RESUMEN
Paenibacillus is one of the genera that has high species diversity and Paenibacillus polymyxa, the type species of the genus, is mainly isolated from plant-associated environments. Among the plant-associated species, Paenibacillus jamilae B.3T (=CECT 5266T=DSM 13815T=KACC 10925T=KCTC 13919T) was proposed to be a novel species according to 16S rRNA gene similarity and DNA-DNA relatedness with related species, including Paenibacillus polymyxa. Nevertheless, in the description of Paenibacillus jamilae the used strain of Paenibacillus polymyxa was not the type strain of this species. In this work we found that the type strains of both species showed 16S rRNA gene similarity of 99.6â%. Therefore, in this study, we sequenced the genome of Paenibacillus jamilae KACC 10925T and compared it with those of the type strain of Paenibacillus polymyxa ATCC 842T and other phylogenetically related species. Genome relatedness value calculated by DNA-DNA hybridization between type strains of Paenibacillus polymyxa and Paenibacillus jamilae was 73.5â%, which is higher than the threshold value (70â%). For more objective and repeatable results of genome relatedness, we analysed an average nucleotide identity (ANI) between two strains. Our results showed that ANI value between the type strains of Paenibacillus jamilae and Paenibacillus polymyxa is 98.5â%, a phylogenetic distance also higher than the threshold values (95~96â%). These values were proposed by Yoon et al. (2017). In addition, their phylogenetic distance based on 92 bacterial core genes is highly close compared to other species. These mean that Paenibacillus jamilae and Paenibacillus polymyxa should be reclassified as a single species. Based on the results from genomic level comparison as well as reexamination results of physiological and chemotaxonomic features, we propose reclassification of Paenibacillus jamilae as a later heterotypic synonym of Paenibacillus polymyxa.
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Paenibacillus polymyxa/clasificación , Paenibacillus/clasificación , Filogenia , Técnicas de Tipificación Bacteriana , ADN Bacteriano/genética , Genes Bacterianos , Genómica , Hibridación de Ácido Nucleico , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADNRESUMEN
Members of the genus Weissella are mostly found in fermented plant material. Among the Weissella species, two species, Weissella thailandensis and Weissella jogaejeotgali, were isolated from foods fermented from marine animals. The two species showed a high level of 16S rRNA gene similarity (99.39â%), whereas they exhibited a moderate level of DNA-DNA hybridization relatedness (63.9â%) in an earlier study. In this study, we determined the whole genome sequence of W. thailandensis KCTC 3751T and compared it to those of W. jogaejeotgali FOL01T and other related species. The average nucleotide identity value between the type strains of W. thailandensis and W. jogaejeotgali was 96.4â%, which is clearly higher than the cut-off proposed for bacterial species. We, therefore, propose to reclassify W. jogaejeotgali as a later heterotypic synonym of W. thailandensis.
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Alimentos Fermentados/microbiología , Filogenia , Weissella/clasificación , Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano/genética , Ácidos Grasos/química , Hibridación de Ácido Nucleico , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , TailandiaRESUMEN
BACKGROUND & AIMS: Obesity and metabolic syndrome have been associated with alterations to the intestinal microbiota. However, few studies examined the effects of obesity on the intestinal immune system. We investigated changes in subsets of intestinal CD4+ T-helper (TH) cells with obesity and the effects of gut-tropic TH17 cells in mice on a high-fat diet (HFD). METHODS: We isolated immune cells from small intestine and adipose tissue of C57BL/6 mice fed a normal chow diet or a HFD for 10 weeks and analyzed the cells by flow cytometry. Mice fed a vitamin A-deficient HFD were compared with mice fed a vitamin A-sufficient HFD. Obese RAG1-deficient mice were given injections of only regulatory T cells or a combination of regulatory T cells and TH17 cells (wild type or deficient in integrin ß7 subunit or interleukin 17 [IL17]). Mice were examined for weight gain, fat mass, fatty liver, glucose tolerance, and insulin resistance. Fecal samples were collected before and after T cell transfer and analyzed for microbiota composition by metagenomic DNA sequencing and quantitative polymerase chain reaction. RESULTS: Mice placed on a HFD became obese, which affected the distribution of small intestinal CD4+ TH cells. Intestinal tissues from obese mice had significant reductions in the proportion of TH17 cells but increased proportion of TH1 cells, compared with intestinal tissues from nonobese mice. Depletion of vitamin A in obese mice further reduced the proportion of TH17 cells in small intestine; this reduction correlated with more weight gain and worsening of glucose intolerance and insulin resistance. Adoptive transfer of in vitro-differentiated gut-tropic TH17 cells to obese mice reduced these metabolic defects, which required the integrin ß7 subunit and IL17. Delivery of TH17 cells to intestines of mice led to expansion of commensal microbes associated with leanness. CONCLUSIONS: In mice, intestinal TH17 cells contribute to development of a microbiota that maintains metabolic homeostasis, via IL17. Gut-homing TH17 cells might be used to reduce metabolic disorders in obese individuals.
