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BACKGROUND: The first angiotensin receptor/neprilysin inhibitor on the market, sacubitril-valsartan, has shown marked improvements in death and hospitalization for heart failure among adults, and is now approved for use in pediatric heart failure. While the ongoing PANORAMA-HF trial is evaluating the effectiveness of sacubitril-valsartan for pediatric patients with a failing systemic left ventricle, the enrollment criteria do not include the majority of pediatric heart failure patients. Additional studies are needed. METHODS: Using the TriNetX database, we performed a propensity score matched, retrospective cohort study to assess the incidence of a composite of all-cause mortality or heart transplant within 1 year. The 519 patients who received sacubitril-valsartan were compared to 519 matched controls who received an angiotensin converting enzyme inhibitor (ACE) or angiotensin II receptor blocker (ARB). RESULTS: There was no significant difference in the incidence of the composite outcome with sacubitril-valsartan over an ACE/ARB (13.3% vs 13.2%, p = 0.95), or among the components of mortality (5.0% vs 5.8%, p = 0.58) or heart transplantation (8.7% vs 7.5%, p = 0.50). Patients who were receiving full goal-directed medical therapy (14.4% vs 16.0%, p = 0.55) also showed no difference in the composite outcome. We observed a significantly increased incidence of hypotension (10% vs 5.2%, p = 0.006) and a trend toward reduced number of hospitalizations per year (mean (SD) 1.3 (4.4) vs 2.0 (9.1), p = 0.09). CONCLUSIONS: Sacubitril-valsartan is not associated with a decrease in the composite of all-cause mortality or heart transplantation within 1 year. Future studies should evaluate the possible reduction in hospitalizations and optimal dosing to minimize hypotension.
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Aminobutiratos , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Compuestos de Bifenilo , Combinación de Medicamentos , Insuficiencia Cardíaca , Tetrazoles , Valsartán , Humanos , Aminobutiratos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Estudios Retrospectivos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Valsartán/uso terapéutico , Masculino , Femenino , Niño , Antagonistas de Receptores de Angiotensina/uso terapéutico , Tetrazoles/uso terapéutico , Preescolar , Adolescente , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Lactante , Resultado del Tratamiento , Trasplante de Corazón , Puntaje de PropensiónRESUMEN
BACKGROUND: Higher prenatal ambient air pollution exposure has been associated with impaired neurodevelopment in preschoolers and school-aged children. The purpose of this study was to explore the relationships between prenatal ambient air pollution exposure and neurodevelopment during infancy. METHODS: This study examined 161 Latino mother-infant pairs from the Southern California Mother's Milk Study. Exposure assessments included prenatal nitrogen dioxide (NO2) and particulate matter smaller than 2.5 and 10 microns in diameter (PM2.5 and PM10, respectively). The pregnancy period was also examined as three windows, early, mid, and late, which describe the first, middle, and last three months of pregnancy. Infant neurodevelopmental outcomes at 2 years of age were measured using the Bayley-III Scales of Infant and Toddler Development. Multivariable linear models and distributed lag linear models (DLM) were used to examine relationships between prenatal exposures and neurodevelopmental scores, adjusting for socioeconomic status, breastfeeding frequency, time of delivery, pre-pregnancy body mass index, and infant birthweight and sex. RESULTS: Higher prenatal exposure to PM10 and PM2.5 was negatively associated with composite cognitive score (ß = -2.01 [-3.89, -0.13] and ß = -1.97 [-3.83, -0.10], respectively). In addition, higher average prenatal exposure to PM10 was negatively associated with composite motor (ß = -2.35 [-3.95, -0.74]), scaled motor (ß = -0.77 [-1.30, -0.24]), gross motor (ß = -0.37 [-0.70, -0.04]), fine motor (ß = -0.40 [-0.71, -0.09]), composite language (ß = -1.87 [-3.52, -0.22]), scaled language (ß = -0.61 [-1.18, -0.05]) and expressive communication scaled scores (ß = -0.36 [-0.66, -0.05]). DLMs showed that higher prenatal air pollution exposure during mid and late pregnancy was inversely associated with motor, cognitive, and communication language scores. CONCLUSIONS: Higher exposure to air pollutants during pregnancy, particularly in the mid and late prenatal periods, was inversely associated with scaled and composite motor, cognitive, and language scores at 2 years. These results indicate that prenatal ambient air pollution may negatively impact neurodevelopment in early life.
