RESUMEN
Due to the lack of new antimicrobial drug discovery in recent years and an ever-growing prevalence of multidrug-resistant "superbugs", there is a pressing need to explore alternative ways to combat pathogenic bacterial and fungal infections. Building upon our previous work in the field of medicinal phytochemistry, the present study is focused on designing, synthesizing, and testing the altered bioactivity of new variants of two original bioactive molecules found in the Argemone mexicana plant. Herein, we report upon 14 variants of berberine and four variants of chelerythrine that have been screened against a pool of 12 microorganisms (five Gram-positive and four Gram-negative bacteria, and three fungi). Additionally, the crystal structures of two berberine variants are described. Several berberine variants show enhanced antibacterial activity compared to the unaltered plant-derived molecule. We also report promising preliminary tumor cytotoxicity effects for a number of the berberine derivatives.
RESUMEN
Allosensitized children listed with a requirement for a negative prospective crossmatch have high mortality. Previously, we found that listing with the intent to accept the first suitable organ offer, regardless of the possibility of a positive crossmatch (TAKE strategy), results in a survival advantage from the time of listing compared to awaiting transplantation across a negative crossmatch (WAIT). The cost-effectiveness of these strategies is unknown. We used Markov modeling to compare cost-effectiveness between these waitlist strategies for allosensitized children listed urgently for heart transplantation. We used registry data to estimate costs and waitlist/posttransplant outcomes. We assumed patients remained in hospital after listing, no positive crossmatches for WAIT, and a base-case probability of a positive crossmatch of 47% for TAKE. Accepting the first suitable organ offer cost less ($405 904 vs. $534 035) and gained more quality-adjusted life years (3.71 vs. 2.79). In sensitivity analyses, including substitution of waitlist data from children with unacceptable antigens specified during listing, TAKE remained cost-saving or cost-effective. Our findings suggest acceptance of the first suitable organ offer for urgently listed allosensitized pediatric heart transplant candidates is cost-effective and transplantation should not be denied because of allosensitization status alone.
Asunto(s)
Ahorro de Costo , Trasplante de Corazón/economía , Trasplante de Corazón/métodos , Prueba de Histocompatibilidad/economía , Listas de Espera , Niño , Preescolar , Estudios de Cohortes , Análisis Costo-Beneficio , Bases de Datos Factuales , Urgencias Médicas , Femenino , Rechazo de Injerto , Supervivencia de Injerto , Trasplante de Corazón/efectos adversos , Prueba de Histocompatibilidad/métodos , Costos de Hospital , Humanos , Lactante , Masculino , Cadenas de Markov , Selección de Paciente , Pediatría , Pronóstico , Sistema de Registros , Medición de Riesgo , Sensibilidad y Especificidad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Allosensitized children who require a negative prospective crossmatch have a high risk of death awaiting heart transplantation. Accepting the first suitable organ offer, regardless of the possibility of a positive crossmatch, would improve waitlist outcomes but it is unclear whether it would result in improved survival at all times after listing, including posttransplant. We created a Markov decision model to compare survival after listing with a requirement for a negative prospective donor cell crossmatch (WAIT) versus acceptance of the first suitable offer (TAKE). Model parameters were derived from registry data on status 1A (highest urgency) pediatric heart transplant listings. We assumed no possibility of a positive crossmatch in the WAIT strategy and a base-case probability of a positive crossmatch in the TAKE strategy of 47%, as estimated from cohort data. Under base-case assumptions, TAKE showed an incremental survival benefit of 1.4 years over WAIT. In multiple sensitivity analyses, including variation of the probability of a positive crossmatch from 10% to 100%, TAKE was consistently favored. While model input data were less well suited to comparing survival when awaiting transplantation across a negative virtual crossmatch, our analysis suggests that taking the first suitable organ offer under these circumstances is also favored.
