RESUMO
A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2-4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.
Assuntos
Esclerose Lateral Amiotrófica , Demência Frontotemporal , Esclerose Lateral Amiotrófica/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Éxons/genética , Demência Frontotemporal/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Neurônios Motores/patologia , Proteínas do Tecido NervosoRESUMO
A major function of TAR DNA-binding protein-43 (TDP-43) is to repress the inclusion of cryptic exons during RNA splicing. One of these cryptic exons is in UNC13A, a genetic risk factor for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of cryptic UNC13A in disease is heightened by the presence of a risk haplotype located within the cryptic exon itself. Here, we revealed that TDP-43 extreme N-terminus is important to repress UNC13A cryptic exon inclusion. Further, we found hnRNP L, hnRNP A1, and hnRNP A2B1 bind UNC13A RNA and repress cryptic exon inclusion, independently of TDP-43. Finally, higher levels of hnRNP L protein associate with lower burden of UNC13A cryptic RNA in ALS/FTD brains. Our findings suggest that while TDP-43 is the main repressor of UNC13A cryptic exon inclusion, other hnRNPs contribute to its regulation and may potentially function as disease modifiers.
Assuntos
Esclerose Lateral Amiotrófica , Demência Frontotemporal , Ribonucleoproteínas Nucleares Heterogêneas Grupo L , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Éxons/genética , Demência Frontotemporal/genética , Ribonucleoproteínas Nucleares Heterogêneas/genética , RNA , Proteínas do Tecido Nervoso/metabolismoRESUMO
[This corrects the article DOI: 10.1371/journal.pbio.3002028.].
RESUMO
A GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), while a CGG trinucleotide repeat expansion in FMR1 leads to the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). These GC-rich repeats form RNA secondary structures that support repeat-associated non-AUG (RAN) translation of toxic proteins that contribute to disease pathogenesis. Here we assessed whether these same repeats might trigger stalling and interfere with translational elongation. We find that depletion of ribosome-associated quality control (RQC) factors NEMF, LTN1 and ANKZF1 markedly boost RAN translation product accumulation from both G4C2 and CGG repeats while overexpression of these factors reduces RAN production in both reporter assays and C9ALS/FTD patient iPSC-derived neurons. We also detected partially made products from both G4C2 and CGG repeats whose abundance increased with RQC factor depletion. Repeat RNA sequence, rather than amino acid content, is central to the impact of RQC factor depletion on RAN translation-suggesting a role for RNA secondary structure in these processes. Together, these findings suggest that ribosomal stalling and RQC pathway activation during RAN translation inhibits the generation of toxic RAN products. We propose augmenting RQC activity as a therapeutic strategy in GC-rich repeat expansion disorders.
Assuntos
Esclerose Lateral Amiotrófica , Proteína C9orf72 , Demência Frontotemporal , Biossíntese de Proteínas , Proteínas Ribossômicas , Expansão das Repetições de Trinucleotídeos , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Ataxia , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Expansão das Repetições de DNA/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Sequência Rica em GC , Células HEK293 , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Ribossomos/metabolismo , Ribossomos/genética , Tremor , Expansão das Repetições de Trinucleotídeos/genética , Proteínas Ribossômicas/metabolismoRESUMO
Hexanucleotide G4C2 repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G4C2 repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72450 mice. However, chronic administration of anti-GA antibodies in AAV-(G4C2)149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.
Assuntos
Genes Reguladores , Poli A , Animais , Humanos , Camundongos , Complexo Antígeno-Anticorpo , Proteína C9orf72/genética , Dipeptídeos , Modelos Animais de DoençasRESUMO
COVID-19 lockdown and social distancing measures have restricted funerals and memorial events and have limited the face-to-face social networks that grieving people might normally be able to draw upon for emotional support. However, while there is considerable expert informed speculation about the impacts of grief and "COVID bereavement", detailed accounts of experiences of bereavement and bereavement support during the pandemic have the potential to enrich and provide nuance and subtlety to the evidence base. This paper draws on diary accounts of bereavement support volunteers in the UK, who have been providing support for the bereaved through these challenging times. These reveal layers of complexity to the experiences of loss, grief and bereavement during these extraordinary times. However, they also point to a number of additional themes that lend a more positive valence to the suspension of normal social expectations and memorial practices associated with the pandemic, which, we argue should be reflected upon for their potential to address the discontents of contemporary governance of end of life and bereavement.
