RESUMEN
RNA modifications are dynamic chemical entities that expand the RNA lexicon and regulate RNA fate. The most abundant modification present in mRNAs, N6-methyladenosine (m6A), has been implicated in neurogenesis and memory formation. However, whether additional RNA modifications may be playing a role in neuronal functions and in response to environmental queues is largely unknown. Here we characterize the biochemical function and cellular dynamics of two human RNA methyltransferases previously associated with neurological dysfunction, TRMT1 and its homolog, TRMT1-like (TRMT1L). Using a combination of next-generation sequencing, LC-MS/MS, patient-derived cell lines and knockout mouse models, we confirm the previously reported dimethylguanosine (m2,2G) activity of TRMT1 in tRNAs, as well as reveal that TRMT1L, whose activity was unknown, is responsible for methylating a subset of cytosolic tRNAAla(AGC) isodecoders at position 26. Using a cellular in vitro model that mimics neuronal activation and long term potentiation, we find that both TRMT1 and TRMT1L change their subcellular localization upon neuronal activation. Specifically, we observe a major subcellular relocalization from mitochondria and other cytoplasmic domains (TRMT1) and nucleoli (TRMT1L) to different small punctate compartments in the nucleus, which are as yet uncharacterized. This phenomenon does not occur upon heat shock, suggesting that the relocalization of TRMT1 and TRMT1L is not a general reaction to stress, but rather a specific response to neuronal activation. Our results suggest that subcellular relocalization of RNA modification enzymes may play a role in neuronal plasticity and transmission of information, presumably by addressing new targets.
Asunto(s)
Encéfalo/metabolismo , Núcleo Celular/metabolismo , Neuroblastoma/patología , Neuronas/metabolismo , Fracciones Subcelulares/metabolismo , ARNt Metiltransferasas/metabolismo , Animales , Femenino , Ratones , Ratones Noqueados , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuronas/citología , ARNt Metiltransferasas/genéticaRESUMEN
RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps.
Asunto(s)
Enfermedad/genética , Procesamiento Postranscripcional del ARN , ARN/química , Animales , HumanosRESUMEN
BACKGROUND AND PURPOSE: Intrahospital time delays significantly affect the neurological outcome of stroke patients with large-vessel occlusion. This study was conducted to determine whether a one-stop management can reduce intrahospital times of patients with acute large-vessel occlusion. METHODS: In this observational study, we report the first 30 consecutive stroke patients imaged and treated in the same room. As part of our protocol, we transported patients with a National Institutes of Health Stroke Scale score of ≥10 directly to the angio suite, bypassing multidetector computed tomography (CT). Preinterventional imaging consisted of noncontrast flat detector CT and flat detector CT angiography, acquired with an angiography system. Patients with large-vessel occlusions remained on the angio table and were treated with mechanical thrombectomy; patients with small artery occlusions were treated with intravenous thrombolysis, whereas patients with an intracranial hemorrhage and stroke mimics were treated as per guidelines. Door-to-groin puncture times were recorded and compared with our past results. RESULTS: Thirty patients were transferred directly to our angio suite from June to December 2016. The time from symptom onset to admission was 105 minutes. Ischemic stroke was diagnosed in 22 of 30 (73%) patients, 4 of 30 (13.5%) had an intracranial hemorrhage, and 4 of 30 (13.5) were diagnosed with a Todd's paresis. Time from admission to groin puncture was 20.5 minutes. Compared with 44 patients imaged with multidetector CT in the first 6 months of 2016, door-to-groin times were significantly reduced (54.5 minutes [95% confidence interval, 47-61] versus 20.5 minutes [95% confidence interval, 17-26]). CONCLUSIONS: In this small series, a one-stop management protocol of selected stroke patients using latest generation flat detector CT led to a significant reduction of intrahospital times.