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Contaminantes Atmosféricos , Contaminación del Aire , Efectos Tardíos de la Exposición Prenatal , Lactante , Femenino , Humanos , Embarazo , Niño , Efectos Tardíos de la Exposición Prenatal/epidemiología , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Material Particulado/efectos adversos , Material Particulado/análisis , Modelos Lineales , Exposición a Riesgos Ambientales/efectos adversos , Exposición Materna/efectos adversosRESUMEN
Epidemiological studies in adults have shown that exposure to ambient air pollution (AAP) is associated with the composition of the adult gut microbiome, but these relationships have not been examined in infancy. We aimed to determine if 6-month postnatal AAP exposure was associated with the infant gut microbiota at 6 months of age in a cohort of Latino mother-infant dyads from the Southern California Mother's Milk Study (n = 103). We estimated particulate matter (PM2.5 and PM10) and nitrogen dioxide (NO2) exposure from birth to 6-months based on residential address histories. We characterized the infant gut microbiota using 16S rRNA amplicon sequencing at 6-months of age. At 6-months, the gut microbiota was dominated by the phyla Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. Our results show that, after adjusting for important confounders, postnatal AAP exposure was associated with the composition of the gut microbiota. As an example, PM10 exposure was positively associated with Dialister, Dorea, Acinetobacter, and Campylobacter while PM2.5 was positively associated with Actinomyces. Further, exposure to PM10 and PM2.5 was inversely associated with Alistipes and NO2 exposure was positively associated with Actinomyces, Enterococcus, Clostridium, and Eubacterium. Several of these taxa have previously been linked with systemic inflammation, including the genera Dialister and Dorea. This study provides the first evidence of significant associations between exposure to AAP and the composition of the infant gut microbiota, which may have important implications for future infant health and development.
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Contaminantes Atmosféricos , Contaminantes Ambientales , Microbioma Gastrointestinal , Dióxido de Nitrógeno/efectos adversos , Adulto , Contaminantes Atmosféricos/efectos adversos , Humanos , Lactante , Material Particulado/efectos adversos , ARN Ribosómico 16S/genéticaRESUMEN
There is a growing body of evidence that a substantial number of protein domains identified as DNA-binding also interact with RNA to regulate biological processes. Several recent studies have revealed that the Sox2 transcription factor binds RNA through its high-mobility group box (HMGB) domain in vitro and in vivo. A high degree of conservation of this domain among members of the Sox family of transcription factors suggests that RNA-binding activity may be a general feature of these proteins. To address this hypothesis, we examined a subset of HMGB domains from human Sox family of proteins for their ability to bind both DNA and RNA in vitro. We observed selective, high-affinity interactions between Sox family HMGB domains and various model RNA elements, including a four-way junction RNA, a hairpin RNA with an internal bulge, G-quadruplex RNA, and a fragment of long noncoding RNA ES2, which is known to directly interact with Sox2. Importantly, the HMGB domains bind these RNA ligands significantly tighter than nonconsensus dsDNA and in some cases with affinities rivaling those of their consensus dsDNA sequences. These data suggest that RNA binding is a conserved feature of the Sox family of transcription factors with the potential to modulate unappreciated biological functions.
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Primary cilia are non-motile plasma membrane extrusions that display a variety of receptors and mechanosensors. Loss of function results in ciliopathies, which have been strongly linked with congenital heart disease, as well as abnormal development and function of most organ systems. Adults with congenital heart disease have high rates of acquired heart failure, and usually die from a cardiac cause. Here we explore primary cilia's role in acquired heart disease. Intraflagellar Transport 88 knockout results in reduced primary cilia, and knockout from cardiac endothelium produces myxomatous degeneration similar to mitral valve prolapse seen in adult humans. Induced primary cilia inactivation by other mechanisms also produces excess myocardial hypertrophy and altered scar architecture after ischemic injury, as well as hypertension due to a lack of vascular endothelial nitric oxide synthase activation and the resultant left ventricular dysfunction. Finally, primary cilia have cell-to-cell transmission capacity which, when blocked, leads to progressive left ventricular hypertrophy and heart failure, though this mechanism has not been fully established. Further research is still needed to understand primary cilia's role in adult cardiac pathology, especially heart failure.