RESUMO
BACKGROUND AND PURPOSE: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures. METHODS: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels. RESULTS: Plasma t-tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non-Ataxia Signs was associated with t-tau in ataxic patients (p = 0.004). Pre-ataxic carriers showed higher cerebrospinal fluid t-tau and p-tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t-tau was elevated in MJDTg mice compared to wild-type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001). CONCLUSION: Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.
Assuntos
Doença de Machado-Joseph , Proteínas de Neurofilamentos , Proteínas tau , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Cerebelo/química , Heterozigoto , Humanos , Doença de Machado-Joseph/sangue , Doença de Machado-Joseph/líquido cefalorraquidiano , Doença de Machado-Joseph/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genéticaRESUMO
Nursing informatics competencies are vital to benefit from information technologies to improve patient outcomes. It is essential to use a reliable and valid instrument for evaluating competencies. The Technology Informatics Guiding Educational Reform-Based Assessment of Nursing Informatics Competencies Tool is a valid and reliable tool used to evaluate nursing informatics competencies in nurses who primarily speak English. This cross-sectional research aimed to evaluate the psychometric properties of a Turkish version of the instrument. Data were collected from 518 nurses working in two university hospitals in Istanbul, Turkey. The tool was translated into Turkish, validated by professional experts, back-translated, and analyzed. Thirty nurses completed the tool twice for test-retest reliability. A four-factor structure identified in exploratory factor analysis (73.64% of the total variance with all items loaded >0.40 [0.44-0.88] for each factor). Cronbach's α reliability coefficients of the subsets were .98 for basic computer skills, .97 for clinical information management, and .98 for information literacy. The total item correlations for subsets were between 0.57 and 0.84. The Turkish version of the Technology Informatics Guiding Educational Reform-Based Assessment of Nursing Informatics Competencies demonstrated sufficient reliability and validity for assessing nursing informatics competencies within Turkish culture.
Assuntos
Tecnologia da Informação , Informática em Enfermagem , Competência Profissional , Psicometria/estatística & dados numéricos , Tradução , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Inquéritos e Questionários , TurquiaRESUMO
Significant transcriptome alterations are detected in the brain of patients with amyotrophic lateral sclerosis (ALS), including carriers of the C9orf72 repeat expansion and C9orf72-negative sporadic cases. Recently, the expression of repetitive element transcripts has been associated with toxicity and, while increased repetitive element expression has been observed in several neurodegenerative diseases, little is known about their contribution to ALS. To assess whether aberrant expression of repetitive element sequences are observed in ALS, we analysed RNA sequencing data from C9orf72-positive and sporadic ALS cases, as well as healthy controls. Transcripts from multiple classes and subclasses of repetitive elements (LINEs, endogenous retroviruses, DNA transposons, simple repeats, etc.) were significantly increased in the frontal cortex of C9orf72 ALS patients. A large collection of patient samples, representing both C9orf72 positive and negative ALS, ALS/FTLD, and FTLD cases, was used to validate the levels of several repetitive element transcripts. These analyses confirmed that repetitive element expression was significantly increased in C9orf72-positive compared to C9orf72-negative or control cases. While previous studies suggest an important link between TDP-43 and repetitive element biology, our data indicate that TDP-43 pathology alone is insufficient to account for the observed changes in repetitive elements in ALS/FTLD. Instead, we found that repetitive element expression positively correlated with RNA polymerase II activity in postmortem brain, and pharmacologic modulation of RNA polymerase II activity altered repetitive element expression in vitro. We conclude that increased RNA polymerase II activity in ALS/FTLD may lead to increased repetitive element transcript expression, a novel pathological feature of ALS/FTLD.
