Angioblast-mesenchyme induction of early kidney development is mediated by Wt1 and Vegfa

Most studies on kidney development have considered the interaction of the metanephric mesenchyme and the ureteric bud to be the major inductive event that maintains tubular differentiation and branching morphogenesis. The mesenchyme produces Gdnf, which stimulates branching, and the ureteric bud stimulates continued growth of the mesenchyme and differentiation of nephrons from the induced mesenchyme. Null mutation of the Wt1 gene eliminates outgrowth of the ureteric bud, but Gdnf has been identified as a target of Pax2, but not of Wt1. Using a novel system for microinjecting and electroporating plasmid expression constructs into murine organ cultures, it has been demonstrated that Vegfa expression in the mesenchyme is regulated by Wt1. Previous studies had identified a population of Flk1-expressing cells in the periphery of the induced mesenchyme, and adjacent to the stalk of the ureteric bud, and that Vegfa was able to stimulate growth of kidneys in organ culture. Here it is demonstrated that signaling through Flk1 is required to maintain expression of Pax2 in the mesenchyme of the early kidney, and for Pax2 to stimulate expression of Gdnf. However, once Gdnf stimulates branching of the ureteric bud, the Flk1-dependent angioblast signal is no longer required to maintain branching morphogenesis and induction of nephrons. Thus, this work demonstrates the presence of a second set of inductive events, involving the mesenchymal and angioblast populations, whereby Wt1-stimulated expression of Vegfa elicits an as-yet-unidentified signal from the angioblasts, which is required to stimulate the expression of Pax2 and Gdnf, which in turn elicits an inductive signal from the ureteric bud.

Differential gene expression in the developing mouse ureter

In many instances, kidney dysgenesis results as a secondary consequence to defects in the development of the ureter. Through the use of mouse genetics a number of genes associated with such malformations have been identified, however, the cause of many other abnormalities remain unknown. In order to identify novel genes involved in ureter development we compared gene expression in embryonic day (E) 12.5, E15.5 and postnatal day (P) 75 ureters using the Compugen mouse long oligo microarrays. A total of 248 genes were dynamically upregulated and 208 downregulated between E12.5 and P75. At E12.5, when the mouse ureter is comprised of a simple cuboidal epithelium surrounded by ureteric mesenchyme, genes previously reported to be expressed in the ureteric mesenchyme, foxC1 and foxC2 were upregulated. By E15.5 the epithelial layer develops into urothelium, impermeable to urine, and smooth muscle develops for the peristaltic movement of urine towards the bladder. The development of these two cell types coincided with the upregulation of UPIIIa, RAB27b and PPAR gamma reported to be expressed in the urothelium, and several muscle genes, Acta1, Tnnt2, Myocd, and Tpm2. In situ hybridization identified several novel genes with spatial expression within the smooth muscle, Acta1; ureteric mesenchyme and smooth muscle, Thbs2 and Co15a2; and urothelium, Kcnj8 and Adh1. This study marks the first known report defining global gene expression of the developing mouse ureter and will provide insight into the molecular mechanisms underlying kidney and lower urinary tract malformations. (c) 2005 Elsevier B.V. All rights reserved.

The DVD animal model of schizophrenia: Effects of low maternal vitamin D on brain dopamine

Background: We have previously shown that the offspring of vitamin D3 depleted rats have enlarged ventricles and altered neurotrophin profiles (reduced NGF and GDNF). These findings enhance the biological plausibility that low prenatal vitamin D may be a risk factor for schizophrenia. Our recent behavioural studies have found that adult rats with developmental vitamin D deficiency (DVD) have a subtle increase in baseline locomotor activity and a heightened response to dopamine (DA) antagonists. The aim of this study was to investigate brain DA neurochemistry in the DVD model. Methods: We examined cerebrums and striatal tissue from neonates and a variety of brain tissues from the remaining littermates at adulthood. DA, DOPAC, HVA, serotonin and 5HIAA were analysed by HPLC. Single point comparisons for DA1, DA2 and NMDA receptors were also assessed in these tissues. Results: Significant increases in DA and HVA were found in brains from DVD deplete neonates (P=0.01). However, DA and its metabolites were not increased in either the neonate or adult striatum, however there was a trend towards increased DA and its metabolites in the accumbens (P=0.1). Receptor densities were unaffected by prenatal vitamin D levels. Conclusions: Although the effect of maternal diet appears to increase DA production and turnover in neonatal brain, this does not persist into adulthood. Thus other factors must underlie the increased locomotor activity noted in these animals. Future experiments will concentrate on monitoring accumbens and striatal DA release and turnover using microdialysis in pharmacologically challenged behavioural paradigms. References: Eyles D, Brown J; Mackay-Sim A, McGrath J, Feron F. (2003) Vitamin D3 and brain development. Neuroscience 118 (3) 641–653. Burne T, McGrath J, Eyles D, Mackay-Sim A. Behavioural characterization of vitamin D receptor knockout mice. (2005) Behavioural Brain Res: 157 299–308.

Nanostructured lipid carriers for nose-to-brain delivery in neurodegenerative diseases therapy

191 p.

Uso de dexmedetomidina como tratamiento coadyuvante de síndrome de abstinencia alcohólica: revisión sistemática

El objetivo de este estudio es establecer si la dexmedetomidina (DEX) es segura y efectiva para el manejo coadyuvante de síndrome de abstinencia a alcohol (SAA) a través de la búsqueda de evidencia científica. Metodología: se realiza una revisión sistemática de literatura publicada y no publicada desde enero de 1989 hasta febrero 2016 en PubMed, Embase, Scopus, Bireme, Cochrane library y en otras bases de datos y portales. Los criterios de inclusión fueron ensayos clínicos aleatorizados y no aleatorizados, estudios cuasi-experimentales, estudios de cohorte, y estudios de casos y controles; que incluyeron pacientes mayores de 18 años hospitalizados con diagnóstico de SAA y donde se usó DEX como terapia coadyuvante. Resultados: 7 estudios, 477 pacientes, se incluyeron en el análisis final. Se encontraron dos ensayos clínicos aleatorizados, tres estudios de casos y controles y dos estudios de cohorte retrospectivo. Solo uno de los estudios fue doble ciego y utilizó placebo como comparador. Análisis y conclusiones: en los estudios experimentales se determinan que el uso de DEX como terapia coadyuvante en el manejo de SAA tiene significancia clínica y estadística para disminuir dosis de BZD en las primeras 24 horas de tratamiento; pero no demostraron tener otros beneficios clínicos. En los estudios no aleatorizados existe consenso que relaciona el uso de DEX con menores dosis de BZD de forma temprana. Recomendaciones: no se recomienda el uso de DEX en SAA de forma rutinaria. Se recomienda usar DEX solo en casos en el que exista evidencia fallo terapéutico a BZD.