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For over two decades, telestroke has been utilized as a means for improving acute access to a stroke specialist when this expertise is otherwise unavailable. During this time, telestroke use has increased and improvements in care metrics have been widely reported. Several telestroke model variations are utilized; each has different workflow implications. A successful telestroke system should include adequate protocols and training, equipment, documentation system, and tracking of quality metrics. Upfront costs of needed technology and devices, credentialing hurdles, and limited reimbursement are all reported barriers to the utilization of telestroke. Emphasis on safety measures during the COVID-19 pandemic resulted in the dramatic upscaling of telehealth utilization, although overall stroke volumes declined in many areas in the early phases of the pandemic. Going forward, continued reduction in cost of required devices and broadband connections, increased use of automated and advanced analytical software, and a universal licensing and credentialing system are needed to continue the expansion of telestroke use.
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COVID-19 , Acidente Vascular Cerebral , Telemedicina , Humanos , Pandemias , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/terapia , Telemedicina/métodos , Terapia TrombolíticaRESUMO
WHAT IS KNOWN AND OBJECTIVE: Paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD) is a direct-acting antiviral (DAA) approved for the treatment of chronic hepatitis C virus. We report on a probable interaction between PrOD with ribavirin and warfarin. CASE DESCRIPTION: Two weeks after the start of PrOD with ribavirin, the patient's international normalized ratio (INR) became subtherapeutic. Eleven weeks into therapy and following a 125% total increase in the weekly warfarin dose, therapeutic INR was achieved. Thirteen days after DAA therapy was completed and discontinued, the patient's INR became critically supratherapeutic. WHAT IS NEW AND CONCLUSION: Patients on PrOD plus ribavirin with warfarin should have INR followed closely upon initiation and discontinuation of therapy due to a probable drug interaction.
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Anilidas/efeitos adversos , Anticoagulantes/uso terapêutico , Carbamatos/efeitos adversos , Compostos Macrocíclicos/efeitos adversos , Ribavirina/uso terapêutico , Ritonavir/efeitos adversos , Sulfonamidas/efeitos adversos , Uracila/análogos & derivados , Varfarina/uso terapêutico , 2-Naftilamina , Anilidas/uso terapêutico , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Ciclopropanos , Interações Medicamentosas , Quimioterapia Combinada/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Humanos , Lactamas Macrocíclicas , Compostos Macrocíclicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Uracila/efeitos adversos , Uracila/uso terapêutico , ValinaRESUMO
Determining acute ischemic stroke (AIS) etiology is fundamental to secondary stroke prevention efforts but can be diagnostically challenging. We trained and validated an automated classification tool, StrokeClassifier, using electronic health record (EHR) text from 2039 non-cryptogenic AIS patients at 2 academic hospitals to predict the 4-level outcome of stroke etiology adjudicated by agreement of at least 2 board-certified vascular neurologists' review of the EHR. StrokeClassifier is an ensemble consensus meta-model of 9 machine learning classifiers applied to features extracted from discharge summary texts by natural language processing. StrokeClassifier was externally validated in 406 discharge summaries from the MIMIC-III dataset reviewed by a vascular neurologist to ascertain stroke etiology. Compared with vascular neurologists' diagnoses, StrokeClassifier achieved the mean cross-validated accuracy of 0.74 and weighted F1 of 0.74 for multi-class classification. In MIMIC-III, its accuracy and weighted F1 were 0.70 and 0.71, respectively. In binary classification, the two metrics ranged from 0.77 to 0.96. The top 5 features contributing to stroke etiology prediction were atrial fibrillation, age, middle cerebral artery occlusion, internal carotid artery occlusion, and frontal stroke location. We designed a certainty heuristic to grade the confidence of StrokeClassifier's diagnosis as non-cryptogenic by the degree of consensus among the 9 classifiers and applied it to 788 cryptogenic patients, reducing cryptogenic diagnoses from 25.2% to 7.2%. StrokeClassifier is a validated artificial intelligence tool that rivals the performance of vascular neurologists in classifying ischemic stroke etiology. With further training, StrokeClassifier may have downstream applications including its use as a clinical decision support system.