Assuntos
Proteína C9orf72/genética , Idoso , Esclerose Lateral Amiotrófica/genética , Autopsia , Encéfalo/metabolismo , Proteína C9orf72/metabolismo , Estudos de Casos e Controles , Expansão das Repetições de DNA/genética , Feminino , Lobo Frontal/metabolismo , Degeneração Lobar Frontotemporal/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Doenças Neurodegenerativas/genética , RNA Polimerase II , Sequências Repetitivas de Ácido Nucleico/genética , Análise de Sequência de RNA , Ativação TranscricionalRESUMO
The aggregation and mislocalization of RNA-binding proteins leads to the aberrant regulation of RNA metabolism and is a key feature of many neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. However, the pathological consequences of abnormal deposition of TDP-43 and other RNA-binding proteins remain unclear, as the specific molecular events that drive neurodegeneration have been difficult to identify and continue to be elusive. Here, we provide novel insight into the complexity of the RNA-binding protein network by demonstrating that the inclusion of exon 17b in the SORT1 mRNA, a pathologically relevant splicing event known to be regulated by TDP-43, is also considerably affected by additional RNA-binding proteins, such as hnRNP L, PTB/nPTB and hnRNP A1/A2. Most importantly, the expression of hnRNP A1/A2 and PTB/nPTB is significantly altered in patients with frontotemporal dementia with TDP-43-positive inclusions (FTLD-TDP), indicating that perturbations in RNA metabolism and processing in FTLD-TDP are not exclusively driven by a loss of TDP-43 function. These results also suggest that a comprehensive assessment of the RNA-binding protein network will dramatically advance our current understanding of the role of TDP-43 in disease pathogenesis, as well as enhance both diagnostic and therapeutic capabilities.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Processamento Alternativo , Proteínas de Ligação a DNA/genética , Degeneração Lobar Frontotemporal/genética , Mutação , Neurônios/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Éxons , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Ribonucleoproteína Nuclear Heterogênea A1 , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo , Humanos , Íntrons , Camundongos , Dados de Sequência Molecular , Neurônios/patologia , Transdução de SinaisRESUMO
To evaluate the efficacy of nontransplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 with Alagille syndrome (ALGS), 16 with familial intrahepatic cholestasis-1 (FIC1), 18 with bile salt export pump (BSEP) disease, and 4 others with low γ-glutamyl transpeptidase disease (levels <100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBDs), 11 ileal exclusions (IEs), and seven gallbladder-to-colon (GBC) diversions. Serum total bilirubin decreased after PEBD in FIC1 (8.1 ± 4.0 vs. 2.9 ± 4.1 mg/dL, preoperatively vs. 12-24 months postoperatively, respectively; P = 0.02), but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695 ± 465 vs. 457 ± 319 mg/dL, preoperatively vs. 12-24 months postoperatively, respectively; P = 0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182 ± 70 vs. 260 ± 73 IU/L, preoperatively vs. 24 months; P = 0.03), but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS, 100% vs. 9% severe; FIC1, 64% vs. 10%; BSEP, 50% vs. 20%, preoperatively vs. >24 months postoperatively, respectively; P < 0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%; P = 0.03). Overall, there were 15 major complications after surgery. Twelve patients (3 ALGS, 3 FIC1, and 6 BSEP) subsequently underwent liver transplantation. CONCLUSION: This was a multicenter analysis of nontransplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally, although not uniformly, result in improvement of pruritus and cholestasis. (Hepatology 2017;65:1645-1654).
Assuntos
Colestase Intra-Hepática/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/estatística & dados numéricos , Circulação Êntero-Hepática , Adolescente , Criança , Pré-Escolar , Colestase Intra-Hepática/sangue , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIM OF THE STUDY: To report a family with a novel TRIO gene mutation associated with phenotype of cerebellar ataxia. MATERIALS AND METHODS: Seven family members of Caribbean descent were recruited through our ataxia research protocol; of the family members, the mother and all 3 children were found to be affected with severe young-onset and rapidly progressive truncal and appendicular ataxia leading to early disability. Array comparative genomic hybridization, mitochondrial DNA analysis, and whole-exome sequencing were performed on 3 of the family members (mother and 2 daughters). RESULTS: While the maternal grandmother, great uncle and great aunt were unaffected, the mother and 3 children displayed cognitive dysfunction, severe ataxia, spasticity, and speech disturbances. Age of onset ranged between 3 and 17 years, with average current disease duration of 21 years. Whole-exome sequencing showed a variant p.A1214V in exon 22 of the TRIO gene in 3 of the family members. Array comparative genomic hybridization and mitochondrial DNA analysis were normal. The same variant was later discovered in all but one family member. CONCLUSIONS AND CLINICAL IMPLICATIONS: The TRIO p.A1214V variant is associated with cerebellar ataxia in the studied family; it was present in all affected and unaffected family members. Phenotype is severe and broad. Anticipation seems to be present (based on 2 affected generations). It is warranted to screen additional familial early-onset and rapidly progressive ataxia cases for this genotype. TRIO gene mutations may well represent a novel spinocerebellar ataxia subtype.