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Ciliopatías , Cardiopatías Congénitas , Insuficiencia Cardíaca , Cilios/metabolismo , Ciliopatías/metabolismo , Corazón , Cardiopatías Congénitas/metabolismo , Insuficiencia Cardíaca/metabolismo , HumanosRESUMEN
The Lake Michigan Ozone Study 2017 (LMOS 2017) was a collaborative multiagency field study targeting ozone chemistry, meteorology, and air quality observations in the southern Lake Michigan area. The primary objective of LMOS 2017 was to provide measurements to improve air quality modeling of the complex meteorological and chemical environment in the region. LMOS 2017 science questions included spatiotemporal assessment of nitrogen oxides (NO x = NO + NO2) and volatile organic compounds (VOC) emission sources and their influence on ozone episodes; the role of lake breezes; contribution of new remote sensing tools such as GeoTASO, Pandora, and TEMPO to air quality management; and evaluation of photochemical grid models. The observing strategy included GeoTASO on board the NASA UC-12 aircraft capturing NO2 and formaldehyde columns, an in situ profiling aircraft, two ground-based coastal enhanced monitoring locations, continuous NO2 columns from coastal Pandora instruments, and an instrumented research vessel. Local photochemical ozone production was observed on 2 June, 9-12 June, and 14-16 June, providing insights on the processes relevant to state and federal air quality management. The LMOS 2017 aircraft mapped significant spatial and temporal variation of NO2 emissions as well as polluted layers with rapid ozone formation occurring in a shallow layer near the Lake Michigan surface. Meteorological characteristics of the lake breeze were observed in detail and measurements of ozone, NOx, nitric acid, hydrogen peroxide, VOC, oxygenated VOC (OVOC), and fine particulate matter (PM2.5) composition were conducted. This article summarizes the study design, directs readers to the campaign data repository, and presents a summary of findings.
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Certain transcription factors are proposed to form functional interactions with RNA to facilitate proper regulation of gene expression. Sox2, a transcription factor critical for maintenance of pluripotency and neurogenesis, has been found associated with several lncRNAs, although it is unknown whether these interactions are direct or via other proteins. Here we demonstrate that human Sox2 interacts directly with one of these lncRNAs with high affinity through its HMG DNA-binding domain in vitro. These interactions are primarily with double-stranded RNA in a non-sequence specific fashion, mediated by a similar but not identical interaction surface. We further determined that Sox2 directly binds RNA in mouse embryonic stem cells by UV-cross-linked immunoprecipitation of Sox2 and more than a thousand Sox2-RNA interactions in vivo were identified using fRIP-seq. Together, these data reveal that Sox2 employs a high-affinity/low-specificity paradigm for RNA binding in vitro and in vivo.
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ARN/metabolismo , Factores de Transcripción SOXB1/metabolismo , Animales , Secuencia de Bases , Unión Competitiva , ADN/metabolismo , Masculino , Ratones , Modelos Moleculares , Células Madre Embrionarias de Ratones/metabolismo , Unión Proteica , Dominios Proteicos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factores de Transcripción SOXB1/química , Eliminación de Secuencia , Electricidad EstáticaRESUMEN
The glucocorticoid receptor (GR) binds the noncoding RNA Gas5 via its DNA-binding domain (DBD) with functional implications in pro-apoptosis signaling. Here, we report a comprehensive in vitro binding study where we have determined that GR-DBD is a robust structure-specific RNA-binding domain. GR-DBD binds to a diverse range of RNA hairpin motifs, both synthetic and biologically derived, with apparent mid-nanomolar affinity while discriminating against uniform dsRNA. As opposed to dimeric recognition of dsDNA, GR-DBD binds to RNA as a monomer and confers high affinity primarily through electrostatic contacts. GR-DBD adopts a discrete RNA-bound state, as assessed by NMR, distinct from both free and DNA-bound. NMR and alanine mutagenesis suggest a heightened involvement of the C-terminal α-helix of the GR-DBD in RNA-binding. RNA competes for binding with dsDNA and occurs in a similar affinity range as dimer binding to the canonical DNA element. Given the prevalence of RNA hairpins within the transcriptome, our findings strongly suggest that many RNAs have potential to impact GR biology.