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Determining the etiology of an acute ischemic stroke (AIS) is fundamental to secondary stroke prevention efforts but can be diagnostically challenging. We trained and validated an automated classification machine intelligence tool, StrokeClassifier, using electronic health record (EHR) text data from 2,039 non-cryptogenic AIS patients at 2 academic hospitals to predict the 4-level outcome of stroke etiology determined by agreement of at least 2 board-certified vascular neurologists' review of the stroke hospitalization EHR. StrokeClassifier is an ensemble consensus meta-model of 9 machine learning classifiers applied to features extracted from discharge summary texts by natural language processing. StrokeClassifier was externally validated in 406 discharge summaries from the MIMIC-III dataset reviewed by a vascular neurologist to ascertain stroke etiology. Compared with stroke etiologies adjudicated by vascular neurologists, StrokeClassifier achieved the mean cross-validated accuracy of 0.74 (±0.01) and weighted F1 of 0.74 (±0.01). In the MIMIC-III cohort, the accuracy and weighted F1 of StrokeClassifier were 0.70 and 0.71, respectively. SHapley Additive exPlanation analysis elucidated that the top 5 features contributing to stroke etiology prediction were atrial fibrillation, age, middle cerebral artery occlusion, internal carotid artery occlusion, and frontal stroke location. We then designed a certainty heuristic to deem a StrokeClassifier diagnosis as confidently non-cryptogenic by the degree of consensus among the 9 classifiers, and applied it to 788 cryptogenic patients. This reduced the percentage of the cryptogenic strokes from 25.2% to 7.2% of all ischemic strokes. StrokeClassifier is a validated artificial intelligence tool that rivals the performance of vascular neurologists in classifying ischemic stroke etiology for individual patients. With further training, StrokeClassifier may have downstream applications including its use as a clinical decision support system.
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Although a decrease in stroke admissions during the SARS-CoV-2 pandemic has been observed, detailed analyses of the evolution of stroke metrics during the pandemic are lacking. We analyzed changes in stroke presentation, in-hospital systems-of-care, and treatment time metrics at two representative Comprehensive Stroke Centers (CSCs) during the first year of Coronavirus disease 2019 pandemic. From January 2018 to May 2021, data from stroke presentations to two CSCs were obtained. The study duration was split into: period 0 (prepandemic), period 1 (Wave 1), period 2 (Lull), and period 3 (Wave 2). Acute stroke therapies rates and workflow times were compared among pandemic and prepandemic periods. Analyses were adjusted for age, sex, comorbidities, and pre-morbid care needs. There was a significant decrease in monthly hospital presentations of stroke during Wave 1. Both centers reported declines in reperfusion therapies during Wave 1, slowly catching up but never to pre pandemic numbers, and dropping again in Wave 2. Both CSCs experienced in-hospital workflow delays during Waves 1 and 2, and even during the Lull period. Our results highlight the need for proactive strategies to reduce barriers to workflow and hospital avoidance for stroke patients during crisis periods.
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COVID-19 , Acidente Vascular Cerebral , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Pandemias , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapia , Comorbidade , Estudos RetrospectivosRESUMO
INTRODUCTION: Sex-specific differences in ischemic stroke outcomes are prevalent. We sought to investigate sex differences in the determinants of reperfusion and functional outcomes after endovascular thrombectomy (EVT) for emergent large vessel occlusion ischemic stroke (ELVO). METHODS: Patients presenting to a single referral center with an anterior circulation ELVO that underwent EVT from 2011 to 2019 were included in this retrospective analysis. Sex differences in history, presentation, adequate reperfusion (TICI 2b-3), and 90-day good outcome [delta modified Rankin Scale (mRS) ≤ 2 from pre-stroke] were examined. Multivariable logistic regression analyses were performed to assess sex-specific associations with outcomes. RESULTS: Three hundred and eighty-one consecutive ELVO patients were identified. Women (N = 193) were older (75 vs 64 years, p < 0.0001), had more pre-stroke disability (17% vs 9%, p = 0.032), more atrial fibrillation (41% vs 30%, p = 0.033), but less carotid atherosclerosis (8% vs 16%, p = 0.027). Rates of TICI 2b-3 and good outcome were similar between sexes. Carotid atherosclerosis (OR 0.315, 95% CI 0.130, 0.762) and dissection (OR 0.124, 95% CI 0.027, 0.569) independently decreased the odds of TICI 2b-3 among men but not women. Older age, more severe stroke, and not achieving TICI 2b-3 independently decreased the odds of good outcome among both sexes, while prior stroke (OR 0.258, 95% CI 0.083, 0.797) and hemorrhagic transformation (OR 0.111, 0.021, 0.592) were determinants exclusive to men. CONCLUSION: In a real-world analysis of ELVO stroke patients treated with EVT, we found that despite advanced age and more pre-stroke disability, women have comparable reperfusion rates and functional outcomes compared to men. Sex-specific determinants of reperfusion and functional outcome were identified that require further study.
