†These authors contributed equally to this work.We examined secretory granule dynamics using total internal reflection fluorescence microscopy in normal pancreatic b cells and their mutants devoid of Rab27a and/or its effector, granuphilin, which play critical roles in the docking and recruitment of insulin granules to the plasma membrane. In the early phase of glucose stimulation in wild-type cells, we observed marked fusion of granules recruited from a relatively distant area, in parallel with that from granules located underneath the plasma membrane. Furthermore, despite a lack of granules directly attached to the plasma membrane, both spontaneous and evoked fusion was increased in granuphilin-null cells. In addition to these granuphilin-null phenotypes, Rab27a/granuphilin doubly deficient cells showed the decreases in granules located next to the docked area and in fusion from granules near the plasma membrane in the early phase of glucose-stimulated secretion, similar to Rab27a-mutated cells. Thus, the two proteins play nonoverlapping roles in insulin exocytosis: granuphilin acts on the granules underneath the plasma membrane, whereas Rab27a acts on those in a more distal area. These findings demonstrate that, in contrast to our conventional understanding, stable attachment of secretory granules to the plasma membrane is not prerequisite but temporally inhibitory for both spontaneous and evoked fusion.

Summary:We report a 91-year-old woman presenting bowel obstruction due to impacted gallstone, who was the oldest patient which has been reported in Japanese scientific literature. The patient was referred to our hospital due to vomiting and abdominal pain. Computed tomography and abdominal X-ray showed dilated loops of small intestine associated with air-fluid levels, pneumobilia, and a calcified mass in the left iliac fossa. After the diagnosis of bowel obstruction due to gallstone was made, an enterotomy and lithotomy was performed under spinal anesthesia. The postoperative recovery was uneventful. We also reviewed 176 cases of gallstone ileus which were reported in the Japanese literature in the past 20 years. The retrospective analysis demonstrated that one-stage enterolithotomy alone may be acceptable as the first choice of operative treatment. The gallstone ileus is a rare, but important disease because urgent and appropriate surgical therapy is required.

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