Islet architecture in adult mice is actively maintained by Robo2 expression in ß cells.

A fundamental question in developmental biology is whether tissue architectures formed during development are set for life, or require continuous maintenance signals, and if so, what are those signals. The islets of Langerhans in the pancreas can serve as an elegant model tissue to answer these questions. Islets have a non-random spatial architecture, which is important to proper glucose homeostasis. Islet architecture forms during embryonic development, in a morphogenesis process partially involving expression of Roundabout (Robo) receptors in ß cells, and their ligand, Slit, in the surrounding mesenchyme. Whether islet architecture is set during development and remains passive in adulthood, or whether it requires active maintenance throughout life, has not been determined. Here we conditionally deleted Robo2 in ß cells of adult mice and observed their islet architecture following a two-month chase. We show that deleting Robo2 in adult ß cells causes significant loss of islet architecture without affecting ß cell identity, maturation, or stress, indicating that Robo2 plays a role in actively maintaining adult islet architecture. Understanding the factors required to maintain islet architecture, and thus optimize islet function, is important for developing future diabetes therapies.

Aortic abutment after direct vertebral rotation: plowing of pedicle screws.

STUDY DESIGN: Retrospective case series. OBJECTIVE: To report the occurrence of pedicle screw plow after individual-level direct vertebral rotation (DVR) that resulted in critical screw proximity to the aorta, from three institutions over a four-year period (2004-2008). SUMMARY OF BACKGROUND DATA: Thoracic pedicle screws are generally accepted as safe implants that possess sufficient strength to correct the coronal, sagittal, and now transverse plane deformities associated with scoliosis. Structural failure of the bone resulting in translation of the screw in the transverse plane, defined as plow, can occur with individual-level DVR. METHODS: We performed a retrospective review of all pediatric patients who underwent posterior spinal fusion with pedicle screws for neuromuscular and idiopathic scoliosis and underwent postoperative computed tomographic scan. We identified all patients who required a secondary procedure for implant removal because of malposition of the screw. RESULTS: Six patients with lateral screw direction after a DVR maneuver required screw removal because of proximity to the aorta. All patients had intraoperative confirmation of adequate screw placement before introducing the rod and performing derotation. CONCLUSIONS.: The biologic limitations of vertebrae are approached as we strive to achieve further correction of the spine. Surgeons' experience and methods to assess proper screw placement may give a false sense of adequate final implant position after DVR. Vigilance to ensure proper pedicle screw position can avoid potential iatrogenic catastrophes.

Amyloid beta-protein stimulates the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in human cerebrovascular smooth muscle cells.

The accumulation of fibrillar amyloid-beta protein (A beta) in cerebral blood vessels, a condition known as cerebral amyloid angiopathy (CAA), is a key pathological feature of Alzheimer's disease and certain related disorders and is intimately associated with cerebrovascular cell death both in vivo and in vitro. Moreover, severe CAA leads to loss of vessel wall integrity and cerebral hemorrhage. Although the basis for these latter pathological consequences in CAA remains unresolved alterations in local proteolytic mechanisms may be involved. Here we show that pathogenic forms of A beta stimulate the expression of plasminogen activator activity in cultured human cerebrovascular smooth muscle (HCSM) cells, an in vitro model of CAA. RNase protection assays and plasminogen zymography showed that urokinase-type plasminogen activator (uPA) was responsible for this activity. There was preferential accumulation of uPA on the HCSM cell surface that was mediated through a concomitant increase in expression of the uPA receptor. In the presence of plasminogen there was robust degradation of A beta that was added to the HCSM cells resulting in restoration of cell viability. This suggests that increased expression of uPA may initially serve as a protective mechanism leading to localized degradation and clearance of the pathogenic stimulus A beta. On the other hand, chronic expression of uPA and plasminogen activation led to a profound loss of HCSM cell attachment. This suggests that a similar prolonged effect in vivo in the cerebral vessel wall may contribute to loss of integrity and cerebral hemorrhage in CAA.