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OBJECTIVE: to describe the clinical and safety outcomes between andexanet alfa (AA) and 4-factor prothrombin complex concentrate (4F-PCC) for the reversal of apixaban or rivaroxaban in the setting of an intracranial hemorrhage (ICH). METHODS: A retrospective, multicentered descriptive study was conducted in hospitalized patients 18 years of age or older from June 2018 to October 2019 who received AA or 4F-PCC for the reversal of apixaban or rivaroxaban in the setting of ICH. Patients were excluded if they had received 4F-PCC prior to AA after its addition to the institution wide formulary. Other exclusion criteria were history or presence of heparin-induced thrombocytopenia or disseminated intravascular coagulation, estimated hematoma volume of >60 mL, Glasgow Coma Scores <7, or no repeat CT head scan. Information was collected from the electronic medical records. The primary outcome was the achievement of excellent or good hemostatic efficacy upon the repeat computer tomography (CT) scan performed after the infusion of study drugs. Secondary outcomes included disposition, survival to hospital discharge, 30-day readmission, length of hospital stay, length of ICU stay, incidence of thromboembolic events. RESULTS: A total of 24 patients were included in the study, of which 9 received AA and 15 received 4F-PCC. The achievement of excellent or good hemostatic efficacy upon repeat CT scan occurred in 7 (77.8%) patients in the AA group and in 14 (93.3%) patients in the 4-F PCC group. All patients in the AA group survived to hospital discharge with no 30-day morality and 86.7% patients in the 4F-PCC group. CONCLUSION: This study suggests that real-world clinical and safety outcomes between andexanet alfa and 4F-PCC for the reversal of factor Xa inhibitors in the setting of ICH are similar to ones reported in clinical trials.
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Hemostáticos , Rivaroxabana , Humanos , Adolescente , Adulto , Rivaroxabana/efeitos adversos , Estudos Retrospectivos , Fatores de Coagulação Sanguínea/uso terapêutico , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/tratamento farmacológico , Fator Xa/uso terapêutico , Hemostáticos/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Anticoagulantes/efeitos adversosAssuntos
Miopatias Congênitas Estruturais , Miosite de Corpos de Inclusão , Miosite , Humanos , Miosite de Corpos de Inclusão/complicações , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/genética , Músculo Esquelético , Miopatias Congênitas Estruturais/diagnóstico , Miopatias Congênitas Estruturais/genética , FenótipoRESUMO
BACKGROUND: In 2015, the Centers for Medicare and Medicaid Services (CMS) and the Joint Commission launched the sepsis core measures in an attempt to decrease sepsis morbidity and mortality. Recent studies call into question the multiple treatment measures in early goal-directed therapy on which these CMS measures are based. OBJECTIVES: The purpose of this study is to compare the utilization of resources due to the implementation of the sepsis core measures while examining whether complying with these treatment guidelines decreases patient mortality. METHODS: Data were collected on patients suspected of sepsis in a suburban academic emergency department. These data were collected over the course of 3 consecutive years. The data collected included lactates, blood cultures, and antibiotics (vancomycin, piperacillin/tazobactam) ordered. The mortality rate of patients with a final diagnosis of sepsis present on arrival was calculated for a 3-month period of each year and compared. RESULTS: There was no difference in the mortality rates of patients with sepsis across the 3 years. There was an increase in the amount of piperacillin/tazobactam and vancomycin administered. There was a significant increase in the number of lactates and blood cultures ordered per patient across all 3 years. CONCLUSIONS: There was no difference in the mortality rate of patients with a final diagnosis of sepsis. However, there was a significant increase in the utilization of resources to care for these patients. As a result of the overutilization of these resources, the cost for both patients and hospitals has increased without improvement in mortality.