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Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Idoso , Isquemia Encefálica/complicações , Isquemia Encefálica/epidemiologia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Caracteres Sexuais , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/cirurgia , Trombectomia , Resultado do TratamentoRESUMO
Electronic health record (EHR) datasets are statistically powerful but are subject to ascertainment bias and missingness. Using the Mass General Brigham multi-institutional EHR, we approximated a community-based cohort by sampling patients receiving longitudinal primary care between 2001-2018 (Community Care Cohort Project [C3PO], n = 520,868). We utilized natural language processing (NLP) to recover vital signs from unstructured notes. We assessed the validity of C3PO by deploying established risk models for myocardial infarction/stroke and atrial fibrillation. We then compared C3PO to Convenience Samples including all individuals from the same EHR with complete data, but without a longitudinal primary care requirement. NLP reduced the missingness of vital signs by 31%. NLP-recovered vital signs were highly correlated with values derived from structured fields (Pearson r range 0.95-0.99). Atrial fibrillation and myocardial infarction/stroke incidence were lower and risk models were better calibrated in C3PO as opposed to the Convenience Samples (calibration error range for myocardial infarction/stroke: 0.012-0.030 in C3PO vs. 0.028-0.046 in Convenience Samples; calibration error for atrial fibrillation 0.028 in C3PO vs. 0.036 in Convenience Samples). Sampling patients receiving regular primary care and using NLP to recover missing data may reduce bias and maximize generalizability of EHR research.
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Small cell lung cancer (SCLC) is a rapidly progressive, aggressive metastatic and lethal subtype of lung cancer. Unfortunately, there has been little progress regarding the development of novel treatments for SCLC. However, lurbinectedin, a transcriptional inhibitor, has emerged as a potential novel treatment for cancer. It produces antitumor efficacy by inhibiting oncogenic transcription activity, inducing the accumulation of DNA double-strand breaks and modulating the tumor microenvironment (TME). Data from phase I/II trials indicates that lurbinectedin has significant antitumor efficacy and tolerable adverse effects in SCLC patients. Furthermore, lurbinectedin is efficacious in platinum-sensitive and platinum-resistant SCLC patients and in those with SCLC relapse after second-line treatment. In 2020, the U.S. Food and Drug Administration (FDA) approved lurbinectedin for the treatment of adult patients with metastatic SCLC or for patients that have received platinum-based chemotherapy. In this review, we discuss the molecular profile and the preclinical and clinical studies of lurbinectedin in the treatment of SCLC patients.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Adulto , Carbolinas , Compostos Heterocíclicos de 4 ou mais Anéis , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Microambiente TumoralRESUMO
The identification of oncogenic drivers and the subsequent development of targeted therapies have been established as biomarker-based care for metastatic non-small cell lung cancer (NSCLC) patients. Rearranged during transfection (RET) events have been reported to be oncogenic drivers in NSCLC and were more common in patients who i) were young; ii) had adenocarcinoma histology; and iii) had never smoked. Phase II studies indicated the limited efficacy of multi-targeted tyrosine kinase inhibitors in patients with NSCLC that have a confirmed RET event. Consequently, there has been ongoing research to develop more potent and specific RET tyrosine kinase inhibitors. Recently, a novel and specific RET inhibitor, pralsetinib (BLU-667), has been reported to have excellent efficacy and low off-target toxicity in RET cancer patients. In this review, we summarize the clinical data regarding the use of pralsetinib in NSCLC patients.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-ret , Pirazóis , Piridinas , PirimidinasRESUMO