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Traslado Adoptivo , Inmunidad Mucosa , Resistencia a la Insulina , Intestino Delgado/inmunología , Síndrome Metabólico/prevención & control , Obesidad/prevención & control , Células Th17/trasplante , Animales , Células Cultivadas , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Heces/microbiología , Microbioma Gastrointestinal/inmunología , Genotipo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Interacciones Huésped-Patógeno , Cadenas beta de Integrinas/genética , Cadenas beta de Integrinas/metabolismo , Interleucina-17/deficiencia , Interleucina-17/genética , Intestino Delgado/metabolismo , Intestino Delgado/microbiología , Masculino , Síndrome Metabólico/genética , Síndrome Metabólico/inmunología , Síndrome Metabólico/microbiología , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/genética , Obesidad/inmunología , Obesidad/microbiología , Fenotipo , Células Th17/inmunología , Células Th17/microbiología , Factores de Tiempo , Deficiencia de Vitamina A/complicacionesRESUMEN
Randomized controlled clinical trials are conducted to determine whether a new treatment is safe and efficacious compared to a standard therapy. We consider randomized clinical trials with right censored time to event endpoint, called survival time here. The two-sample log-rank test is popularly used to test if the experimental therapy has a longer survival distribution than the control therapy or not. We consider an early stopping for futility only or for both futility and efficacy. For planning such clinical trials, this article presents two-stage designs that are optimal in the sense that either the maximal sample size or the expected sample size when the experimental therapy is futile or superior is minimized under the given type I and II error rates. Optimal designs for a range of design parameters are tabulated and evaluated using simulations.
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Ensayos Clínicos Fase II como Asunto , Interpretación Estadística de Datos , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Inutilidad Médica , Proyectos de Investigación , Tamaño de la Muestra , Tasa de SupervivenciaRESUMEN
Our goal was to examine the effect of area-level deprivation on patient survival time for seven major cancers - stomach, colon, liver, lung, breast, cervix, and thyroid cancer. Data on 10,902 subjects who were diagnosed with major cancers from 2010 and 2011 in Busan were collected regarding the survival time along with several important prognostic factors and an area-level deprivation index was constructed from education, income, unemployment, and welfare assistance, to assess the comprehensive area-level socioeconomic status. A multilevel Cox proportional hazard model was used to investigate the effects of multiple risk factors such as gender, age, tumor stage, diagnosis path, and the area-level deprivation. After adjusting for risk factors the area-level deprivation index was found to be significant in associating with higher hazard rate for several cancers. Estimated hazard ratios (95% CI) were 1.08 (0.99-1.18), 1.23 (1.12-1.36), 1.36 (1.21-1.53) for the second, the third, and the fourth quartile of deprivation index groups, respectively, when compared to the least deprived group. When compared with the least deprived group, the more deprived group showed significant decrease in survival time for major cancers. This novel finding may contribute to the literature regarding the association of area-level socioeconomic status and highlight the importance of careful monitoring of socioeconomic characteristics for cancer prevention and care services.