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Serviço Hospitalar de Emergência/normas , Guias de Prática Clínica como Assunto , Sepse/terapia , Antibacterianos/uso terapêutico , Biomarcadores/sangue , Hemocultura , Centers for Medicare and Medicaid Services, U.S. , Fidelidade a Diretrizes , Mortalidade Hospitalar , Humanos , Estudos Retrospectivos , Sepse/mortalidade , Estados UnidosRESUMO
Adult neurogenesis is actively studied in part because of the potential to manipulate endogenous neural stem and progenitor cells for tissue repair. Although constitutive generation of neurons in the adult rodent olfactory bulb and hippocampal dentate gyrus is widely accepted and stroke-induced generation of striatal inhibitory neurons consistently observed, evidence supporting the generation of neurons in the neocortex after neuronal loss remains slim. Nevertheless, a few studies suggested that targeted apoptosis of neocortical glutamatergic neurons could trigger the generation of new ones in the adult brain. In light of such studies, we tested whether apoptosis of glutamatergic cortical neurons using two novel transgenic approaches in mice, an inducible Caspase-8 protein and an inducible diphtheria toxin gene, results in new neurons. After a thorough analysis, no new neurons were detected in the neocortex. Interestingly, an increase in the expression of the neuroblast marker DCX was observed in both models, in some cases in cells with morphologies previously associated with poststroke neuroblasts, but DCX(+) cells coexpressed the oligodendrocyte precursor marker Olig2, suggesting caution when using DCX as a marker for neuroblasts after injury. Given that the adult neocortex lacks an innate potential to regenerate lost glutamatergic neurons, future strategies should concentrate on manipulating the differentiation potential of endogenous or exogenous precursor cells.
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Apoptose/fisiologia , Glutamatos/fisiologia , Neocórtex/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Caspase 8/genética , Toxina Diftérica/genética , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Proteínas Associadas aos Microtúbulos/biossíntese , Degeneração Neural/genética , Degeneração Neural/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Neuropeptídeos/biossíntese , Fator de Transcrição 2 de Oligodendrócitos , Regulação para CimaRESUMO
BACKGROUND: The early telencephalon shares molecular features with the early mid-hindbrain region. In particular, these two developing brain areas each have a signaling center that secretes FGFs and an adjacent one that secretes WNTs. WNTs and FGFs each play essential roles in regulating cell fates in both the telencephalon and mid-hindbrain. Despite this similarity, telencephalic and mid-hindbrain precursors express distinct genes and ultimately generate different cell types, tissue morphologies, and neural functions. RESULTS: Here we show that genetically increasing the level of ß-catenin, a mediator of canonical WNT signaling, in the anterior neural plate causes a loss of telencephalic characteristics and a gain of mid-hindbrain characteristics. CONCLUSION: These results, together with previous ones demonstrating that increased WNT signaling in the anterior neural plate increases FGF expression, suggest that the levels of WNT and FGF signaling regulate telencephalic versus mid-hindbrain fates.
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Mesencéfalo/metabolismo , Placa Neural/metabolismo , Rombencéfalo/metabolismo , beta Catenina/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Mesencéfalo/embriologia , Camundongos , Camundongos Mutantes , Placa Neural/embriologia , Rombencéfalo/embriologia , Telencéfalo/embriologia , Telencéfalo/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/genéticaRESUMO
Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.
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Esclerose Lateral Amiotrófica , COVID-19 , Doença dos Neurônios Motores , Humanos , Doença dos Neurônios Motores/diagnóstico , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/terapia , Estudos Prospectivos , PandemiasRESUMO
Amyotrophic lateral sclerosis (ALS) involves progressive motor neuron loss, leading to paralysis and death typically within 3-5 years of diagnosis. Dysfunctional astrocytes may contribute to disease and glial cell line-derived neurotrophic factor (GDNF) can be protective. Here we show that human neural progenitor cells transduced with GDNF (CNS10-NPC-GDNF) differentiated to astrocytes protected spinal motor neurons and were safe in animal models. CNS10-NPC-GDNF were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study (NCT02943850). The primary endpoint of safety at 1 year was met, with no negative effect of the transplant on motor function in the treated leg compared with the untreated leg. Tissue analysis of 13 participants who died of disease progression showed graft survival and GDNF production. Benign neuromas near delivery sites were common incidental findings at post-mortem. This study shows that one administration of engineered neural progenitors can provide new support cells and GDNF delivery to the ALS patient spinal cord for up to 42 months post-transplantation.