Assuntos
Ataxia Cerebelar , Adolescente , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Humanos , Mutação , Linhagem , FenótipoRESUMO
Aberrant tau protein accumulation drives neurofibrillary tangle (NFT) formation in several neurodegenerative diseases. Currently, efforts to elucidate pathogenic mechanisms and assess the efficacy of therapeutic targets are limited by constraints of existing models of tauopathy. In order to generate a more versatile mouse model of tauopathy, somatic brain transgenesis was utilized to deliver adeno-associated virus serotype 1 (AAV1) encoding human mutant P301L-tau compared with GFP control. At 6 months of age, we observed widespread human tau expression with concomitant accumulation of hyperphosphorylated and abnormally folded proteinase K resistant tau. However, no overt neuronal loss was observed, though significant abnormalities were noted in the postsynaptic scaffolding protein PSD95. Neurofibrillary pathology was also detected with Gallyas silver stain and Thioflavin-S, and electron microscopy revealed the deposition of closely packed filaments. In addition to classic markers of tauopathy, significant neuroinflammation and extensive gliosis were detected in AAV1-Tau(P301L) mice. This model also recapitulates the behavioral phenotype characteristic of mouse models of tauopathy, including abnormalities in exploration, anxiety, and learning and memory. These findings indicate that biochemical and neuropathological hallmarks of tauopathies are accurately conserved and are independent of cell death in this novel AAV-based model of tauopathy, which offers exceptional versatility and speed in comparison with existing transgenic models. Therefore, we anticipate this approach will facilitate the identification and validation of genetic modifiers of disease, as well as accelerate preclinical assessment of potential therapeutic targets.
Assuntos
Encéfalo/ultraestrutura , Modelos Animais de Doenças , Tauopatias , Proteínas tau/metabolismo , Animais , Comportamento Animal , Morte Celular , Humanos , Camundongos , Camundongos Transgênicos , Emaranhados Neurofibrilares/diagnóstico por imagem , Neurônios/patologia , Tauopatias/genética , Tauopatias/metabolismo , Tauopatias/patologia , Ultrassonografia , Proteínas tau/genéticaRESUMO
We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive "multi-omic" analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis.
Assuntos
Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Cerebelo/metabolismo , Metilação de DNA , Lobo Frontal/metabolismo , alfa 1-Antitripsina/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Proteína C9orf72/metabolismo , Cerebelo/patologia , Expansão das Repetições de DNA , Éxons , Lobo Frontal/patologia , Humanos , alfa 1-Antitripsina/metabolismoRESUMO
OBJECTIVE: To describe the outcome of young adults treated for hypoxemic respiratory failure with extracorporeal membrane oxygenation as neonates. DESIGN: The study was designed as a multisite, cross sectional survey. SETTING: The survey was completed electronically or on paper by subjects and stored in a secure data base. SUBJECTS: Subjects were surviving neonatal extracorporeal membrane oxygenation patients from eight institutions who were18 years old or older. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A questionnaire modified from the 2011 Behavioral Risk Factor Surveillance System and the 2011 National Health Interview Survey with additional unique questions was completed by subjects. Results were compared to age-matched national Behavioral Risk Factor Surveillance System and National Health Interview Survey data. One hundred and forty-six subjects participated (8.9% of eligible candidates). The age at questionnaire submission was 23.7 ± 2.89 years. Subjects differed statistically from national cohorts by being more satisfied with life (93% vs 84.2%); more educated (some college or degree; 80.1% vs 57.7%); more insured for healthcare (89.7% vs 72.3%); less frequent users of healthcare in the last 12 months (47.3% vs 58.2%); more limited because of physical, mental, and developmental problems (19.9% vs 10.9%); and having more medical complications. Furthermore, learning problems occurred in 29.5% of the study cohort. The congenital diaphragmatic hernia group was generally less healthy and less well educated, but equally satisfied with life. Perinatal variables contributed little to outcome prediction. CONCLUSIONS: Most young adult survivors in this study cohort treated with extracorporeal membrane oxygenation as neonates are satisfied with their lives, working and/or in college, in good health and having families. These successes are occurring despite obstacles involving health issues such as asthma, attention deficit disorder, learning difficulties, and vision and hearing problems; this is especially evident in the congenital diaphragmatic hernia cohort. Selection bias inherent in such a long-term study may limit generalizability, and it is imperative to note that our sample may not be representative of the whole.
