DISC1 regulates N-methyl-D-aspartate receptor dynamics: abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness.

The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-methyl-D-aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of the translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether, our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers.

Application of paclitaxel-eluting metal mesh stents within the pig ureter: an experimental study.

OBJECTIVE: The purpose of the present study is to compare the standard bare metal stents (BMS) with the Paclitaxel-Drug Eluting Stent (DES) in the ureter of a pig model. MATERIALS AND METHODS: We report on an experimental study with ten female pigs weighing between 25 and 30 kg. The stents were randomly placed in either the right or left ureter in each of 10 study animals, for a total of 20 stented ureters. Ten ureters were stented with an R-Stent (Orbus Medical Technologies, Hoevelaken Netherlands), and ten with a Paclitaxel-Eluting Coronary Stent (Boston Scientific, Natick, MA, USA). Patency was measured by radiograph of the nephrostomy tract, intravenous urography and virtual endoscopy at 24 hours and 21 days after the initial procedure, respectively. RESULTS: Free flow of urine through the stents into the bladder was documented in all stented ureters 24 hours after stent insertion by radiograph of the nephrostomy tract. At the 21 day follow-up examination, 5 R-Stents were found to be completely occluded and two partially stenosed, whereas no occluded stent was detected in the Paclitaxel-DES group. Pathology examination of the stents at 21 days follow-up showed that the obstructed R-Stents generated severe inflammation with metaplasia of the urothelium. The Paclitaxel-Eluting MS generated a mild inflammatory response within the ureteral lumen at the site of the stent, without hindering ureteral patency. R-stents proved to develop more hyperplasia compared to the Paclitaxel-Eluting MS. CONCLUSIONS: Paclitaxel-DES, when compared with the standard R- Stent BMS, generated less inflammation and/or hyperplasia of the surrounding tissues, thus maintaining ureteral patency. Long-term animal trials are required to further validate our results.