OBJECTIVE: To determine whether providing teleneurology (TN) consultations aiding in determination of death by neurologic criteria (DNC) to a bedside intensivist is feasible and whether timely access and expert input increase the quality of the DNC examination and identification of potential organ donors, we reviewed retrospective data related to outcomes of such consultations. METHODS: Between November 2017 and March 2019, TN consults were requested for sequential comatose patients in the intensive care unit (ICU). We recorded patients' demographic information, causes leading to coma or suspected DNC, and the results of TN consultations. We obtained data on the number of referrals to the organ bank and number of organ donors. RESULTS: Ninety-nine consults were performed with a median time from request to start of the consult of 20.2 minutes (interquartile range 5.4-65.3 minutes). Eighty consults were requested for determination of prognosis, whereas 19 consults were requested for supervision of the DNC examination. In 1 of 80 (1.2%) prognostication consults, the patient was determined by the neurologist to require assessment of DNC and was found to meet DNC criteria; determination of DNC occurred in 11 of the 19 (57.9%) consultations for a supervised DNC examination. In a comparison of the pre-TN (94 months) and post-TN (17 months) periods, there was 2.56-fold increase in the proportion of patients meeting DNC criteria who were medically suitable for donation (pre-TN 8.9% vs post-TN 21.1%, p = 0.02) and a 2.12-fold increase in the proportion of donors (pre-TN 6.14% vs post-TN 13.1%, p = 0.14). CONCLUSIONS: It is feasible to perform TN consultations for patients with severe neurologic damage and to allow expert supervision for DNC examination. Having a teleneurologist as part of the ICU assessment team helped differentiate severe neurologic deficits from DNC and was associated with increase in organ donation.
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Morte Encefálica/diagnóstico , Exame Neurológico/métodos , Neurologia/métodos , Encaminhamento e Consulta , Telemedicina/métodos , Idoso , Feminino , Parada Cardíaca/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doadores de Tecidos/provisão & distribuiçãoRESUMO
Background Performance of existing atrial fibrillation (AF) risk prediction models in poststroke populations is unclear. We evaluated predictive utility of an AF risk model in patients with acute stroke and assessed performance of a fully refitted model. Methods and Results Within an academic hospital, we included patients aged 46 to 94 years discharged for acute ischemic stroke between 2003 and 2018. We estimated 5-year predicted probabilities of AF using the Cohorts for Heart and Aging Research in Genomic Epidemiology for Atrial Fibrillation (CHARGE-AF) model, by recalibrating CHARGE-AF to the baseline risk of the sample, and by fully refitting a Cox proportional hazards model to the stroke sample (Re-CHARGE-AF) model. We compared discrimination and calibration between models and used 200 bootstrap samples for optimism-adjusted measures. Among 551 patients with acute stroke, there were 70 incident AF events over 5 years (cumulative incidence, 15.2%; 95% CI, 10.6%-19.5%). Median predicted 5-year risk from CHARGE-AF was 4.8% (quartile 1-quartile 3, 2.0-12.6) and from Re-CHARGE-AF was 16.1% (quartile 1-quartile 3, 8.0-26.2). For CHARGE-AF, discrimination was moderate (C statistic, 0.64; 95% CI, 0.57-0.70) and calibration was poor, underestimating AF risk (Greenwood-Nam D'Agostino chi-square, P<0.001). Calibration with recalibrated baseline risk was also poor (Greenwood-Nam D'Agostino chi-square, P<0.001). Re-CHARGE-AF improved discrimination (P=0.001) compared with CHARGE-AF (C statistic, 0.74 [95% CI, 0.68-0.79]; optimism-adjusted, 0.70 [95% CI, 0.65-0.75]) and was well calibrated (Greenwood-Nam D'Agostino chi-square, P=0.97). Conclusions Covariates from an established AF risk model enable accurate estimation of AF risk in a poststroke population after recalibration. A fully refitted model was required to account for varying baseline AF hazard and strength of associations between covariates and incident AF.