Assuntos
Oxigenação por Membrana Extracorpórea , Nível de Saúde , Satisfação Pessoal , Qualidade de Vida/psicologia , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Sobreviventes/psicologia , Adolescente , Adulto , Estudos Transversais , Feminino , Indicadores Básicos de Saúde , Inquéritos Epidemiológicos , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Síndrome do Desconforto Respiratório do Recém-Nascido/complicações , Síndrome do Desconforto Respiratório do Recém-Nascido/psicologia , Resultado do Tratamento , Adulto JovemRESUMO
Information technology use in healthcare delivery mandates a prepared workforce. The initial Health Information Technology Competencies tool resulted from a 2-year transatlantic effort by experts from the US and European Union to identify approaches to develop skills and knowledge needed by healthcare workers. It was determined that competencies must be identified before strategies are established, resulting in a searchable database of more than 1000 competencies representing five domains, five skill levels, and more than 250 roles. Health Information Technology Competencies is available at no cost and supports role- or competency-based queries. Health Information Technology Competencies developers suggest its use for curriculum planning, job descriptions, and professional development.The Chamberlain College of Nursing informatics research team examined Health Information Technology Competencies for its possible application to our research and our curricular development, comparing it originally with the TIGER-based Assessment of Nursing Informatics Competencies and Nursing Informatics Competency Assessment of Level 3 and Level 4 tools, which examine informatics competencies at four levels of nursing practice. Additional analysis involved the 2015 Nursing Informatics: Scope and Standards of Practice. Informatics is a Health Information Technology Competencies domain, so clear delineation of nursing-informatics competencies was expected. Researchers found TIGER-based Assessment of Nursing Informatics Competencies and Nursing Informatics Competency Assessment of Level 3 and Level 4 differed from Health Information Technology Competencies 2016 in focus, definitions, ascribed competencies, and defined levels of expertise. When Health Information Technology Competencies 2017 was compared against the nursing informatics scope and standards, researchers found an increase in the number of informatics competencies but not to a significant degree. This is not surprising, given that Health Information Technology Competencies includes all healthcare workers, while the TIGER-based Assessment of Nursing Informatics Competencies and Nursing Informatics Competency Assessment of Level 3 and Level 4 tools and the American Nurses Association Nursing Informatics: Scope and Standards of Practice are nurse specific. No clear cross mapping across these tools and the standards of nursing informatics practice exists. Further examination and review are needed to translate Health Information Technology Competencies as a viable tool for nursing informatics use in the US.
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Alfabetização Digital , Capacitação de Usuário de Computador/normas , Informática Médica/normas , Informática em Enfermagem/normas , Currículo , Humanos , Informática em Enfermagem/educação , Pesquisa em Enfermagem , Estados UnidosRESUMO
Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1-PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRN's interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN588â593, residues critical for PGRN-SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1-PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients.
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Proteínas Adaptadoras de Transporte Vesicular/genética , Endocitose/efeitos dos fármacos , Demência Frontotemporal/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Piridinas/farmacologia , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Linhagem Celular Tumoral , Demência Frontotemporal/patologia , Variação Genética , Células HEK293 , Haploinsuficiência , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Linfócitos/metabolismo , Progranulinas , Reprodutibilidade dos TestesRESUMO
Sortilin 1 regulates the levels of brain progranulin (PGRN), a neurotrophic growth factor that, when deficient, is linked to cases of frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43)-positive inclusions (FTLD-TDP). We identified a specific splicing enhancer element that regulates the inclusion of a sortilin exon cassette (termed Ex17b) not normally present in the mature sortilin mRNA. This enhancer element is consistently present in sortilin RNA of mice and other species but absent in primates, which carry a premature stop codon within the Ex17b sequence. In the absence of TDP-43, which acts as a regulatory inhibitor, Ex17b is included in the sortilin mRNA. In humans, in contrast to mice, the inclusion of Ex17b in sortilin mRNA generates a truncated, nonfunctional, extracellularly released protein that binds to but does not internalize PGRN, essentially acting as a decoy receptor. Based on these results, we propose a potential mechanism linking misregulation of sortilin splicing with altered PGRN metabolism.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Splicing de RNA/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Motivos de Aminoácidos , Animais , Sequência de Bases , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Endocitose , Elementos Facilitadores Genéticos/genética , Éxons/genética , Glicina/metabolismo , Humanos , Camundongos , Modelos Biológicos , Dados de Sequência Molecular , Progranulinas , Ligação Proteica , Biossíntese de Proteínas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the "c9RAN proteins" thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.