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Neoplasias/patología , Clase Social , Adolescente , Adulto , Factores de Edad , Anciano , Consumo de Bebidas Alcohólicas , Índice de Masa Corporal , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/mortalidad , Modelos de Riesgos Proporcionales , Sistema de Registros , República de Corea , Factores de Riesgo , Factores Sexuales , Fumar , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Intestinal microbiota play an important role in maintaining the homeostasis of the host immune system. To analyze the alteration of the intestinal microbial community structure in Korean Crohn's disease (CD) patients, we performed a comparative metagenomic analysis between healthy people and CD patients using fecal samples and mucosal tissues of ileocecal valve. METHODS: 16S rRNA genes from fecal samples or mucosal tissues of 35 CD patients and 15 healthy controls (HC) were amplified using a universal primer set and sequenced with GS FLX Titanium. The microbial composition and diversity of each sample were analyzed with the mothur pipeline, and the association between microbial community and clinical characteristics of the patients were investigated. RESULTS: The contribution of bacterial groups to the intestinal microbial composition differed between CD and HC, especially in fecal samples. Global structure and individual bacterial abundance of intestinal microbial community were different between feces and ileocecal tissues in HC. In CD patients with active stage, relative abundances of Gammaproteobacteria and Fusobacteria were higher in both fecal and mucosal tissue samples. Moreover, the intestinal microbial community structure was altered by anti-tumor necrosis factor (anti-TNF) treatment. CONCLUSIONS: Our 16S rRNA sequence data demonstrate intestinal dysbiosis at the community level in Korean CD patients, which is similar to alterations of the intestinal microbial community seen in the western counterparts. Clinical disease activity and anti-TNF treatment might affect the intestinal microbial community structure in CD patients.
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Enfermedad de Crohn/microbiología , ADN Ribosómico/genética , Disbiosis/microbiología , Microbioma Gastrointestinal/genética , ARN Ribosómico 16S/genética , Acidobacteria/genética , Actinobacteria/genética , Adulto , Antiinflamatorios no Esteroideos/uso terapéutico , Pueblo Asiatico , Azatioprina/uso terapéutico , Bacteroidetes/genética , Estudios de Casos y Controles , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/etnología , Disbiosis/etnología , Heces/microbiología , Femenino , Firmicutes/genética , Fusobacterias/genética , Gammaproteobacteria/genética , Fármacos Gastrointestinales/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Infliximab/uso terapéutico , Mucosa Intestinal/microbiología , Masculino , Mesalamina/uso terapéutico , Prednisolona/uso terapéutico , Proteobacteria/genética , República de Corea , Análisis de Secuencia de ADN , Análisis de Secuencia de ARN , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Although statistical methodology is well-developed for comparing diagnostic tests in terms of their sensitivity and specificity, comparative inference about predictive values is not. In this paper, we consider the analysis of studies comparing operating characteristics of two diagnostic tests that are measured on all subjects and have test outcomes from multiple sites with varying number of sites among subjects. We have developed a new approach for comparing sensitivity, specificity, positive predictive value, and negative predictive value with simple variance calculation and, in particular, focus on comparing tests using difference of positive and negative predictive values. Simulation studies are conducted to show the performance of our approach. We analyze real data on patients with lung cancer, based on their diagnostic tests, to illustrate the methodology.
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Biometría/métodos , Pruebas Diagnósticas de Rutina , Modelos Estadísticos , Simulación por Computador , Humanos , Valor Predictivo de las Pruebas , Sensibilidad y EspecificidadRESUMEN
A logistic regression method can be applied to regressing the [Formula: see text]-year survival probability to covariates, if there are no censored observations before time [Formula: see text]. But if some observations are incomplete due to censoring before time [Formula: see text], then the logistic regression cannot be applied. Jung (1996) proposed to modify the score function for logistic regression to accommodate the right-censored observations. His modified score function, motivated for a consistent estimation of regression parameters, becomes a regular logistic score function if no observations are censored before time [Formula: see text]. In this article, we propose a modification of Jung's estimating function for an optimal estimation for the regression parameters in addition to consistency. We prove that the optimal estimator is more efficient than Jung's estimator. This theoretical comparison is illustrated with a real example data analysis and simulations.
