Safety and efficacy of a novel ureteral occlusion device.

OBJECTIVE: To evaluate the safety of a novel ureteral occlusion device and compare its performance with that of other devices and guidewires. METHODS: The XenX (Xenolith Medical) was tested in an ex vivo porcine model to determine the percentage of denuded urothelium because of manipulation within the ureter, the capacity to prevent stone migration during laser lithotripsy, stent compatibility, and the ability to be used for stent placement. Comparative evaluations of the insertion forces and maneuverability were conducted in an in vitro ureter model with the XenX, Stone Cone (Boston Scientific), NTrap (Cook Urological), HiWire (Cook Urological), Roadrunner (Cook Urological), and Sensor (Boston Scientific). Stone migration efficacy was measured using a controlled distribution of stones in 4- and 10-mm silicone tubing with the XenX, NTrap, and Stone Cone. RESULTS: The XenX was safely manipulated within the ureter, prevented significant particle migration during laser lithotripsy, and effectively placed stents. The NTrap required the greatest force when attempting to navigate past a stone (P = .0003), followed by the Stone Cone (P = .009), with little difference among the other devices (P > .72). No differences were found for the passing forces (P = .061), interval to pass (P = .30), or number of attempts to pass the stone (P = .68). The XenX prevented stone migration the most, with more notable differences in the 10- than in the 4-mm tubing. CONCLUSION: Ex vivo evaluations hold promise for the XenX to be safely and effectively used during ureteroscopic procedures. Clinical evaluations are warranted to confirm the safety and performance of the XenX relative to the other ureteral occlusion devices.

Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy.

Anergic B cells are characterized by impaired signaling and activation after aggregation of their antigen receptors (BCR). The molecular basis of this impairment is not understood. In studies reported here, Src homology-2 (SH2)-containing inositol 5-phosphatase SHIP-1 and its adaptor Dok-1 were found to be constitutively phosphorylated in anergic B cells, and activation of this inhibitory circuit was dependent on Src-family kinase activity and consequent to biased BCR immunoreceptor tyrosine-based activation motif (ITAM) monophosphorylation. B cell-targeted deletion of SHIP-1 caused severe lupus-like disease. Moreover, absence of SHIP-1 in B cells led to loss of anergy as indicated by restoration of BCR signaling, loss of anergic surface phenotype, and production of autoantibodies. Thus, chronic BCR signals maintain anergy in part via ITAM monophosphorylation-directed activation of an inhibitory signaling circuit involving SHIP-1 and Dok-1.

Downstream of kinase, p62(dok), is a mediator of Fc gamma IIB inhibition of Fc epsilon RI signaling.

The low-affinity receptor for IgG, Fc gamma RIIB, is expressed widely in the immune system and functions to attenuate Ag-induced immune responses. In mast cells, coaggregation of Fc gamma RIIB with the high-affinity IgE receptor, Fc epsilon RI, leads to inhibition of Ag-induced degranulation and cytokine production. Fc gamma RIIB inhibitory activity requires a conserved motif within the Fc gamma RIIB cytoplasmic domain termed the immunoreceptor tyrosine-based inhibition motif. When coaggregated with an activating receptor (e.g., Fc epsilon RI, B cell Ag receptor), Fc gamma RIIB is rapidly phosphorylated on tyrosine and recruits the SH2 domain-containing inositol 5-phosphatase (SHIP). However, the mechanisms by which SHIP mediates Fc gamma RIIB inhibitory function in mast cells remain poorly defined. In this report we demonstrate that Fc gamma RIIB coaggregation with Fc epsilon RI stimulates enhanced SHIP tyrosine phosphorylation and association with Shc and p62(dok). Concurrently, enhanced p62(dok) tyrosine phosphorylation and association with RasGAP are observed, suggesting that SHIP may mediate Fc gamma RIIB inhibitory function in mast cells via recruitment of p62(dok) and RasGAP. Supporting this hypothesis, recruitment of p62(dok) to Fc epsilon RI is sufficient to inhibit Fc epsilon RI-induced calcium mobilization and extracellular signal-regulated kinase 1/2 activation. Interestingly, both the amino-terminal pleckstrin homology and phosphotyrosine binding domains and the carboxyl-terminal proline/tyrosine-rich region of p62(dok) can mediate inhibition, suggesting activation of parallel downstream signaling pathways that converge at extracellular signal-regulated kinase 1/2 activation. Finally, studies using gene-ablated mice indicate that p62(dok) is dispensable for Fc gamma RIIB inhibitory signaling in mast cells. Taken together, these data suggest a role for p62(dok) as a mediator of Fc gamma RIIB inhibition of Fc epsilon RI signal transduction in mast cells.