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Proteínas de Unión al ADN/química , ADN/química , ARN/química , Receptores de Glucocorticoides/química , Secuencia de Bases , Sitios de Unión , Unión Competitiva , ADN/genética , ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Modelos Moleculares , Conformación de Ácido Nucleico , Unión Proteica , Dominios Proteicos , ARN/metabolismo , Receptores de Glucocorticoides/metabolismoRESUMEN
RNAs directly regulate a vast array of cellular processes, emphasizing the need for robust approaches to fluorescently label and track RNAs in living cells. Here, we develop an RNA imaging platform using the cobalamin riboswitch as an RNA tag and a series of probes containing cobalamin as a fluorescence quencher. This highly modular 'Riboglow' platform leverages different colored fluorescent dyes, linkers and riboswitch RNA tags to elicit fluorescence turn-on upon binding RNA. We demonstrate the ability of two different Riboglow probes to track mRNA and small noncoding RNA in live mammalian cells. A side-by-side comparison revealed that Riboglow outperformed the dye-binding aptamer Broccoli and performed on par with the gold standard RNA imaging system, the MS2-fluorescent protein system, while featuring a much smaller RNA tag. Together, the versatility of the Riboglow platform and ability to track diverse RNAs suggest broad applicability for a variety of imaging approaches.
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Colorantes Fluorescentes , Microscopía Fluorescente/instrumentación , ARN/química , Riboswitch , Animales , Aptámeros de Nucleótidos , Línea Celular Tumoral , Color , Escherichia coli , Fluorescencia , Proteínas Fluorescentes Verdes , Células HEK293 , Células HeLa , Humanos , Plásmidos/metabolismo , ARN Nuclear Pequeño/químicaRESUMEN
BACKGROUND: Dyspnea is a common and ambiguous complaint that results in 3.4 million emergency department (ED) visits annually. While learners may encounter lists of differential diagnoses to consider while in training, often these lists are not empirically based. We sought to establish an evidence-based differential diagnosis for dyspnea and to determine whether normal vital signs can rule out a life-threatening diagnosis. METHODS: We analyzed data from the National Hospital Ambulatory Medical Care Survey from 2005 to 2014 for ED visits with a chief complaint of dyspnea and tallied the principal discharge diagnosis. We included 10,170 sampled ED visits by adults with a chief complaint of dyspnea, representing nearly 42 million visits nationally. We then calculated the most common principal discharge diagnoses by age group and the frequency of abnormal respiratory vital signs in cases with life-threatening diagnoses. RESULTS: The most represented age group was 45 to 64 years (31.6%). Most visits were discharged directly from the ED (57.5%), while 8.1% required admission to an intensive care unit (ICU). The most common diagnosis in patients aged 18 to 44 was acute asthma exacerbation (14.8%). Obstructive chronic bronchitis was the most common specified diagnosis in both patients ages 45 to 64 (11.1%) and patients ages 65 to 79 (12.4%), while congestive heart failure was the most common for patients ages 80 and over (15.9%). Respiratory vital signs were frequently normal in the 44.6% of visits that resulted in a potentially life-threatening diagnosis but corresponded to increased ICU utilization when abnormal. CONCLUSIONS: For patients with dyspnea, the high utilization of ICUs highlights the importance of an accurate differential. The frequencies established here can be used as pretest probabilities in Bayesian analysis to improve the accuracy of differential diagnosis lists.