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Biometría/métodos , Análisis de Regresión , Análisis de Supervivencia , Simulación por Computador , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Fenobarbital/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Convulsiones/epidemiología , Convulsiones/prevención & control , Distribuciones EstadísticasRESUMEN
Four Gram-stain-negative, aerobic, rod-shaped bacterial strains, MM-124, MM-126, NB-68 and NB-77, were isolated from the coastal seawater or a region with a bloom of sea sparkle around Geoje island in Korea. The sequence similarity values of the 16S rRNA gene between the isolates and Sulfitobacter mediterraneus DSM 12244(T) ranged from 97.7 to 98.2%, and phylogenetic relationships suggested that they belong to a phylogenetic branch that includes the genera Sulfitobacter and Roseobacter. The isoprenoid quinone of all three novel strains was ubiquinone-10 and the major fatty acid was cis-vaccenic acid, as in other species of the genus Sulfitobacter. However, there were several differences in the morphological, physiological and biochemical characteristics among the four strains and the reference species of the genus Sulfitobacter. Moreover, the average nucleotide identity values between the three sequenced isolates and the reference strains were below 76.33, indicating that genomic variation exists between the isolates and reference strains. Chemotaxonomic characteristics together with phylogenetic affiliations and genomic distances illustrate that strains MM-124, NB-68 and NB-77 represent novel species of the genus Sulfitobacter, for which the names Sulfitobacter geojensis sp. nov. (type strain MM-124(T)â=KCTC 32124(T)â=JCM 18835(T)), Sulfitobacter noctilucae sp. nov. (type strain NB-68(T)â=KCTC 32122(T)â=JCM 18833(T)) and Sulfitobacter noctilucicola sp. nov. (type strain NB-77(T)â=KCTC 32123(T)â=JCM 18834(T)) are proposed.
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Filogenia , Rhodobacteraceae/clasificación , Agua de Mar/microbiología , Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano/genética , Datos de Secuencia Molecular , Hibridación de Ácido Nucleico , Ácidos Oléicos/química , ARN Ribosómico 16S/genética , República de Corea , Rhodobacteraceae/genética , Rhodobacteraceae/aislamiento & purificación , Análisis de Secuencia de ADN , Ubiquinona/análogos & derivados , Ubiquinona/químicaRESUMEN
Phase II clinical trials are often conducted to determine whether a new treatment is sufficiently promising to warrant a major controlled clinical evaluation against a standard therapy. We consider single-arm phase II clinical trials with right censored survival time responses where the ordinary one-sample logrank test is commonly used for testing the treatment efficacy. For planning such clinical trials, this paper presents two-stage designs that are optimal in the sense that the expected sample size is minimized if the new regimen has low efficacy subject to constraints of the type I and type II errors. Two-stage designs, which minimize the maximal sample size, are also determined. Optimal and minimax designs for a range of design parameters are tabulated along with examples.
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Supervivencia sin Enfermedad , Proyectos de Investigación , Algoritmos , Ensayos Clínicos Fase II como Asunto/estadística & datos numéricos , Interpretación Estadística de Datos , Humanos , Tamaño de la Muestra , Resultado del TratamientoRESUMEN
Given the recognized involvement of the gut microbiome in the development of obesity, considerable efforts are being made to discover probiotics capable of preventing and managing obesity. In this study, we report the discovery of Lactiplantibacillus plantarum GBCC_F0227, isolated from fermented food, which exhibited superior triglyceride catabolism efficacy compared to L. plantarum WCSF1. Molecular analysis showed elevated expression levels of α/ß hydrolases with lipase activity (abH04, abH08_1, abH08_2, abH11_1, and abH11_2) in L. plantarum GBCC_F0227 compared to L. plantarum WCFS1, demonstrating its enhanced lipolytic activity. In a high-fat-diet (HFD)-induced mouse obesity model, the administration of L. plantarum GBCC_F0227 mitigated weight gain, reduced blood triglycerides, and diminished fat mass. Furthermore, L. plantarum GBCC_F0227 upregulated adiponectin gene expression in adipose tissue, indicative of favorable metabolic modulation, and showed robust growth and low cytotoxicity, underscoring its industrial viability. Therefore, our findings encourage the further investigation of L. plantarum GBCC_F0227's therapeutic applications for the prevention and treatment of obesity and associated metabolic diseases.
