Publications

Exogenous sphingosine 1-phosphate (S1P) is an effective cardioprotectant against ischemic injury. We have investigated the hypothesis that S1P is also an important endogenous cardioprotectant released during both ischemic preconditioning (IPC) and ischemic postconditioning (IPOST). IPC of ex vivo rat hearts was instituted by two cycles of 3 min ischemia-5 min reperfusion prior to 40 min of index ischemia and then 40 min of reperfusion. IPC resulted in 70% recovery of left ventricular developed pressure (LVDP) upon reperfusion and a small infarct size (10%). VPC23019 (VPC), a specific antagonist of S1P(1 and 3) G protein-coupled receptors (GPCRs), when present during preconditioning blocked protection afforded by two cycles of IPC. VPC also blocked preconditioning of isolated rat cardiac myocytes subjected to hypoxia-reoxygenation injury. Increased release of S1P from myocytes in response to IPC was also demonstrated. These data indicate that S1P is released from myocytes in response to IPC and protects by binding to S1P GPCRs. In the ex vivo heart, if a third cycle of IPC was added to increase release of endogenous mediators, then the need for any individual mediator (e.g., S1P) was diminished and VPC had little effect. The adenosine antagonist 8-(p-sulfophenyl)-theophylline (8-SPT) likewise inhibited protection by two cycles but not three cycles of IPC, but VPC plus 8-SPT inhibited protection by three cycles of IPC. Similar to IPC, IPOST induced by four postindex ischemia cycles of 15 s reperfusion-15 s ischemia resulted in 66% recovery of LVDP and a 7% infarct size. When VPC was present during postconditioning and reperfusion, LVDP only recovered by 26% and the infarct size increased to 27%. Adding an additional cycle of IPOST reduced the inhibitory effect of VPC and 8-SPT individually, but not their combined effect. These studies reveal that S1P is an important mediator of both IPC and IPOST that is released along with adenosine during each cycle of IPC or IPOST.

BACKGROUND

Teleteaching of endoscopy has been limited by the exorbitant cost and time inherent in high-quality digital endoscopy video transmission. The Digital Video Transport System (DVTS) transmitted over advanced networks, such as Internet2 and the Asia-Pacific Advanced Network (APAN), provides a unique infrastructure for sharing uncompressed digital videos of endoscopy. This may allow high-quality, real-time, international training of diagnostic and therapeutic endoscopy techniques at a low cost.

OBJECTIVE

To test the proof of concept of long-distance teaching through live, interactive, high-resolution video transmission by using advanced networks and the DVTS. We used teleteaching of image-enhanced endoscopy techniques as a model.

DESIGN

Prospective multicenter pilot study.

SETTING AND PARTICIPANTS

Trainees, faculty, and staff at 3 international endoscopy units.

INTERVENTION

An image-enhanced endoscopy video lecture with advanced-network technologies.

MAIN OUTCOME MEASUREMENTS

We compared image-based prelecture and postlecture test scores and secondarily assessed technical feasibility and quality.

RESULTS

The DVTS transmitted over advanced networks successfully transmitted uncompressed, high-resolution, digital lectures with endoscopic video (digital video format 720 x 480 pixels). Postsession scores improved. Participants highly rated the technical and informational quality. The majority reported a definite interest in participating in future sessions, with a mean rating (out of 5 [scale 1-5]) of 4.7 +/- 0.5.

LIMITATIONS

Pilot study with a limited number of participants and sessions.

CONCLUSION

The DVTS transmitted over advanced networks such as Internet2 and APAN can provide the infrastructure for transmission of high-resolution, uncompressed video endoscopy for the purpose of teleteaching endoscopy.

Induction of effective osteoclastogenesis by RANK (receptor activator of NF-kappaB) requires costimulation by ITAM-coupled receptors. In humans, the TREM-2 (triggering receptor expressed on myeloid cells 2) ITAM-coupled receptor plays a key role in bone remodeling, as patients with TREM-2 mutations exhibit defective osteoclastogenesis and bone lesions. We have identified a new rapidly induced costimulatory pathway for RANK signaling that is dependent on TREM-2 and mediated by calcium signaling. TREM-2-dependent calcium signals are required for RANK-mediated activation of calcium/calmodulin-dependent protein kinase (CaMK)II and downstream MEK and ERK MAPKs that are important for osteoclastogenesis. IL-10 inhibited RANK-induced osteoclastogenesis and selectively inhibited calcium signaling downstream of RANK by inhibiting transcription of TREM-2. Down-regulation of TREM-2 expression resulted in diminished RANKL-induced activation of the CaMK-MEK-ERK pathway and decreased expression of the master regulator of osteoclastogenesis NFATc1. These findings provide a new mechanism of inhibition of human osteoclast differentiation. The results also yield insights into crosstalk between ITAM-coupled receptors and heterologous receptors such as RANK, and they identify a mechanism by which IL-10 can suppress cellular responses to TNFR family members.