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Fibrilação Atrial , AVC Isquêmico , Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Humanos , Incidência , Pessoa de Meia-Idade , Medição de Risco/métodos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologiaRESUMO
INTRODUCTION: Since approval by the United States Food and Drug Administration in 1996, alteplase utilization rates for acute ischemic stroke have increased. Despite its efficacy for improving stroke outcomes, however, the majority of ischemic stroke patients still do not receive alteplase. To address this issue, different methods for improving access to alteplase have been tested with varying degrees of success. AREAS COVERED: This article gives an overview of the recent approaches pursued to improve access to alteplase for acute ischemic stroke patients. Utilization of stroke systems of care, quality metrics, and quality-improvement initiatives to improve alteplase treatment rates are discussed. The implementation of Telestroke networks to improve access and timely evaluation by a stroke specialist are also reviewed. Lastly, this review discusses the use of neuroimaging techniques to identify alteplase candidates in stroke of unknown symptom onset or beyond the 4.5-h treatment window. EXPERT COMMENTARY: Expanding access to alteplase therapy for acute ischemic stroke is a multi-faceted approach. Specific considerations based on region, population, and health-care resources should be considered for each strategy. Neuroimaging approaches to identify alteplase-eligible patients beyond the 4.5-h treatment window are a recent development in acute stroke care that holds promise for increasing alteplase treatment rates.
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Isquemia Encefálica/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/uso terapêutico , Administração Intravenosa , Fibrinolíticos/uso terapêutico , Humanos , Terapia Trombolítica/métodos , Resultado do Tratamento , Estados Unidos , United States Food and Drug AdministrationRESUMO
The iliac crest is the sampling site for minimal residual disease (MRD) monitoring in multiple myeloma (MM). However, the disease distribution is often heterogeneous, and imaging can be used to complement MRD detection at a single site. We have investigated patients in complete remission (CR) during first-line or salvage therapy for whom MRD flow cytometry and the two imaging modalities positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) were performed at the onset of CR. Residual focal lesions (FLs), detectable in 24% of first-line patients, were associated with short progression-free survival (PFS), with DW-MRI detecting disease in more patients. In some patients, FLs were only PET positive, indicating that the two approaches are complementary. Combining MRD and imaging improved prediction of outcome, with double-negative and double-positive features defining groups with excellent and dismal PFS, respectively. FLs were a rare event (12%) in first-line MRD-negative CR patients. In contrast, patients achieving an MRD-negative CR during salvage therapy frequently had FLs (50%). Multi-region sequencing and imaging in an MRD-negative patient showed persistence of spatially separated clones. In conclusion, we show that DW-MRI is a promising tool for monitoring residual disease that complements PET and should be combined with MRD.
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Imagem de Difusão por Ressonância Magnética/métodos , Citometria de Fluxo/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mieloma Múltiplo/terapia , Neoplasia Residual/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Biomarcadores Tumorais/genética , Seguimentos , Humanos , Mieloma Múltiplo/patologia , Neoplasia Residual/diagnóstico por imagem , Neoplasia Residual/etiologia , Prognóstico , Indução de Remissão , Taxa de Sobrevida , Transplante Autólogo , Sequenciamento do ExomaRESUMO
In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of "fitter" clones may be anticipated. However, an imbalanced distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53, and mutations affecting mitogen-activated protein kinase genes. We show that the extent of spatial heterogeneity is positively associated with the size of biopsied focal lesions consistent with regional outgrowth of advanced clones. The results support a model for multiple myeloma progression with clonal sweeps in the early phase and regional evolution in advanced disease. We suggest that multi-region investigations are critical to understanding intra-patient heterogeneity and the evolutionary processes in multiple myeloma.In multiple myeloma, malignant cells expand within bone marrow. Here, the authors use multi-region sequencing in patient samples to analyse spatial clonal architecture and heterogeneity, providing novel insight into multiple myeloma progression and evolution.
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Medula Óssea/patologia , Mieloma Múltiplo/genética , Plasmócitos/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Idoso , Idoso de 80 Anos ou mais , Inibidor de Quinase Dependente de Ciclina p18/genética , Progressão da Doença , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/genética , Mieloma Múltiplo/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fator de Transcrição STAT3/genética , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/genéticaRESUMO
The purpose of this study is to identify prognostic markers and treatment targets using a clinically certified sequencing panel in multiple myeloma. We performed targeted sequencing of 578 individuals with plasma cell neoplasms using the FoundationOne Heme panel and identified clinically relevant abnormalities and novel prognostic markers. Mutational burden was associated with maf and proliferation gene expression groups, and a high-mutational burden was associated with a poor prognosis. We identified homozygous deletions that were present in multiple myeloma within key genes, including CDKN2C, RB1, TRAF3, BIRC3 and TP53, and that bi-allelic inactivation was significantly enriched at relapse. Alterations in CDKN2C, TP53, RB1 and the t(4;14) were associated with poor prognosis. Alterations in RB1 were predominantly homozygous deletions and were associated with relapse and a poor prognosis which was independent of other genetic markers, including t(4;14), after multivariate analysis. Bi-allelic inactivation of key tumor suppressor genes in myeloma was enriched at relapse, especially in RB1, CDKN2C and TP53 where they have prognostic significance.