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We study the analysis of a joint association between a genetic marker with both binary (case-control) and quantitative (continuous) traits, where the quantitative trait values are only available for the cases due to data sharing and outcome-dependent sampling. Data sharing becomes common in genetic association studies, and the outcome-dependent sampling is the consequence of data sharing, under which a phenotype of interest is not measured for some subgroup. The trend test (or Pearson's test) and F-test are often, respectively, used to analyze the binary and quantitative traits. Because of the outcome-dependent sampling, the usual F-test can be applied using the subgroup with the observed quantitative traits. We propose a modified F-test by also incorporating the genotype frequencies of the subgroup whose traits are not observed. Further, a combination of this modified F-test and Pearson's test is proposed by Fisher's combination of their P-values as a joint analysis. Because of the correlation of the two analyses, we propose to use a Gamma (scaled chi-squared) distribution to fit the asymptotic null distribution for the joint analysis. The proposed modified F-test and the joint analysis can also be applied to test single trait association (either binary or quantitative trait). Through simulations, we identify the situations under which the proposed tests are more powerful than the existing ones. Application to a real dataset of rheumatoid arthritis is presented.
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Estudios de Casos y Controles , Modelos Genéticos , Modelos Estadísticos , Carácter Cuantitativo Heredable , Artritis Reumatoide/genética , Cromosomas Humanos Par 1 , Simulación por Computador , Estudio de Asociación del Genoma Completo , Humanos , Difusión de la Información , Polimorfismo de Nucleótido SimpleRESUMEN
Genetic association studies in practice often involve multiple traits resulting from a common disease mechanism, and samples for such studies are often stratified based on some trait outcomes. In such situations, statistical methods using only one of these traits may be inadequate and lead to under-powered tests for detecting genetic associations. We propose in this article an estimation and testing procedure for evaluating the shared-association of a genetic marker on the joint distribution of multiple traits of a common disease. Specifically, we assume that the disease mechanism involves both quantitative and qualitative traits, and our samples could be stratified based on the qualitative trait. Through a joint likelihood function, we derive a class of estimators and test statistics for evaluating the shared genetic association on both the quantitative and qualitative traits. Our simulation study shows that the joint likelihood test procedure is potentially more powerful than association tests based on separate traits. Application of our proposed procedure is demonstrated through the rheumatoid arthritis data provided by the Genetic Analysis Workshop 16 (GAW16).
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Estudios de Asociación Genética/estadística & datos numéricos , Análisis de Regresión , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/genética , Biometría/métodos , Humanos , Funciones de Verosimilitud , Modelos Genéticos , Modelos Estadísticos , Péptidos Cíclicos/inmunología , Polimorfismo de Nucleótido Simple , Sitios de Carácter CuantitativoRESUMEN
Given that the active use of certain smartphone applications is associate with problematic smartphone use, it has been proposed that certain smartphone applications are more addictive than others, such as Social Networking Services (SNS). Still, studies that consider smartphone users' main usage application which are known to influence the users' problematic smartphone use, such as SNS, remain to be explored. Thus, the current study aims to investigate the psychological and motivational predictors of problematic smartphone use in a sample of smartphone-based SNS users whose main device usage is SNS. A series of mean comparison tests and binary logistic regression were performed in this study. Of the 433 smartphone-based SNS users, 218 were male (50.3%) and 215 were female (49.7%). Age of 433 participants ranged from 20 to 40, and mean age was 30.75 (SD = 7.84). 73 participants (16.9%) were sorted into the high-risk problematic smartphone use group and 360 participants (83.1%) were categorized as the normal user group. The finding from binary regression analysis showed that reward responsiveness from the Behavioral Activation System (BAS), a lack of self-control, and anxiety significantly increased the odds of problematic smartphone use of the smartphone-based SNS users. Reward responsiveness was found to be the most powerful predictor. Our findings broaden the existing literature and provide implications to reduce addictive smartphone use relating to smartphone-based SNS usage.