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Disnea/etiología , Servicio de Urgencia en Hospital/estadística & datos numéricos , Signos Vitales/fisiología , Enfermedad Aguda/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Asma/epidemiología , Teorema de Bayes , Estudios Transversales , Diagnóstico Diferencial , Disnea/epidemiología , Femenino , Encuestas de Atención de la Salud , Insuficiencia Cardíaca/epidemiología , Humanos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Alta del Paciente/estadística & datos numéricos , Adulto JovenRESUMEN
Bamboos are one of the fastest growing plants on Earth, and are widely considered to have high ability to capture and sequester atmospheric carbon, and consequently to mitigate climate change. We tested this hypothesis by measuring carbon dioxide (CO2 ) emissions from bamboo culms and comparing them with their biomass sequestration potential. We analysed diurnal effluxes from Bambusa vulgaris culm surface and gas mixtures inside hollow sections of various bamboos using gas chromatography. Corresponding variations in gas pressure inside the bamboo section and culm surface temperature were measured. SEM micrographs of rhizome and bud portions of bamboo culms were also recorded. We found very high CO2 effluxes from culm surface, nodes and buds of bamboos. Positive gas pressure and very high concentrations of CO2 were observed inside hollow sections of bamboos. The CO2 effluxes observed from bamboos were very high compared to their carbon sequestration potential. Our measurements suggest that bamboos are net emitters of CO2 during their lifespan.
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Bambusa/metabolismo , Dióxido de Carbono/metabolismo , Carbono/metabolismo , Cambio Climático , Rizoma/metabolismo , TemperaturaRESUMEN
Domestic ruminants and Wild ungulates can act as reservoir hosts for Mycobacterium bovis, causative agent for bovine tuberculosis (BTB) in animals and man. Bovine tuberculosis (BTB) is endemic in pastoral livestock in Tanzania. There is lack of information on genotypic distribution of M. bovis in animals at wildlife-livestock interface areas and in wildlife conserved areas. The objectives of this study were to characterize and determine the spatial distribution of M. bovis isolates. Tissue samples from cattle and wildlife were cultured and analyzed using deletion typing and spoligotyping techniques. Eight (8.9%) M. bovis strains were isolated from cattle and confirmed by RD4 and RD9 polymerize chain reaction (PCR) assays. Spoligotype SB1467 was the dominant pattern 62.5% (n = 8) in infected animals, two isolates belonged to a newly reported type SB2190, and one isolate belonged to SB0133. The spoligotype patterns of SB1467 and SB0133 were closely related (96.9%) while SB2190 was less related (59.4%) to SB0133, the relatedness amongst spoligotypes were associated with spacer position 15. No M. bovis was isolated from hunted wild animals. The current study has identified a novel spoligotype SB2190. The current data suggest that wild animals in Mikumi-Selous ecosystem are at risk of acquiring M. bovis infection due to occasional interaction by sharing of pasture and water sources between wildlife and livestock. Integrated efforts by all stakeholders are crucial for controlling spread of tuberculosis at livestock/wildlife/human interface areas.
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Mycobacterium bovis/genética , Tuberculosis Bovina/microbiología , Animales , Animales Salvajes/microbiología , Técnicas de Tipificación Bacteriana/métodos , Bovinos , Reservorios de Enfermedades/microbiología , Reservorios de Enfermedades/veterinaria , Ecosistema , Variación Genética , Mycobacterium bovis/clasificación , Mycobacterium bovis/aislamiento & purificación , Prevalencia , Tanzanía/epidemiología , Tuberculosis Bovina/epidemiología , Tuberculosis Bovina/transmisiónRESUMEN
Urban regions are hotspots of greenhouse gas emissions which include CO(2), CH(4), N(2)O, etc. Methane is a strong greenhouse gas which is produced from a number of sources including fossil fuel combustion, municipal waste, and sewage processing, etc. Ground level mixing ratio of methane in the tropical coastal city of Thiruvananthapuram in South India, during calm early morning period was measured. Measurements were done during both winter and summer seasons. Concentrations were significantly higher than global average value. Intra-city variation in ground level mixing ratio was also significant. Ground level methane concentration at Thiruvananthapuram urban area showed maximum value of 3.16 ppmV. Under stable atmospheric conditions in early morning, ground level mixing ratio of methane was 2.79 ppmV in winter and 2.54 ppmV during summer. The spatial distribution of methane concentration shows correlation with urban heat island.