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Mieloma Múltiplo/genética , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Humanos , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia , Prognóstico , Proteína do Retinoblastoma/genéticaAssuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos , Agentes de Imunomodulação/uso terapêutico , Mieloma Múltiplo/patologia , Mutação , Ubiquitina-Proteína Ligases/genética , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genéticaRESUMO
The purpose of this project was to identify large numbers of Arabidopsis genes with essential functions during seed development. More than 120,000 T-DNA insertion lines were generated following Agrobacterium-mediated transformation. Transgenic plants were screened for defective seeds and putative mutants were subjected to detailed analysis in subsequent generations. Plasmid rescue and TAIL-PCR were used to recover plant sequences flanking insertion sites in tagged mutants. More than 4200 mutants with a wide range of seed phenotypes were identified. Over 1700 of these mutants were analyzed in detail. The 350 tagged embryo-defective (emb) mutants identified to date represent a significant advance toward saturation mutagenesis of EMB genes in Arabidopsis. Plant sequences adjacent to T-DNA borders in mutants with confirmed insertion sites were used to map genome locations and establish tentative identities for 167 EMB genes with diverse biological functions. The frequency of duplicate mutant alleles recovered is consistent with a relatively small number of essential (EMB) genes with nonredundant functions during seed development. Other functions critical to seed development in Arabidopsis may be protected from deleterious mutations by extensive genome duplications.
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Arabidopsis/genética , Arabidopsis/fisiologia , Mutagênese Insercional , Alelos , Cromossomos/genética , Cruzamentos Genéticos , Genoma de Planta , Modelos Genéticos , Mutação , Fenótipo , Plantas Geneticamente Modificadas , Plasmídeos/metabolismo , Reação em Cadeia da Polimerase , Transformação GenéticaRESUMO
BACKGROUND: The purposes of this study were to investigate the pharmacokinetics of methylphenidate hydrochloride (Ritalin) in the human brain, to compare them with those of cocaine, and to evaluate whether cocaine and methylphenidate compete for the same binding sites. METHODS: We used positron emission tomography to measure the temporal and spatial distribution of carbon 11 (11C)-labeled methylphenidate. These results were compared with those obtained previously for [11C]cocaine. Eight healthy male subjects, 20 to 51 years of age, were scanned with [11C]methylphenidate. Three were tested twice to assess test-retest variability, four were tested at baseline and after administration of methylphenidate, and one was tested with [11C]methylphenidate and [11C]cocaine. Two baboons were scanned to evaluate whether there was competition between cocaine and methylphenidate for the same binding sites in the brain. RESULTS: The uptake of [11C]methylphenidate in the brain was high (mean +/- SD, 7.5% +/- 1.5%), and the maximal concentration occurred in striatum. Pretreatment with methylphenidate decreased binding only in striatum (40%). Although the regional distribution of [11C]methylphenidate, was identical to that of [11C]cocaine and they competed with each other for the same binding sites, these two drugs differed markedly in their pharmacokinetics. Clearance of [11C]methylphenidate from striatum (90 minutes) was significantly slower than that of [11C]cocaine (20 minutes). For both drugs, their fast uptake in striatum paralleled the experience of the "high." For methylphenidate, the high decreased very rapidly despite significant binding of the drug in the brain. In contrast, for cocaine, the decline in the high paralleled its fast rate of clearance from the brain. CONCLUSION: We speculate that because the experience of the high is associated with the fast uptake of cocaine and methylphenidate in the brain, the slow clearance of methylphenidate from the brain may serve as a limiting factor in promoting its frequent self-administration.