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Background: Serum asialo α1-acid gycoprotein (AsAGP) is a novel biomarker specific to liver fibrosis. Aim: To evaluate the diagnostic efficacy of serum AsAGP levels in classifying the severity of liver fibrosis and differentiating liver cirrhosis (LC) in patients with chronic hepatitis B (CHB) from healthy controls. Methods: Overall, 206 subjects were prospectively enrolled. LC was diagnosed based on liver stiffness levels (>11 kPa) measured using transient elastography. Serum AsAGP levels were measured using an antibody-lectin sandwich immunoassay. We investigated the diagnostic performance by comparing serum AsAGP levels among healthy control, CHB, and CHB with LC groups. Sensitivity, specificity, and optimal AsAGP cut-off values were also calculated. Results: Serum AsAGP levels were significantly different between healthy controls, CHB patients, and CHB patients with LC (1.04 ± 0.31 µg/mL, 1.12 ± 0.34 µg/mL, 1.51 ± 0.43 µg/mL respectively; p < 0.001). Serum AsAGP levels positively correlated with liver stiffness (r = 0.46, p < 0.001). AUROC of healthy control versus CHB with LC was 0.821 (p < 0.001, optimal cut-off 1.036 µg/mL). AUROC of healthy control versus CHB was 0.624 (p = 0.049, optimal cut-off level 0.934 µg/mL). AUROC of CHB versus CHB with LC was 0.765, (p < 0.001, optimal cut-off 1.260 µg/mL). Conclusions: Serum AsAGP levels in CHB patients with LC were significantly higher than those in healthy controls and CHB patients. AsAGP levels showed good diagnostic performance in predicting advanced fibrosis and cirrhosis, which suggests a potential role as a biomarker for predicting the progression of liver disease in CHB.
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Here, we present the high-quality draft genome sequence of the agar-degrading marine gammaproteobacterium Alteromonadaceae sp. strain G7, which was isolated from coastal seawater to be utilized as a bioresource for production of agar-derived biofuels. The 3.91-Mb genome contains a number of genes encoding algal polysaccharide-degrading enzymes such as agarases and sulfatases.
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Alteromonadaceae/genética , Genoma Bacteriano , Agar/metabolismo , Alteromonadaceae/aislamiento & purificación , Alteromonadaceae/metabolismo , Composición de Base , Secuencia de Bases , ADN Bacteriano/genética , Glicósido Hidrolasas/genética , Datos de Secuencia Molecular , Plásmidos , Agua de Mar/microbiología , Análisis de Secuencia de ADN , Sulfatasas/genéticaRESUMEN
Burkholderia pyrrocinia CH-67 was isolated from forest soil as a biocontrol agent to be utilized in agriculture. Here, we report the 8.05-Mb draft genome sequence of this bacterium. Its genome contains genes involved in biosynthesis of secondary metabolites and plant growth promotion, which may contribute to probiotic effects on plants.
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Burkholderia/genética , ADN Bacteriano/química , ADN Bacteriano/genética , Genoma Bacteriano , Análisis de Secuencia de ADN , Antifúngicos/metabolismo , Vías Biosintéticas/genética , Burkholderia/aislamiento & purificación , Burkholderia/metabolismo , Datos de Secuencia Molecular , Plantas , Probióticos , Microbiología del Suelo , ÁrbolesRESUMEN
Endophytes live inside plant tissues without causing any harm and may even benefit plants. Here, we provide the high-quality genome sequence of Burkholderia sp. strain KJ006, an endophytic bacterium of rice with antifungal activity. The 6.6-Mb genome, consisting of three chromosomes and a single plasmid, contains genes related to plant growth promotion or degradation of aromatic compounds.
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Burkholderia/genética , ADN Bacteriano/química , ADN Bacteriano/genética , Genoma Bacteriano , Análisis de Secuencia de ADN , Antifúngicos/metabolismo , Burkholderia/aislamiento & purificación , Burkholderia/metabolismo , Cromosomas Bacterianos , Endófitos/genética , Endófitos/aislamiento & purificación , Endófitos/metabolismo , Genes Bacterianos , Hidrocarburos Aromáticos/metabolismo , Redes y Vías Metabólicas/genética , Datos de Secuencia Molecular , Oryza/microbiología , PlásmidosRESUMEN
CONTEXT: While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. OBJECTIVES: To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. DESIGN, SETTING, AND PATIENTS: A randomized, 2 × 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤ 45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. INTERVENTIONS: Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. MAIN OUTCOME MEASURES: The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. RESULTS: The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P = .96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (−0.9% [95% CI, −6.6% to 4.9%], P = .76) or day 7 (1.1% [95% CI, −4.7% to 6.9%], P = .70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. CONCLUSION: Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00684021.
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Trasplante de Médula Ósea/métodos , Infarto del Miocardio/terapia , Disfunción Ventricular Izquierda/terapia , Anciano , Método Doble Ciego , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Factores de Tiempo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/complicacionesRESUMEN
CONTEXT: Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE: To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS: A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION: Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES: Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS: Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION: Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00824005.