Fragile X mental retardation is caused by absence of the RNAbinding protein fragile X mental retardation protein (FMRP), encoded by the FMR1 gene. There is increasing evidence that FMRP regulates transport and modulates translation of some mRNAs. We studied neurotransmitter-activated synaptic protein synthesis in fmr1-knockout mice. Synaptoneurosomes from knockout mice did not manifest accelerated polyribosome assembly or protein synthesis as it occurs in wild-type mice upon stimulation of group I metabotropic glutamate receptors. Direct activation of protein kinase C did not compensate in the knockout mouse, indicating that the FMRP-dependent step is further along the signaling pathway. Visual cortices of young knockout mice exhibited a lower proportion of dendritic spine synapses containing polyribosomes than did the cortices of wild-type mice, corroborating this finding in vivo. This deficit in rapid neurotransmitter-controlled local translation of specific proteins may contribute to morphological and functional abnormalities observed in patients with fragile X syndrome.dendrites ͉ metabotropic glutamate receptor ͉ mRNA ͉ plasticity ͉ ultrastructure F ragile X mental retardation syndrome is an inherited, Xlinked disorder. In most patients, methylation of an extreme expansion (200-1,000 repeats) of a (CGG)n trinucleotide repeat in the 5Ј UTR of the FMR1 gene blocks transcription of fmr1 mRNA (1). The resulting absence of fragile X mental retardation protein (FMRP) causes the syndrome, which is characterized by mental retardation, macroorchidism, and behavioral abnormalities (2). The brains of these patients exhibit an unusual, spindly appearance of the dendritic spines as well as an overabundance of spines (3, 4), a morphology that resembles early postnatal tissue.The function of FMRP is unknown; in neurons much of the protein is found in dendrites (5). FMRP contains RNA-binding elements (6) and is associated with actively translating polyribosomes in the brain (7-9). Several laboratories have described sets of mRNAs bound by FMRP (10-12), and specific motifs involved in FMRP binding of some mRNAs have been identified (13,14). Recently, we demonstrated (10) that several members of a subset of mRNAs bound by FMRP in intact cells are differentially distributed and͞or translated in dendritic, as compared to somatic, subcellular domains. This finding suggests direct involvement of FMRP in transport and͞or translation of mRNA in dendrites. Antar et al. (15) have demonstrated rapid transport of FMRP into dendrites upon KCl depolarization. We report here that a dynamic aspect of translation, neurotransmitter-induced rapid initiation, is directly impacted by the absence of FMRP.Protein translation in dendrites was suggested by early descriptions of postsynaptic polyribosomal aggregates (PRAs) during synaptogenesis and in the visual cortex of rats reared in complex environments, indicating the importance of local translation for synaptic plasticity (16,17). Components necessary for translation are present postsynaptic...

BACKGROUND AND AIMS The optimal type of stent for the palliation of malignant biliary obstruction in patients with pancreatic adenocarcinoma undergoing neoadjuvant chemoradiotherapy with curative intent is not known. We performed a prospective trial comparing 3 types of biliary stents—fully covered self-expandable metal stents (fcSEMSs), uncovered self-expandable metal stents (uSEMSs), and plastic stents—to determine which best optimized cost effectiveness and important clinical outcomes. METHODS In this prospective, randomized trial, consecutive patients with malignant biliary obstruction from newly diagnosed pancreatic adenocarcinoma who were to start neoadjuvant chemoradiotherapy were randomized to receive fcSEMSs, uSEMSs, or plastic stents during index ERCP. The primary outcomes were time to stent occlusion, attempted surgical resection, or death after the initiation of neoadjuvant therapy and the secondary outcomes were total patient costs associated with the stent, including the index ERCP cost, downstream hospitalization cost due to stent occlusion, and the cost associated with procedural adverse event. RESULTS A total of 54 patients were randomized and reached the primary endpoint; 16 patients in the fcSEMS group, 17 in the uSEMS group, and 21 in the plastic group. No baseline demographic or tumor characteristic differences were noted between groups. fcSEMSs had a longer time to stent occlusion compared with uSEMSs and plastic stents (219 vs. 88 and 75 days, p<0.01), although the groups had equivalent rates of stent occlusion, attempted surgical resection, and death. Although SEMS placement cost more during index ERCP (uSEMS = $24,874 and fcSEMS = $22,729 vs plastic = $18,701, p <0.01), they resulted in higher procedural adverse event costs per patient (uSEMS $5521 and fcSEMS=$12,701 vs plastic = $0, p<0.01). Conversely, plastic stents resulted in a $11,458 hospitalization cost per patient due to stent occlusion, compared with $2301 for uSEMSs and $0 for fcSEMSs (p<0.01). The total cost of the index ERCP, procedural adverse events associated with the index ERCP and adverse events from stent occlusion were similar between stent types (fcSEMSs = $41,112; uSEMSs = $41,475; and plastic = $39,955; p=1.00). There was no difference between groups in terms of number of days hospitalized for index ERCP adverse event and/or stent occlusion, although fcSEMSs resulted in fewer total days (3) of neoadjuvant treatment delay than uSEMSs (39) or plastic stents (79) (p<0.01). CONCLUSIONS In a prospective trial comparing fcSEMSs, uSEMSs, and plastic stents for malignant biliary obstruction in patients undergoing neoadjuvant therapy with curative intent for pancreatic adenocarcinoma, no stent type was superior in optimizing cost effectiveness, although fcSEMS resulted in fewer days of neoadjuvant treatment delay and a longer time to stent occlusion. (ClincialTrials.gov, number NCT01038713)

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