Variation of Human Neural Stem Cells Generating Organizer States In Vitro before Committing to Cortical Excitatory or Inhibitory Neuronal Fates.

Better understanding of the progression of neural stem cells (NSCs) in the developing cerebral cortex is important for modeling neurogenesis and defining the pathogenesis of neuropsychiatric disorders. Here, we use RNA sequencing, cell imaging, and lineage tracing of mouse and human in vitro NSCs and monkey brain sections to model the generation of cortical neuronal fates. We show that conserved signaling mechanisms regulate the acute transition from proliferative NSCs to committed glutamatergic excitatory neurons. As human telencephalic NSCs develop from pluripotency in vitro, they transition through organizer states that spatially pattern the cortex before generating glutamatergic precursor fates. NSCs derived from multiple human pluripotent lines vary in these early patterning states, leading differentially to dorsal or ventral telencephalic fates. This work furthers systematic analyses of the earliest patterning events that generate the major neuronal trajectories of the human telencephalon.

Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents.

Here, we report the discovery of a novel anticonvulsant drug with a molecular organization based on the unique scaffold of rufinamide, an anti-epileptic compound used in a clinical setting to treat severe epilepsy disorders such as Lennox-Gastaut syndrome. Although accumulating evidence supports a working mechanism through voltage-gated sodium (Nav) channels, we found that a clinically relevant rufinamide concentration inhibits human (h)Nav1.1 activation, a distinct working mechanism among anticonvulsants and a feature worth exploring for treating a growing number of debilitating disorders involving hNav1.1. Subsequent structure-activity relationship experiments with related N-benzyl triazole compounds on four brain hNav channel isoforms revealed a novel drug variant that (1) shifts hNav1.1 opening to more depolarized voltages without further alterations in the gating properties of hNav1.1, hNav1.2, hNav1.3, and hNav1.6; (2) increases the threshold to action potential initiation in hippocampal neurons; and (3) greatly reduces the frequency of seizures in three animal models. Altogether, our results provide novel molecular insights into the rational development of Nav channel-targeting molecules based on the unique rufinamide scaffold, an outcome that may be exploited to design drugs for treating disorders involving particular Nav channel isoforms while limiting adverse effects.

Existen diferencias en la sobrevida de pacientes e injertos renales con 3 años de funcionamiento, según si su proveniencia fue de donantes vivos o fallecidos / Are there differences in the survival of patients with kidney graft functioning during 3 years, as if the donor was dead or alive?

Antecedentes: El trasplante renal (TxR) es el tratamiento de elección para la mayoría de los pacientes con insuficiencia renal crónica etapa 5. Clásicamente se ha comunicado que los TxR con donante fallecido presentan una menor sobrevida que los TxR con donante vivo. Objetivos: Determinar si existen diferencias significativas en la superviviencia de pacientes e injertos en trasplantados renales que han alcanzado los 3 años con un injerto funcionante, según si el donante fue un sujeto vivo o fallecido. Conocer si las causas de pérdida del injerto y las complicaciones presentadas durante la evolución del trasplante fueron diferentes entre ellos. Sujetos y Métodos: Se incluyeron 188 pacientes trasplantados en 3 hospitales entre 1976-2001 y que tenían un injerto funcionante al tercer año de la intervención. De ellos, 96 recibieron injerto de donante vivo y 92 de uno fallecido. Resultados: La supervivencia de injertos y pacientes fue similar en ambos grupos. La frecuencia de rechazo crónico como pérdida del injerto fue mayor en sujetos con donante vivo. Los pacientes con donante cadáver se hospitalizaron más frecuentemente por infecciones durante los primeros 3 años y presentaron más frecuentemente una función renal retardada. Conclusiones: No existieron diferencias significativas en la supervivencia de los pacientes o injertos según el tipo de donante en los trasplantados que alcanzaron lo 3 años con un injerto funcionante. Las causas de pérdida de los injertos y las complicaciones durante la evolución fueron similares, con excepción de una incidencia mayor de requirimiento de diálisis post-operatoria y de hospitalizaciones por infecciones en los que recibieron un injerto de un donante fallecido.

Background: Renal transplantation is the treatment of choice for most patients with chronic kidney disease stage 5. Traditionally, it has been reported that kidney transplants in patients with a deceased donor have a lower survival than the ones with a living donor. Aim: To determine whether there are significant differences in patients and grafts survival in kidney transplant recipients who have reached 3 years with a functioning graft, depending on whether the donor was a living or deceased individual. Also, to determine if the causes of graft loss and complications presented during the follow up were different between them. Subjects and Methods: 188 patients transplanted in 3 hospitals (1976 to 2001) and who had a functioning graft in the third year of the intervention. Of these, 96 received grafts from living donors and 92 from deceased donors. Results: Graft and patient survival was similar in both groups. The frequency of graft loss due to chronic rejection was higher in patients with living donors. Patients with deceased donors were hospitalized more frequently for infections during the first three years and more frequently had delayed renal function. Conclusions: No significant differences in the survival of patients or grafts that reached 3 years functioning normally were founded instead the type of donor. The complications during the follow up were similar between both groups, except for a higher incidence of dialysis requirement in the postoperative period and hospitalizations due to infections in patients receiving grafts from deceased donors.

Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis.

Cooperating genetic events are likely to contribute to the phenotypic diversity of KIT-D816V systemic mastocytosis. In this study, 44 patients with KIT-D816V systemic mastocytosis were evaluated for coexisting NRAS, KRAS, HRAS or MRAS mutations. Activating NRAS mutations were identified in 2 of 8 patients with advanced disease. NRAS mutations were not found in patients with indolent systemic mastocytosis. To better understand the clonal evolution of mastocytosis, we evaluated the cell compartments impacted by the NRAS and KIT mutations. Clonal mast cells harbored both mutations. KIT-D816V was not detected in bone marrow CD34(+) progenitors, whereas the NRAS mutation was present. These findings suggest that NRAS mutations may have the potential to precede KIT-D816V in clonal development. Unlike other mature lineages, mast cell survival is dependent on KIT and the presence of these two activating mutations may have a greater impact on the expansion of this cell compartment and in resultant disease severity.