pathways, particularly that of Fas-FasL, causing hepatic injury that can eventually proceed to cirrhosis and end-stage liver disease. Here we report that the hepatocyte growth factor receptor, Met, plays an important part in preventing Fas-mediated apoptosis of hepatocytes by sequestering Fas. We also show that Fas antagonism by Met is abrogated in human fatty liver disease (FLD). Through structure-function studies, we found that a YLGA amino-acid motif located near the extracellular N terminus of the Met alpha-subunit is necessary and sufficient to specifically bind the extracellular portion of Fas and to act as a potent FasL antagonist and inhibitor of Fas trimerization. Using mouse models of FLD, we show that synthetic YLGA peptide tempers hepatocyte apoptosis and liver damage and therefore has therapeutic potential.

Getting started in evidence-based practice for childhood speech-language disorders.

PURPOSE: Evidence-based practice (EBP) entails a critical mindset and rigorous methods that foster the judicious integration of scientific evidence into clinical decision making. The purpose of this tutorial is to present strategies, resources, and examples to help speech-language pathologists get started in EBP for childhood speech and language disorders. METHOD: The tutorial begins with an overview of key principles of EBP, including potential benefits and challenges, and other initial considerations. Five recommended steps for implementing EBP are then presented: posing a question, locating the evidence, appraising the evidence, making and implementing clinical decisions, and evaluating those decisions. Included is a compilation of synthesized evidence resources, such as systematic reviews/meta-analyses and EBP guidelines. Finally, illustrative examples are provided to assist practitioners with integrating research evidence into clinical decision making in childhood speech-language disorders. CONCLUSIONS: Speech-language pathologists who work with children are encouraged to adopt EBP for clinical decision making.

The role of phonological recoding in orthographic learning.

The objective of this research was to explore whether orthographic learning occurs as a result of phonological recoding, as expected from the self-teaching hypothesis. The participants were 32 fourth- and fifth-graders (mean age = 10 years 0 months, SD = 7 months) who performed lexical decisions for monosyllabic real words and pseudowords under two matched experimental conditions: a read aloud condition, wherein items were named prior to lexical decision to promote phonological recoding, and a concurrent articulation condition, presumed to attenuate phonological recoding. Later, orthographic learning of the pseudowords was evaluated using orthographic choice, spelling, and naming tasks. Consistent with the self-teaching hypothesis, targets learned with phonological recoding in the read aloud condition yielded greater orthographic learning than those learned with concurrent articulation. The research confirms the critical nature of phonological recoding in the development of visual word recognition skills and an orthographic lexicon.

Single-word and conversational measures of word-finding proficiency.

Two studies with young adults as participants evaluated the relationship, presumed in the word-finding literature to exist, between slow, inaccurate performances in single-word-naming and semantic-retrieval tasks and disruptions to conversational fluency. The measures evaluated were the frequency of conversational disruptions and the scores from 3 single-word tasks: total time from the Rapid Automatized Naming task (RAN; M. B. Denckla and R. G. Rudel, 1976), standard score from the Brief Test of the Test of Adolescent/Adult Word Finding (TAWF; D. J. German, 1990), and total unique words from the Controlled Oral Word Association task (FAS; A. L. Benton and K. Hamsher, 1978). RAN time was the only significant predictor of the frequency of conversational disruptions, although this relationship was weak (R(2) =.11). In addition, single-word performances did not discriminate between groups of participants with differing levels of conversational fluency. Clinicians are cautioned against identifying word-finding deficits using single-word measures alone. Moreover, the theoretical construct of word-finding difficulties requires additional validation.

Partner Influences on the Social Pretend Play of Children With Language Impairments.

PURPOSE: This study examined the social pretend play and conversational behaviors of children with language impairment (LI) in dyadic interactions with peers. METHOD: The participants (aged 4;3 [years;months] to 6;2) were 3 boys with LI and 4 with typical language development (LN). In this multiple embedded case study, hypotheses regarding the sophistication of verbal interaction and social pretend play were developed and tested with respect to two cases. Each case consisted of five interactions-four involving a child with LI in dyadic play with peers (2 LI, 2 LN), and the last involving the 2 LN peers. The dyad types for each case were LI, mixed, and LN. Within each case, LI dyads were expected to perform less well than mixed dyads, who were, in turn, expected to perform less well than the LN dyad on measures of verbal interaction and social pretend play. Also, greater conversational success was expected in social pretend play than in other forms of play for all dyads. RESULTS: For both cases, the results for verbal sophistication generally conformed to expectations for the dyad types. In contrast, social pretend play behaviors were inconsistent with expectations across dyads and cases. In all dyads, social pretend play yielded greater conversational success than other forms of play. The quality of play varied as a function of partner characteristics, such as responsiveness, theme knowledge, verbal skill, and adaptability. CLINICAL IMPLICATIONS: Clinicians are cautioned to ensure that evaluations of play in children with LI encompass multiple aspects of both play and conversation, as well as observation of children with multiple partners. Likewise, in planning interventions, it may be important to address both play and verbal behaviors and to incorporate opportunities for interaction with multiple partners.