RESUMEN
A 56-year-old man presented with subacute night sweats, fever, and weight loss with worsening dyspnea. Computed tomography (CT) scan demonstrated miliary pattern of nodules evenly distributed throughout all lung fields. Given the patient's CT findings and temporal association with Bacille Calmette-Guerin (BCG) immunotherapy for bladder cancer, the patient was diagnosed with disseminated Mycobacterium bovis secondary to BCG bladder instillations.
Asunto(s)
Neoplasias de la Vejiga Urinaria , Administración Intravesical , Disnea/etiología , Humanos , Masculino , Persona de Mediana Edad , Sudor , Neoplasias de la Vejiga Urinaria/complicaciones , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Pérdida de PesoRESUMEN
This is the first known community transmission case of the novel coronavirus disease (COVID-19) in the United States, with significant public health implications. Diagnosis of COVID-19 is currently confirmed with PCR based testing of appropriate respiratory samples. Given the absence of travel or known exposure history, this patient did not meet the criteria for testing according to CDC guidelines at the time of her presentation. Since this case, any patient with severe disease (eg, ARDS or pneumonia) requiring hospitalization without an explanatory diagnosis can be tested even if no clear source of exposure is identified. While influencing national health policies for revising screening criteria, this case also highlighted significant knowledge gaps in diagnosis and treatment and a desperate need for early, widespread, fast and cheap testing for COVID-19.
Asunto(s)
COVID-19/diagnóstico por imagen , Infecciones Comunitarias Adquiridas/virología , Síndrome de Dificultad Respiratoria/virología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Adulto , Alanina/análogos & derivados , Alanina/uso terapéutico , Antivirales/uso terapéutico , COVID-19/complicaciones , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Factores de Riesgo , Choque Séptico/etiología , Tórax/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Estados Unidos/epidemiología , Tratamiento Farmacológico de COVID-19RESUMEN
We report on an adult with cystic fibrosis (ΔF508/G551D) with severe lung disease (forced expiratory volume (FEV1) in one second 24% predicted) who was admitted for a pulmonary exacerbation. He was managed with maximal medical therapy, but did not have significant improvement until after he was started on ivacaftor on hospital day 15. He subsequently had significant improvement in lung function with normalization of hypercarbia, oxygen saturation on room air, and increase in FEV1 to 36% predicted. Prior to use of ivacaftor he was being assessed for a lung transplant. However, after ivacaftor therapy for 6 months, he is no longer considering this treatment modality due to his improvement of lung function and functional status.
Asunto(s)
Aminofenoles/uso terapéutico , Fibrosis Quística/complicaciones , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/etiología , Quinolonas/uso terapéutico , Adulto , Fibrosis Quística/fisiopatología , Volumen Espiratorio Forzado , Humanos , Enfermedades Pulmonares/fisiopatología , Masculino , Índice de Severidad de la EnfermedadRESUMEN
Mouse APOBEC3 (mA3) is a cytidine deaminase with antiviral activity. mA3 is linked to the Rfv3 virus resistance factor, a gene responsible for recovery from infection by Friend murine leukemia virus, and mA3 allelic variants differ in their ability to restrict mouse mammary tumor virus. We sequenced mA3 genes from 38 inbred strains and wild mouse species, and compared the mouse sequence and predicted structure with human APOBEC3G (hA3G). An inserted sequence was identified in the virus restrictive C57BL strain allele that disrupts a splice donor site. This insertion represents the long terminal repeat of the xenotropic mouse gammaretrovirus, and was acquired in Eurasian mice that harbor xenotropic retrovirus. This viral regulatory sequence does not alter splicing but is associated with elevated mA3 expression levels in spleens of laboratory and wild-derived mice. Analysis of Mus mA3 coding sequences produced evidence of positive selection and identified 10 codons with very high posterior probabilities of having evolved under positive selection. Six of these codons lie in two clusters in the N-terminal catalytically active cytidine deaminase domain (CDA), and 5 of those 6 codons are polymorphic in Rfv3 virus restrictive and nonrestrictive mice and align with hA3G CDA codons that are critical for deaminase activity. Homology models of mA3 indicate that the two selected codon clusters specify residues that are opposite each other along the predicted CDA active site groove, and that one cluster corresponds to an hAPOBEC substrate recognition loop. Substitutions at these clustered mA3 codons alter antiviral activity. This analysis suggests that mA3 has been under positive selection throughout Mus evolution, and identified an inserted retroviral regulatory sequence associated with enhanced expression in virus resistant mice and specific residues that modulate antiviral activity.
Asunto(s)
Citidina Desaminasa/genética , Desaminasa APOBEC-3G , Secuencia de Aminoácidos , Animales , Animales Salvajes/genética , Antirretrovirales/química , Secuencia de Bases , Evolución Molecular , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Insercional , Selección Genética , Homología de Secuencia de Ácido NucleicoRESUMEN
Geminiviruses encapsidate single-stranded DNA genomes that replicate in plant cell nuclei through double-stranded DNA intermediates that associate with cellular histone proteins to form minichromosomes. Like most plant viruses, geminiviruses are targeted by RNA silencing and encode suppressor proteins such as AL2 and L2 to counter this defense. These related proteins can suppress silencing by multiple mechanisms, one of which involves interacting with and inhibiting adenosine kinase (ADK), a cellular enzyme associated with the methyl cycle that generates S-adenosyl-methionine, an essential methyltransferase cofactor. Thus, we hypothesized that the viral genome is targeted by small-RNA-directed methylation. Here, we show that Arabidopsis plants with mutations in genes encoding cytosine or histone H3 lysine 9 (H3K9) methyltransferases, RNA-directed methylation pathway components, or ADK are hypersensitive to geminivirus infection. We also demonstrate that viral DNA and associated histone H3 are methylated in infected plants and that cytosine methylation levels are significantly reduced in viral DNA isolated from methylation-deficient mutants. Finally, we demonstrate that Beet curly top virus L2- mutant DNA present in tissues that have recovered from infection is hypermethylated and that host recovery requires AGO4, a component of the RNA-directed methylation pathway. We propose that plants use chromatin methylation as a defense against DNA viruses, which geminiviruses counter by inhibiting global methylation. In addition, our results establish that geminiviruses can be useful models for genome methylation in plants and suggest that there are redundant pathways leading to cytosine methylation.