Asunto(s)
Angiografía Cerebral , Hemorragias Intracraneales , Admisión del Paciente , Accidente Cerebrovascular , Tomografía Computarizada por Rayos X , Enfermedad Aguda , Femenino , Humanos , Hemorragias Intracraneales/diagnóstico por imagen , Hemorragias Intracraneales/terapia , Masculino , Estudios Prospectivos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapia , Factores de TiempoRESUMEN
OBJECTIVES: Research on Asian American activism is neglected in the collective action literature. This study examined a model of Asian American activism that included a context-specific variable, model minority beliefs, and 3 traditional predictors of collective engagement: experiences of discrimination, collective racial identity, and structural awareness. METHOD: Participants completed a survey on their sociopolitical attitudes and behaviors. All participants identified as Asian American (N = 187; Mage = 32.99) and were generally well-educated (76.8% had a college degree or higher), politically liberal (68.5%), and female (74.2%). RESULTS: Controlling for gender, age, political orientation, and immigrant generation, the results of the serial mediation model revealed that structural awareness, collective racial identity, and model minority beliefs significantly mediated the relationship between discrimination and own-group activism. Results also showed that model minority beliefs negatively predicted own-group activism. CONCLUSIONS: In addition to replicating broad findings from the collective action literature among Asian Americans, this research highlights the importance of contextualized group-based beliefs about inequality (model minority beliefs) for understanding engagement among racial minority groups. (PsycINFO Database Record
Asunto(s)
Asiático/psicología , Grupos Minoritarios/psicología , Identificación Social , Percepción Social , Adulto , Femenino , Identidad de Género , Humanos , Masculino , Encuestas y Cuestionarios , UniversidadesRESUMEN
PURPOSE: The aim of this study was to assess the rate of self-scheduling and self-referral for screening mammography and to assess sociodemographic factors associated with their use in an academic health care system in southern California. METHODS: Patients scheduled for screening mammography between February 1, 2021, and September 20, 2022, were included in this retrospective study. Multivariable logistic regression models were used to assess associations among sociodemographic factors, self-referral, and online self-scheduling pathways. RESULTS: In total, 22,306 patients were scheduled for screening mammography (mean age, 59 years; 66.8% White, 20.4% Asian, and 20.6% Hispanic). Overall, 3,566 (16.0%) used online self-scheduling, and 1,232 (5.5%) self-referred for screening mammography. Patients 70 years or older (versus 50 years or younger) (odds ratio [OR], 0.41; 95% confidence interval [CI], 0.34-0.51), Spanish (versus English) speakers (OR, 0.22; 95% CI, 0.16-0.31), and those on Medicaid (versus commercially insured) (OR, 0.71; 95% CI, 0.50-0.99) were less likely to self-schedule. Hispanic patients (versus non-Hispanic) (OR, 1.39; 95% CI, 1.20-1.61), Asian patients (versus White) (OR, 1.64; 95% CI, 1.46-1.85), and patients residing in the most (versus least) disadvantaged neighborhoods (OR, 1.16; 95% CI, 1.02-1.33) were more likely to self-schedule. Furthermore, patients 70 years or older (versus 50 or younger) (OR, 0.70; 95% CI, 0.52-0.93) and Spanish speakers (OR, 0.05; 95% CI, 0.03-0.09) were less likely to self-refer, whereas Black patients (versus White) (OR, 1.89; 95% CI, 1.30-2.75), patients on Medicaid (versus commercially insured) (OR, 3.70; 95% CI, 2.65-5.13), and patients living in the most (versus least) disadvantaged neighborhoods (OR, 1.52; 95% CI, 1.27-1.82) were more likely to self-refer. CONCLUSIONS: Sociodemographic differences in online patient portal use and self-referral for screening mammography suggest that the two pathways have been successful in addressing some of the existing scheduling barriers and are a step toward closing the disparity gap.