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Contaminantes Atmosféricos/análisis , Ciudades , Metano/análisis , Monitoreo del Ambiente/métodos , Humanos , India , Clima TropicalRESUMEN
Raman Tweezers have been successfully applied to characterize chemically-induced oxidative stress on optically-trapped live, single erythrocytes. There is significant enhancement in Raman peak intensities corresponding to SS and C-S stretching modes that are induced by oxidative stress. This is consistent with the formation of mixed disulphides between protein SH groups and low-molecular-mass thiols such as glutathione during oxidative damage to cells. Enhancement in glutathione level as a protective response against oxidative stress has been observed. Principal component analysis of the data yields good discrimination between spectra of normal and stress-induced red blood cells.
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Eritrocitos/efectos de los fármacos , Estrés Oxidativo , Espectrometría Raman , Eritrocitos/metabolismo , Eritrocitos/fisiología , Glutatión/metabolismo , Humanos , Radical Hidroxilo/farmacología , Pinzas Ópticas , Análisis de Componente PrincipalRESUMEN
BACKGROUND: Deposition of crystals within tubular lumens is a feature of many kidney stone diseases, including crystals of calcium oxalate monohydrate (COM) in primary hyperoxaluria and of 2,8-dihydroxyadenine (DHA) in adenine phosphoribosyltransferase deficiency. Crystals are injurious to renal epithelial cells, but the molecular bases of cell injury have not been well characterized. METHODS: We used a cDNA microarray to identify the time-dependent changes in gene expression associated with the interaction of COM or DHA crystals with primary cultures of normal human kidney cortical epithelial cells. RESULTS: We observed gene expression changes that were common to both crystal types, as well as a number of crystal-specific responses. A subset of genes known to be aberrantly expressed in kidney tissue from stone formers also showed an altered expression in COM- or DHA-treated normal human kidney cortical epithelial cells. CONCLUSIONS: Our results show that cultured epithelial cells exposed to COM or DHA crystals demonstrate cellular responses that may be physiologically relevant, thus suggesting that this experimental system may be useful for elucidating the mechanisms of crystal-induced renal cell injury.
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Células Epiteliales/metabolismo , Perfilación de la Expresión Génica/métodos , Cálculos Renales/metabolismo , Adenina/análogos & derivados , Adenina/toxicidad , Oxalato de Calcio/toxicidad , Línea Celular , Cristalización , Células Epiteliales/efectos de los fármacos , Humanos , Cálculos Renales/inducido químicamente , Cálculos Renales/patología , Análisis de Secuencia por Matrices de Oligonucleótidos/métodosRESUMEN
OBJECTIVE: To compare the efficacy of intravenous ergometrine, intramuscular oxytocin, and oral misoprostol in the control of postpartum hemorrhage. METHODS: Mean blood loss, rates of blood loss between 500 and 1000 ml, hematocrit fall greater than 10%, and need for additional oxytocic agents and nature and rates of adverse effects were assessed in this prospective, randomized, controlled study. RESULTS: All outcomes were similar in the 3 groups. The main adverse effects in the misoprostol group were temperatures higher than 99 degrees F, which normalized within 2 h and shivering, which was mild and self-limiting. CONCLUSIONS: Oral misoprostol is as effective as conventional oxytocic agents in preventing postpartum hemorrhage and can be recommended for use in low-resource settings.