Asunto(s)
Técnicas de Apoyo para la Decisión , Trasplante de Corazón , Cadenas de Markov , Receptores de Trasplantes , Listas de Espera , Aloinjertos , Niño , Preescolar , Femenino , Supervivencia de Injerto , Trasplante de Corazón/mortalidad , Prueba de Histocompatibilidad , Humanos , Lactante , Masculino , Medición de Riesgo , Sensibilidad y Especificidad , Tasa de Supervivencia , Factores de Tiempo , Listas de Espera/mortalidadRESUMEN
BACKGROUND: We examined the prevalence of depressive symptoms in Barbadian youth with histories of infantile malnutrition and in a healthy comparison group and the extent to which the effect of malnutrition was mediated/moderated by maternal depression. METHODS: Depressive symptoms were assessed using a 20-item scale administered to youths (11-17 years of age) who had experienced an episode of protein-energy malnutrition (marasmus or kwashiorkor) during the first year of life and in a comparison group of healthy youths without a history of malnutrition. Their mothers completed the same questionnaire on the same test on three occasions when their children were 5-17 years of age at 2-5-year intervals. RESULTS: The prevalence of depressive symptoms was elevated among previously malnourished youth relative to healthy comparison children (p < .001). When youth depression scores were subjected to a longitudinal multiple regression analysis, adjusting for the effect of maternal depressive symptoms, significant effects due to the history of early childhood malnutrition remained and were not discernibly attenuated from an unadjusted analysis. We also found significant independent effects of maternal depressive symptoms on youth depressive symptoms. CONCLUSION: Early childhood malnutrition contributed independently to depressive symptoms in youths who experienced a significant episode of malnutrition in the first year of life. This relationship was not mediated or moderated by the effects of maternal depression. Whether the later vulnerability to depression is a direct effect of the episode of malnutrition and related conditions early in life or whether it is mediated by the more proximal neurobehavioral effects of the malnutrition remains to be determined.
Asunto(s)
Población Negra/psicología , Trastorno Depresivo/epidemiología , Trastorno Depresivo/psicología , Desnutrición Proteico-Calórica/epidemiología , Desnutrición Proteico-Calórica/psicología , Población Blanca/psicología , Adolescente , Barbados , Niño , Hijo de Padres Discapacitados/psicología , Preescolar , Estudios Transversales , Trastorno Depresivo/diagnóstico , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Madres/psicología , Inventario de Personalidad/estadística & datos numéricos , Desnutrición Proteico-Calórica/diagnóstico , Psicometría , Factores de RiesgoRESUMEN
En una zona endémica de la República de Honduras, se llevó a cabo un ensayo sobre el terreno de la prueba de inmunoabsorbencia ligada a la enzima efectuada en disco de nitrocelulosa (dot-ELISA), como microtécnica rápida y susceptible de interpretarse a simple vista, para el diagnóstico serológico de la leishmaniasis visceral en el hombre. De los 305 sujetos investigados usando una dilución del suero de 1:32, se observaron reacciones positivas en ocho de los nueve casos de leishmaniasis visceral diagnosticada mediante estudio parasitológico que habían recibido tratamiento, en 13 de los 45 familiares de pacientes (grupo expuesto a un gran riesgo) y en ocho de los 244 niños seleccionados al azar en la zona endémica. Se observaron reacciones cruzadas en uno de los tres niños con leishmaniasis cutánea confirmada por estudio parasitológico y en tres de los cuatro adultos con resultados serológicos positivos para enfermedad de Chagas. La determinación de los títulos de punto final de los sueros de los pacientes con leishmaniasis visceral produjo títulos recíprocos que fluctuaron entre 512 y 8 192, inferiores a los que por lo general se encuentran en casos activos no tratados. Esta prueba no requiere instalaciones eléctricas y todos los materiales pueden transportarse fácilmente a pie. Es un procedimiento rápido, sencillo, poco costoso y, no obstante, sensible y relativamente específico en las condiciones propias del terreno. Podría resultar un instrumento valioso para los servicios de atención primaria de salud y para las encuestas epidemiológicas en las numerosas zonas endémicas donde actualmente no es posible efectuar pruebas serológicas
Asunto(s)
Humanos , Masculino , Femenino , Ensayo de Inmunoadsorción Enzimática , Leishmaniasis Visceral/diagnósticoRESUMEN
The dot enzime-linked immunosorbent assay (Dot-Elisa), a rapid visually read microtechnique for serodiagnosis of human visceral lesihsmaniasis, was field-tested in a known endemic area in the Republic of Honduras. Of 305 individuals screened at a serum dilution of 1:32 positive reactions were observed in eight of nine parasitologically diagnosed visceral leishmaniasis patients who had received treatment, 13 of 45 family members of patients (a high-risk group), and eight of 244 randomly selected children in the endemic area. Cross-reactions were observed in one of three children with parasitologically confirmed cutaneous leishmaniasis and three of four adults serologically positive for Chagas'disease. End-point titrations performed on the visceral leishmaniasis sera gave reciprocal titers ranging from 512 to 8 192 which are lower than those usually encountered in untreated active cases. This test does not require electricity, and all materials are easily transportable on foot. It is rapid, simple to perform, and inexpensive, yet sensitive and relatively specific under field condidtions. It could prove to be a valuable tool for primary health care facilities and for epidemiologic survey in the many endemic areas where no serologic testing capability currently exists