Essential Role of the Small GTPase Ran in Postnatal Pancreatic Islet Development

The small GTPase Ran orchestrates pleiotropic cellular responses of nucleo-cytoplasmic shuttling, mitosis and subcellular trafficking, but whether deregulation of these pathways contributes to disease pathogenesis has remained elusive. Here, we generated transgenic mice expressing wild type (WT) Ran, loss-of-function Ran T24N mutant or constitutively active Ran G19V mutant in pancreatic islet β cells under the control of the rat insulin promoter. Embryonic pancreas and islet development, including emergence of insulin+ β cells, was indistinguishable in control or transgenic mice. However, by one month after birth, transgenic mice expressing any of the three Ran variants exhibited overt diabetes, with hyperglycemia, reduced insulin production, and nearly complete loss of islet number and islet mass, in vivo. Deregulated Ran signaling in transgenic mice, adenoviral over-expression of WT or mutant Ran in isolated islets, or short hairpin RNA (shRNA) silencing of endogenous Ran in model insulinoma INS-1 cells, all resulted in decreased expression of the pancreatic and duodenal homeobox transcription factor, PDX-1, and reduced β cell proliferation, in vivo. These data demonstrate that a finely-tuned balance of Ran GTPase signaling is essential for postnatal pancreatic islet development and glucose homeostasis, in vivo

The risk of multiple sclerosis developing in patients with isolated idiopathic optic neuritis in Brazil

We studied 88 patients with isolated idiopathic optic neuritis (IION) in order to evaluate the rate of progression to multiple sclerosis (MS) in Brazil. The patients were reassessed from one month to nine years after the development of the HON (mean follow-up was 4.6 years). There were 52 men and 36 women with ages ranging from three to 59 years (mean 24.3 years). Bilateral optic neuritis occurred in 19 patients whereas sequential involvement of the fellow eye after an interval longer than four weeks occurred in other 19 patients. Recurrences in the same eye occurred in seven cases. Nine patients (10.8%) developed clinically definitive MS - 13.9% of the women and 7.7% of the men with IION. The median age at the time of diagnosis of MS was 25 years. The mean interval between HON and the emergence of other MS signs varied from one month to five years - median one year. Sixty-seven percent of these, patients developed signs of spinal cord involvement. Our findings when compared to published series in different countries are closer to figures reported in Japan than those in the West