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Esclerose Lateral Amiotrófica , Células-Tronco Neurais , Esclerose Lateral Amiotrófica/terapia , Animais , Modelos Animais de Doenças , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Humanos , Medula Espinal , Superóxido DismutaseRESUMO
Exome or genome sequencing was performed to identify the genetic etiology for the clinical presentation of global developmental delay, intellectual disability, and sensorimotor neuropathy with associated distal weakness in two unrelated families. A homozygous frameshift variant c.186delA (p.A63Qfs*3) in the NUDT2 gene was identified in cases 1 and 2 from one family and a third case from another family. Variants in NUDT2 were previously shown to cause intellectual disability, but here we expand the phenotype by demonstrating its association with distal upper and lower extremity weakness due to a sensorimotor polyneuropathy with demyelinating and/or axonal features.
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Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Monoéster Fosfórico Hidrolases/genética , Polineuropatias/genética , Adulto , Criança , Deficiências do Desenvolvimento/diagnóstico , Eletroencefalografia , Eletromiografia , Feminino , Mutação da Fase de Leitura , Humanos , Deficiência Intelectual/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Linhagem , Polineuropatias/diagnóstico , Sequenciamento do Exoma , Adulto JovemRESUMO
COX20/FAM36A encodes a mitochondrial complex IV assembly factor important for COX2 activation. Only one homozygous COX20 missense mutation has been previously described in two separate consanguineous families. We report four subjects with features that include childhood hypotonia, areflexia, ataxia, dysarthria, dystonia, and sensory neuropathy. Exome sequencing in all four subjects identified the same novel COX20 variants. One variant affected the splice donor site of intron-one (c.41A>G), while the other variant (c.157+3G>C) affected the splice donor site of intron-two. cDNA and protein analysis indicated that no full-length cDNA or protein was generated. These subjects expand the phenotype associated with COX20 deficiency.
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Ataxia/genética , Disartria/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Linhagem , FenótipoRESUMO
OBJECTIVE: This study was conducted to evaluate the impact of education on optimizing medication histories in a single-center pediatric emergency department. METHODS: This was a prospective, 2-phase study of 200 patients ages 21 years and younger who presented to the pediatric emergency department in January and February 2017. In phase I of the study, 100 patients were interviewed by both a nurse and a pharmacist. Between phases I and II, the pharmacist educated each nurse and disseminated standardized education materials. In phase II, 100 additional patients were interviewed by both a nurse and a pharmacist. Discrepancies were quantified in both phases of the study. The primary outcome was the distribution of total discrepancies in medications identified. Total discrepancies were defined as a composite of medication name, dose, route, frequency, and time of last dose. RESULTS: A total of 200 medication histories were collected over phases I and II. In phase I (n = 79), the pharmacist identified 185 medications, 88 of which were also identified by the nurse. In phase II (n = 82), the pharmacist identified 180 medications, 95 of which were also identified by the nurse. The distribution of discrepancies per patient and per medication was significantly reduced in regard to dose, route, and frequency documentation. CONCLUSION: Although improvement was observed, barriers beyond a knowledge deficit exist to limit accuracy of medication histories collected by nurses.
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[reaction: see text] An enantioselective total synthesis of (-)-mucocin has been completed. A combination of asymmetric glycolate aldol additions and ring closing metathesis reactions were exploited to construct the C18-C34 and C7-C17 fragments. A selective cross-metathesis reaction was employed as the key step to couple two complex fragments.
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Lactonas/síntese química , Piranos/síntese química , Lactonas/química , Estrutura Molecular , Piranos/química , Rollinia/química , EstereoisomerismoRESUMO
OBJECTIVE: We sought to assess the potential of a widely available source of electronic medication data to prevent medication history errors and resultant inpatient order errors. METHODS: We used admission medication history (AMH) data from a recent clinical trial that identified 1017 AMH errors and 419 resultant inpatient order errors among 194 hospital admissions of predominantly older adult patients on complex medication regimens. Among the subset of patients for whom we could access current Surescripts electronic pharmacy claims data (SEPCD), two pharmacists independently assessed error severity and our main outcome, which was whether SEPCD (1) was unrelated to the medication error; (2) probably would not have prevented the error; (3) might have prevented the error; or (4) probably would have prevented the error. RESULTS: Seventy patients had both AMH errors and current, accessible SEPCD. SEPCD probably would have prevented 110 (35%) of 315 AMH errors and 46 (31%) of 147 resultant inpatient order errors. When we excluded the least severe medication errors, SEPCD probably would have prevented 99 (47%) of 209 AMH errors and 37 (61%) of 61 resultant inpatient order errors. SEPCD probably would have prevented at least one AMH error in 42 (60%) of 70 patients. CONCLUSION: When current SEPCD was available for older adult patients on complex medication regimens, it had substantial potential to prevent AMH errors and resultant inpatient order errors, with greater potential to prevent more severe errors. Further study is needed to measure the benefit of SEPCD in actual use at hospital admission.