Asunto(s)
Neoplasias de la Mama , Portales del Paciente , Estados Unidos , Humanos , Persona de Mediana Edad , Femenino , Mamografía , Estudios Retrospectivos , Neoplasias de la Mama/diagnóstico por imagen , Detección Precoz del Cáncer , Derivación y Consulta , Inequidades en Salud , Tamizaje MasivoRESUMEN
The shift from film to PACS in reading rooms, coupled with escalating case volumes, exposes radiologists to the issues of the modern computer workstation including computer work posture and work-related musculoskeletal disorders (WMSD). Common WMSDs affecting the neck and upper extremities include cervical myofascial pain, shoulder tendonitis, lateral epicondylitis, carpal tunnel syndrome, and cubital tunnel syndrome. This review examines each pathology along with its pathogenesis, clinical features, physical exam findings, and potential risk factors. Furthermore, a comprehensive 11-part physical therapy regimen that is both prophylactic and therapeutic is illustrated and described in detail. One of the objectives of this review is to advocate for the inclusion of a physical therapy regimen in the working routine of diagnostic radiologists to prevent WMSDs. A brief daily commitment to this regimen can help radiologists remain healthy and productive in order to deliver optimal patient care throughout their careers.
Asunto(s)
Enfermedades Musculoesqueléticas , Enfermedades Profesionales , Modalidades de Fisioterapia , Radiólogos , Humanos , Enfermedades Musculoesqueléticas/diagnóstico por imagen , Enfermedades Profesionales/prevención & control , Enfermedades Profesionales/terapia , Factores de RiesgoRESUMEN
Healthcare price transparency is an effort to inform patient decision-making, but also to decrease prices and their variation across healthcare systems for equivalent medical services. The initiative is meaningful only for medical services that are shoppable-such as imaging examinations-for which patients incur out-of-pocket costs. Therefore, several countries in which patients commonly share a portion of their healthcare costs have been implementing mandates to improve healthcare price transparency. However, the provisional implementation has many issues, especially in the United States, including provider non-compliance and limited accessibility of price transparency tools by the general public. Many of the existing tools are not user-friendly, are difficult to navigate, focus on charges and health plan negotiated rates rather than patients' out-of-pocket costs, and disclose prices on the service level instead of per episode of care. As such, the disclosed amounts are often not reliable. Many price transparency tools also lack valid and measurable quality metrics, which can result in a selection of high-cost care as a proxy for high-value care, as well as an increase in healthcare prices when providers want to imply they offer high-quality care. Nevertheless, the impact of the initiatives on patients' decision-making and healthcare costs remains unclear. While transparency initiatives are patient-centric, efforts should be made to increase patient engagement, provide accurate patient-specific out-of-pocket cost information, compare available treatment and provider alternatives, and couple price information with quality metrics to enable making fully informed decisions.
Asunto(s)
Atención a la Salud , Costos de la Atención en Salud , Humanos , Estados Unidos , América del Norte , Calidad de la Atención de Salud , Diagnóstico por ImagenRESUMEN
PURPOSE: Our study fills the spatiotemporal gaps in dry eye disease (DED) epidemiology by using Google Trends as a novel epidemiological tool for geographically mapping DED in relation to environmental risk factors. METHODS: We used Google Trends to extract DED-related queries estimating users' intent from 2004 to 2019 in the United States. We incorporated national climate data to generate heat maps comparing geographic, temporal, and environmental relationships of DED. Multivariable regression models were constructed to generate quadratic forecasts predicting DED and control searches. RESULTS: Our results illustrated the upward trend, seasonal pattern, environmental influence, and spatial relationship of DED search volume across the US geography. Localized patches of DED interest were visualized in urban areas. There was no significant difference in DED queries across the US census regions (P = 0.3543). Regression model 1 predicted DED queries per state (R2 = 0.61), with the significant predictor being urban population [r = 0.56, adjusted (adj.) P < 0.001, n = 50]; model 2 predicted DED searches over time (R2 = 0.97), with significant predictors being control queries (r = 0.85, adj. P = 0.0169, n = 190), time (r = 0.96, adj. P < 0.001, n = 190), time2 (r = 0.97, adj. P < 0.001, n = 190), and seasonality (winter r = -0.04, adj. P = 0.0196, n = 190; spring r = 0.10, adj. P < 0.001, n = 190). CONCLUSIONS: Our study used Google Trends as a novel epidemiologic approach to geographically mapping the US DED. Importantly, urban population and seasonality were stronger risk factors of DED searches than temperature, humidity, sunshine, pollution, or region. Our work paves the way for future exploration of geographic information systems for locating DED and other diseases through online population metrics.