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Ergonovina/administración & dosificación , Tercer Periodo del Trabajo de Parto/efectos de los fármacos , Misoprostol/administración & dosificación , Oxitócicos/administración & dosificación , Oxitocina/administración & dosificación , Hemorragia Posparto/prevención & control , Administración Oral , Femenino , Humanos , Inyecciones Intramusculares , Inyecciones Intravenosas , Embarazo , Estudios Prospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: The objective of this study was to investigate neuropsychological impairment as a genetically mediated risk indicator for schizophrenia while accounting for prevalence of schizotypy signs/symptoms in siblings. METHOD: Cognitive functioning in 25 individuals with schizophrenia, 25 unaffected siblings and 25 unrelated healthy controls, was assessed using neuropsychological tests of sustained attention, memory and learning, executive function, visual-spatial ability and psychomotor performance. RESULTS: Unaffected siblings demonstrated better performance than patients on some measures of memory and learning and executive function. Patients and siblings demonstrated impaired Full Scale IQ and verbal fluency, otherwise siblings performed similarly to healthy controls. Controlling for differences in IQ, the shared deficit in verbal fluency disappeared. CONCLUSION: Patients with schizophrenia and unaffected siblings (without schizotypy personality disorder) shared a neuropsychological deficit in verbal fluency. This deficit appeared to be mediated by IQ. Deficits, which differentiated patients from controls, may not be inherited and perhaps are related to the manifestation or treatment of schizophrenia.
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Trastornos del Conocimiento/etiología , Esquizofrenia/complicaciones , Adulto , Atención , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/genética , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Masculino , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/etiología , Pruebas Neuropsicológicas , Trastornos de la Percepción/diagnóstico , Trastornos de la Percepción/etiología , Trastornos Psicomotores/diagnóstico , Trastornos Psicomotores/etiología , Factores de Riesgo , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Hermanos , Percepción Visual/fisiologíaRESUMEN
During tumor progression, multiple genetic changes in the genome vastly alter the transcriptomes of cancers. Some of these changes, including the mutations of various growth regulatory genes as well as alterations in the transcription of a large number of genes, may lead to resistance to treatment. Therefore, capturing such genomic information of the tumors would enable a physician to decide on the course of treatment options clinically available. Currently, it is still not feasible to identify all the genetic mutations that have occurred in a patient's cancer genome. However, the advent of DNA microarray coupled with the completion of the human genome sequence and the identification of all its genes, have made possible genome-wide gene expression profiling of the cancer genome. In this review, we will focus on the application of expression genomics for identifying signature gene expression profiles in primary cancers to predict response to either radio- or chemotherapy. We envision that transcription profiling of the cancer genomes ultimately will not only reveal how altered gene expression results in resistance to treatment, but also be exploited for predicting and personalizing cancer therapy.
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Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neoplasias/terapia , Animales , Antineoplásicos/uso terapéutico , Progresión de la Enfermedad , Genoma , Genómica , Humanos , Neoplasias/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Resultado del TratamientoRESUMEN
Many studies suggest green tea is a cancer chemopreventive agent. This effect has been attributed to its major constituent (-)-epigallocatechin-3-gallate (EGCG). EGCG is also observed to have cytotoxic anticancer effects, especially when used in combination with certain chemotherapeutic agents. The biochemical actions of EGCG in chemoprevention and anticancer effects have been studied; however, the mechanisms of action are not clearly understood. We show here by expression genomics the effects of EGCG (25 micromol/L) in the Ha-ras gene transformed human bronchial epithelial 21BES cells. We found induction of temporal changes in gene expression and the coalescence of specific genetic pathways by EGCG. In this experimental system, hydrogen peroxide (H2O2) was produced. By treating cells with EGCG in the presence or absence of catalase, we further distinguished gene expression changes that are mediated by H2O2 from those that are H2O2 independent. Many genes and cellular pathways, including genes of the transforming growth factor-beta signaling pathway, were H2O2 dependent because the effects were abolished by catalase. Gene expression changes that were not affected by catalase included those of the bone morphogenetic protein signaling pathway, peptidylprolyl isomerase (cyclophilin)-like 2, alkylated DNA repair enzyme alkB, polyhomeotic-like 2, and homeobox D1. We show further that EGCG and H2O2 differentially transactivated the bone morphogenetic protein and the transforming growth factor-beta response element promoter reporters, respectively, thus confirming results from DNA microarray analysis. The elucidation of gene expression changes between H2O2-dependent and H2O2-independent responses helps us better understand the cancer chemopreventive and anticancer actions of EGCG.