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Sistemas de Informação em Farmácia Clínica , Prescrição Eletrônica , Reembolso de Seguro de Saúde , Erros de Medicação/prevenção & controle , Reconciliação de Medicamentos , Idoso , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Farmácias , Ensaios Clínicos Pragmáticos como Assunto , Estados UnidosRESUMO
Silk from the silkworm, Bombyx mori, has been used as biomedical suture material for centuries. The unique mechanical properties of these fibers provided important clinical repair options for many applications. During the past 20 years, some biocompatibility problems have been reported for silkworm silk; however, contamination from residual sericin (glue-like proteins) was the likely cause. More recent studies with well-defined silkworm silk fibers and films suggest that the core silk fibroin fibers exhibit comparable biocompatibility in vitro and in vivo with other commonly used biomaterials such as polylactic acid and collagen. Furthermore, the unique mechanical properties of the silk fibers, the diversity of side chain chemistries for 'decoration' with growth and adhesion factors, and the ability to genetically tailor the protein provide additional rationale for the exploration of this family of fibrous proteins for biomaterial applications. For example, in designing scaffolds for tissue engineering these properties are particularly relevant and recent results with bone and ligament formation in vitro support the potential role for this biomaterial in future applications. To date, studies with silks to address biomaterial and matrix scaffold needs have focused on silkworm silk. With the diversity of silk-like fibrous proteins from spiders and insects, a range of native or bioengineered variants can be expected for application to a diverse set of clinical needs.
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Materiais Biocompatíveis , Proteínas de Insetos/química , Proteínas de Insetos/uso terapêutico , Animais , Bombyx , Adesão Celular , Fibroínas/química , Microscopia Eletrônica de Varredura , Seda , Resistência à Tração , Engenharia TecidualRESUMO
Chemokines (chemoattractant cytokines) and their receptors are present in the brain and may play roles in both neurodevelopment and neuropathology. Increased brain levels of monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, are found in patients with human immunodeficiency virus type 1 (HIV-1)-associated dementia and other acute and chronic neurologic diseases. Although the function of CCL2 in the brain is unclear, it is believed that upregulation of this chemokine during neuropathologic or neuroinflammatory conditions leads to recruitment of activated monocytes into the brain, where they differentiate into macrophages producing neurotoxic and inflammatory molecules. We recently showed that human fetal brain-derived progenitor cells are susceptible to HIV-1 and JC virus infection, and that differentiation toward an astrocyte phenotype increased virus production from these cells. In the current study, we found that in the absence of infection, progenitors produced moderate levels of CCL2 (5.6 ng per million cells). Astrocyte differentiation over 3 weeks increased CCL2 protein levels 30-fold in a biphasic manner, whereas neuronal differentiation decreased production 20-fold. Electromobility shift assays (EMSAs) demonstrated increased nuclear NF-kappaB levels within 2 h of initiating astrocyte differentiation, and inhibitors of NF-kappaB activation partially blocked the CCL2 increase in differentiating astrocytes. Transfection of progenitors with mutated CCL2 promoter/CAT reporter constructs showed that the distal promoter region, containing NF-kappaB and NF-I binding sites, is important for differentiation-induced CCL2 upregulation. Together these results suggest that the transcription factor NF-kappaB, and possibly NF-I, contribute to the upregulation of CCL2 chemokine production during the differentiation of human progenitor cells toward an astrocyte phenotype.
