RESUMEN
BACKGROUND: Antipsychotic medications, particularly second-generation antipsychotics, are increasingly being used to alleviate the symptoms of schizophrenia and other severe mental disorders in the pediatric population. While evidence-based approaches examining efficacy and safety outcomes have been reported, no review has evaluated prolactin-based adverse events for antipsychotic treatments in schizophrenia and schizophrenia spectrum disorders. METHODS/DESIGN: Searches involving MEDLINE, EMBASE, CENTRAL, PsycINFO, and clinical trial registries (ClinicalTrials.gov, Drug Industry Document Archive [DIDA], International Clinical Trials Registry Platform [ICTRP]) will be used to identify relevant studies. Two reviewers will independently screen abstracts and relevant full-text articles of the papers identified by the initial search according to the prospectively defined eligibility criteria. Data extraction will be conducted in duplicate independently. Pairwise random effects meta-analyses and network meta-analyses will be conducted on individual drug and class effects where appropriate. DISCUSSION: This systematic review will evaluate prolactin-based adverse events of first- and second-generation antipsychotics in the pediatric population with schizophrenia and schizophrenia spectrum disorders. It will also seek to strengthen the evidence base of the safety of antipsychotics by incorporating both randomized controlled trials and observational studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009506.
Asunto(s)
Antipsicóticos/efectos adversos , Prolactina/sangre , Proyectos de Investigación , Esquizofrenia/sangre , Esquizofrenia/tratamiento farmacológico , Adolescente , Niño , Preescolar , Femenino , Galactorrea/sangre , Galactorrea/inducido químicamente , Ginecomastia/sangre , Ginecomastia/inducido químicamente , Humanos , Masculino , Trastornos de la Menstruación/sangre , Trastornos de la Menstruación/inducido químicamente , Disfunciones Sexuales Fisiológicas/sangre , Disfunciones Sexuales Fisiológicas/inducido químicamente , Revisiones Sistemáticas como AsuntoRESUMEN
OBJECTIVE: To compare the efficacy of the three nonergot dopamine-receptor agonists (DAs) pramipexole, ropinirole, and rotigotine for the treatment of early and advanced Parkinson's disease (PD). MATERIALS AND METHODS: Bayesian network meta-analyses were performed separately for early and advanced PD, and at time points 11-16 and 24-28 weeks. Outcomes for early PD included improvement on the Unified Parkinson's Disease Rating Scale (UPDRS) activities in daily life (UPDRS-II), motor function (UPDRS-III), and their subtotal (UPDRS-II + III). Outcomes for advanced PD also included daily "off time" (hours), but not UPDRS-II + III. RESULTS: Totals of 23 and 24 trials informed early and advanced PD analyses. For early PD UPDRS-II at 11-16 weeks, pramipexole and rotigotine were statistically significantly superior to placebo, but ropinirole was not. For UPDRS-III and UPDRS-II + III, all DAs were statistically significantly better than placebo and exhibited similar improvements. At 24-28 weeks, results were also statistically significant for all DAs versus placebo, and the magnitudes of improvements were similar for pramipexole, ropinirole and rotigotine. Advanced PD improvements on UPDRS-II, UPRDS-III, and off time were statistically significant for pramipexole, ropinirole, and rotigotine versus placebo. At 11-16 weeks, rotigotine yielded slightly smaller effects than ropinirole and pramipexole, but credible intervals on differences were wide. For off time, results were near identical. At 24-28 weeks, results were similar for all three outcomes. Ropinirole yielded a slightly higher improvement on UPDRS-III, but a slightly smaller improvement in off time. CONCLUSION: Our analyses suggest that pramipexole, ropinirole, and rotigotine exhibit similar efficacy in the treatment of early and advanced PD.
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BACKGROUND: Stopping smoking is associated with many important improvements in health and quality of life. The use of cessation medications is recommended to increase the likelihood of quitting. However, there is historical and renewed concern that smoking cessation therapies may increase the risk of cardiovascular disease events associated within the quitting period. We aimed to examine whether the 3 licensed smoking cessation therapies-nicotine replacement therapy, bupropion, and varenicline-were associated with an increased risk of cardiovascular disease events using a network meta-analysis. METHODS AND RESULTS: We searched 10 electronic databases, were in communication with authors of published randomized, clinical trials (RCTs), and accessed internal US Food and Drug Administration reports. We included any RCT of the 3 treatments that reported cardiovascular disease outcomes. Among 63 eligible RCTs involving 21 nicotine replacement therapy RCTs, 28 bupropion RCTs, and 18 varenicline RCTs, we found no increase in the risk of all cardiovascular disease events with bupropion (relative risk [RR], 0.98; 95% confidence interval [CI], 0.54-1.73) or varenicline (RR, 1.30; 95% CI, 0.79-2.23). There was an elevated risk associated with nicotine replacement therapy that was driven predominantly by less serious events (RR, 2.29; 95% CI, 1.39-3.82). When we examined major adverse cardiovascular events, we found a protective effect with bupropion (RR, 0.45; 95% CI, 0.21-0.85) and no clear evidence of harm with varenicline (RR, 1.34; 95% CI, 0.66-2.66) or nicotine replacement therapy (RR, 1.95; 95% CI, 0.26-4.30). CONCLUSION: Smoking cessation therapies do not appear to raise the risk of serious cardiovascular disease events.
Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Agonistas Nicotínicos/efectos adversos , Cese del Hábito de Fumar/métodos , Cese del Hábito de Fumar/estadística & datos numéricos , Fumar/tratamiento farmacológico , Fumar/epidemiología , Adulto , Benzazepinas/administración & dosificación , Benzazepinas/efectos adversos , Bupropión/administración & dosificación , Bupropión/efectos adversos , Inhibidores de Captación de Dopamina/administración & dosificación , Inhibidores de Captación de Dopamina/efectos adversos , Femenino , Humanos , Masculino , Nicotina/administración & dosificación , Nicotina/efectos adversos , Agonistas Nicotínicos/administración & dosificación , Quinoxalinas/administración & dosificación , Quinoxalinas/efectos adversos , Factores de Riesgo , VareniclinaRESUMEN
The inhibitor of growth (ING) family of zinc-finger plant homeodomain (PHD)-containing chromatin remodeling protein controls gene expression and has been implicated in the regulation of cell proliferation and death. However, the role of ING proteins in cell differentiation remains largely unexplored. Here, we identify an essential function for ING2 in muscle differentiation. We find that knockdown of ING2 by RNA interference (RNAi) blocks the differentiation of C2C12 cells into myotubes, suggesting that ING2 regulates the myogenic differentiation program. We also characterize a mechanism by which ING2 drives muscle differentiation. In structure-function analyses, we find that the leucine zipper motif of ING2 contributes to ING2-dependent muscle differentiation. By contrast, the PHD domain, which recognizes the histone H3K4me3 epigenetic mark, inhibits the ability of ING2 to induce muscle differentiation. We also find that the Sin3A-HDAC1 chromatin remodeling complex, which interacts with ING2, plays a critical role in ING2-dependent muscle differentiation. These findings define a novel function for ING2 in muscle differentiation and bear significant implications for our understanding of the role of the ING protein family in cell differentiation and tumor suppression.
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Diferenciación Celular , Ensamble y Desensamble de Cromatina , Proteínas de Homeodominio/metabolismo , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Secuencias de Aminoácidos , Animales , Sitios de Unión , Técnicas de Silenciamiento del Gen , Histonas/metabolismo , Proteínas de Homeodominio/química , Humanos , Leucina Zippers , Lisina/metabolismo , Metilación , Ratones , Células Musculares/citología , Células Musculares/metabolismo , Desarrollo de Músculos , Mioblastos/citología , Mioblastos/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Supresoras de Tumor/químicaRESUMEN
Notch and transforming growth factor beta (TGFbeta) play critical roles in endothelial-to-mesenchymal transition (EndMT), a process that is essential for heart development. Previously, we have shown that Notch and TGFbeta signaling synergistically induce Snail expression in endothelial cells, which is required for EndMT in cardiac cushion morphogenesis. Here, we report that Notch activation modulates TGFbeta signaling pathways in a receptor-activated Smad (R-Smad)-specific manner. Notch activation inhibits TGFbeta/Smad1 and TGFbeta/Smad2 signaling pathways by decreasing the expression of Smad1 and Smad2 and their target genes. In contrast, Notch increases SMAD3 mRNA expression and protein half-life and regulates the expression of TGFbeta/Smad3 target genes in a gene-specific manner. Inhibition of Notch in the cardiac cushion of mouse embryonic hearts reduces Smad3 expression. Notch and TGFbeta synergistically up-regulate a subset of genes by recruiting Smad3 to both Smad and CSL binding sites and cooperatively inducing histone H4 acetylation. This is the first evidence that Notch activation affects R-Smad expression and that cooperative induction of histone acetylation at specific promoters underlies the selective synergy between Notch and TGFbeta signaling pathways.
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Células Endoteliales/efectos de los fármacos , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/farmacología , Proteínas Adaptadoras Transductoras de Señales , Animales , Sitios de Unión/genética , Proteínas de Unión al Calcio , Línea Celular , Inmunoprecipitación de Cromatina , Embrión de Mamíferos/embriología , Embrión de Mamíferos/metabolismo , Células Endoteliales/citología , Células Endoteliales/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Immunoblotting , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , Ratones Transgénicos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores Notch/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína smad3/genética , Proteína smad3/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , TransfecciónRESUMEN
Proteomics and targeted gene disruption were used to investigate the catabolism of benzene, styrene, biphenyl, and ethylbenzene in Rhodococcus jostii RHA1, a well-studied soil bacterium whose potent polychlorinated biphenyl (PCB)-transforming properties are partly due to the presence of the related Bph and Etb pathways. Of 151 identified proteins, 22 Bph/Etb proteins were among the most abundant in biphenyl-, ethylbenzene-, benzene-, and styrene-grown cells. Cells grown on biphenyl, ethylbenzene, or benzene contained both Bph and Etb enzymes and at least two sets of lower Bph pathway enzymes. By contrast, styrene-grown cells contained no Etb enzymes and only one set of lower Bph pathway enzymes. Gene disruption established that biphenyl dioxygenase (BPDO) was essential for growth of RHA1 on benzene or styrene but that ethylbenzene dioxygenase (EBDO) was not required for growth on any of the tested substrates. Moreover, whole-cell assays of the delta bphAa and etbAa1::cmrA etbAa2::aphII mutants demonstrated that while both dioxygenases preferentially transformed biphenyl, only BPDO transformed styrene. Deletion of pcaL of the beta-ketoadipate pathway disrupted growth on benzene but not other substrates. Thus, styrene and benzene are degraded via meta- and ortho-cleavage, respectively. Finally, catalases were more abundant during growth on nonpolar aromatic compounds than on aromatic acids. This suggests that the relaxed specificities of BPDO and EBDO that enable RHA1 to grow on a range of compounds come at the cost of increased uncoupling during the latter's initial transformation. The stress response may augment RHA1's ability to degrade PCBs and other pollutants that induce similar uncoupling.