Asunto(s)
Bases de Datos Factuales/tendencias , Síndromes de Ojo Seco/epidemiología , Internet/tendencias , Clima , Estudios Epidemiológicos , Geografía , Humanos , Prevalencia , Factores de Riesgo , Estaciones del Año , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: 7-ketocholesterol (7kCh), a natural byproduct of oxidation in lipoprotein deposits is implicated in the pathogenesis of diabetic retinopathy and age-related macular degeneration (AMD). This study was performed to investigate whether several clinical drugs can inhibit 7kCh-induced caspase activation and mitigate its apoptotic effects on retinal cells in vitro. METHODS: Two populations of retinal cells, human retinal pigment epithelial cells (ARPE-19) and rat neuroretinal cells (R28) were exposed to 7kCh in the presence of the following inhibitors: Z-VAD-FMK (pan-caspase inhibitor), simvastatin, memantine, epicatechin, and Z-IETD-FMK (caspase-8 inhibitor) or Z-ATAD-FMK (caspase-12 inhibitor). Caspase-3/7, -8, and -12 activity levels were measured by fluorochrome caspase assays to quantify cell death. IncuCyte live-cell microscopic images were obtained to quantify cell counts. RESULTS: Exposure to 7kCh for 24 hours significantly increased caspase activities for both ARPE-19 and R28 cells (P < 0.05). In ARPE cells, pretreatment with various drugs had significantly lower caspase-3/7, -8, and -12 activities, reported in % change in mean signal intensity (msi): Z-VAD-FMK (48% decrease, P < 0.01), memantine (decreased 47.8% at 1 µM, P = 0.0039 and 81.9% at 1 mM, P < 0.001), simvastatin (decreased 85.3% at 0.01 µM, P < 0.001 and 84.8% at 0.05 µM, P < 0.001) or epicatechin (83.6% decrease, P < 0.05), Z-IETD-FMK (68.1% decrease, P < 0.01), and Z-ATAD-FMK (47.7% decrease, P = 0.0017). In contrast, R28 cells exposed to 7kCh continued to have elevated caspase-3/7, -8, and -12 activities (between 25.7% decrease and 17.5% increase in msi, P > 0.05) regardless of the pretreatment. CONCLUSION: Several current drugs protect ARPE-19 cells but not R28 cells from 7kCh-induced apoptosis, suggesting that a multiple-drug approach is needed to protect both cells types in various retinal diseases.
RESUMEN
BACKGROUND AND PURPOSE: Thrombectomy has become the standard of care for acute ischaemic stroke due to large vessel occlusion. Aim of this study was to compare the radiological outcomes and time metrics of the various thrombectomy techniques. METHODS: In this retrospective, multicenter study we analysed the data of 450 patients with occlusion of the anterior circulation, treated in five high-volume center from 2013 to 2016. The treatment techniques were divided in three categories: first-pass use of a large-bore aspiration-catheter; first-pass use of a stent-retriever; and primary combined approach (PCA) of an aspiration-catheter and stent-retriever. Primary endpoints were successful reperfusion and groin to reperfusion time. Secondary endpoints were the number of attempts and occurrence of emboli in new territory (ENT). The primary analysis was based on the intention to treat groups (ITT). RESULTS: The ITT-analysis showed significantly higher reperfusion rates, with 86% of successful reperfusion in the PCA-group compared with 73% in the aspiration group and 65% in the stent-retriever group. There was no significant difference in groin to reperfusion time regarding the used technique. The secondary analysis showed an impact of the technique on the number of attempts and the occurrence of ENTs. Lowest ENT rates and attempts were reported with the combined approach. CONCLUSIONS: The combined first-pass deployment of a stent-retriever and an aspiration-catheter was the most effective technique for reperfusion of anterior circulation large vessel occlusion. Our results correlate with the latest single-centrere studies, reporting very high reperfusion rates with PCA variations.