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Astrócitos/metabolismo , Diferenciação Celular/imunologia , Sistema Nervoso Central/embriologia , Quimiocina CCL2/metabolismo , Células-Tronco/metabolismo , Regulação para Cima/imunologia , Complexo AIDS Demência/imunologia , Complexo AIDS Demência/metabolismo , Complexo AIDS Demência/fisiopatologia , Astrócitos/citologia , Astrócitos/imunologia , Sítios de Ligação/fisiologia , Diferenciação Celular/genética , Células Cultivadas , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Quimiocina CCL2/genética , Quimiotaxia/genética , Quimiotaxia/imunologia , HIV-1/imunologia , HIV-1/metabolismo , Humanos , Vírus JC/imunologia , Vírus JC/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fatores de Transcrição NFI/genética , Fatores de Transcrição NFI/metabolismo , Fenótipo , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/metabolismo , Infecções por Polyomavirus/fisiopatologia , Regiões Promotoras Genéticas/genética , Células-Tronco/citologia , Células-Tronco/imunologia , Ativação Transcricional/fisiologia , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/metabolismo , Infecções Tumorais por Vírus/fisiopatologia , Regulação para Cima/genéticaRESUMO
An improved understanding of cellular responses during normal anterior cruciate ligament (ACL) function or repair is essential for clinical assessments, understanding ligament biology, and the implementation of tissue engineering strategies. The present study utilized quantitative real-time RT-PCR combined with univariate and multivariate statistical analyses to establish a quantitative database of marker transcript expression that can provide a "blueprint" of ACL wound healing. Selected markers (collagen types I and III, biglycan, decorin, MMP-1, MMP-2, MMP-9, and TIMP-1) were assessed from 33 torn ACLs harvested during reconstructive surgery. Trends were observed between postinjury period and marker expressions. Significant correlations between marker expression existed and were most prominent between collagen types I and III. Canonical correlation analysis established a relationship between patient demographics and a combination of all marker expressions. The currently observed trends and correlations may assist in identifying appropriate tissue samples and provide a baseline information of marker expression level that can support in vitro optimization of environmental cues for ligament tissue engineering application.
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Ligamento Cruzado Anterior/metabolismo , Ligamento Cruzado Anterior/patologia , Proteínas da Matriz Extracelular/genética , Peptídeo Hidrolases/genética , Transcrição Gênica/genética , Adolescente , Adulto , Fatores Etários , Lesões do Ligamento Cruzado Anterior , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Caracteres SexuaisRESUMO
Since the initial description of progressive multifocal leukoencephalopathy (PML) in 1958, clinical and basic science investigators have demonstrated a growing interest in the area of neurovirology, with a recent focus on polyomaviruses. In this review, the authors present an overview of the biological properties of the human polyomavirus, JC virus (JCV), and its association with PML as the etiologic agent. Additionally, the authors provide a discussion of the current understanding of JCV molecular pathogenesis and therapeutic strategies.
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Antivirais/uso terapêutico , Vírus JC/fisiologia , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Leucoencefalopatia Multifocal Progressiva/virologia , Humanos , Incidência , Leucoencefalopatia Multifocal Progressiva/epidemiologiaRESUMO
JC virus (JCV), a human neurotropic polyomavirus, demonstrates a selective glial cell tropism that causes cell death through lytic infection. Whether these cells die via apoptosis or necrosis following infection with JCV remains unclear. To investigate the mechanism of virus-induced cell death, we used a human central nervous system progenitor-derived astrocyte cell culture model developed in our laboratory. Using in situ DNA hybridization, immunocytochemistry, electron microscopy, and an RNase protection assay, we observed that astrocytes support a progressive JCV infection, which eventually leads to nonapoptotic cell death. Infected astrocyte cell cultures showed no difference from noninfected cells in mRNA expression of the caspase family genes or in any ultrastructural features associated with apoptosis. Infected cells demonstrated striking necrotic features such as cytoplasmic vacuolization, watery cytoplasm, and dissolution of organelles. Furthermore, staining for caspase-3 and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling were not detected in infected astrocyte cultures. Our findings suggest that JCV-induced cell death of these progenitor cell-derived astrocytes does not utilize an apoptosis pathway but exhibits a pattern of cell destruction consistent with necrotic cell death.