Corticothalamic slow oscillations of neuronal activity determine internal brain states. At least in the cortex, the electrical activity is associated with large neuronal Ca(2+) transients. Here we implemented an optogenetic approach to explore causal features of the generation of slow oscillation-associated Ca(2+) waves in the in vivo mouse brain. We demonstrate that brief optogenetic stimulation (3-20 ms) of a local group of layer 5 cortical neurons is sufficient for the induction of global brain Ca(2+) waves. These Ca(2+) waves are evoked in an all-or-none manner, exhibit refractoriness during repetitive stimulation, and propagate over long distances. By local optogenetic stimulation, we demonstrate that evoked Ca(2+) waves initially invade the cortex, followed by a secondary recruitment of the thalamus. Together, our results establish that synchronous activity in a small cluster of layer 5 cortical neurons can initiate a global neuronal wave of activity suited for long-range corticothalamic integration.
The advent of more potent immunosuppressants led to the first successful human upper extremity transplantation in 1998. At this time, > than 100 upper extremity transplants, 30 face transplants and a variety of other vascularized composite allotransplantation (VCA) procedures have been performed around the world. VCA recipients present unique challenges for transplantation. The incidence of acute rejection exceeds 80% in hand and face transplantation and is well documented, whereas reports about antibody-mediated rejection and chronic rejection remain scarce. Immunosuppression protocols commonly used at US centers are derived from solid organ transplantation protocols. Novel approaches to minimize rejections in VCA may include improved HLA matching and considerations towards cytomegalovirus infection status. New graft preservation techniques may decrease immunogenicity prior to transplant. Novel monitoring methods such as valid biomarkers, ultrasound biomicroscopy and sentinel flaps may enable earlier diagnosis of rejection. Cell-based therapies are being explored in order to achieve immunosuppressive regimen minimization or even tolerance induction. The efficacy of local immunosuppression in clinical VCA remains controversial. In conclusion, although immunosuppressive strategies adapted from SOT have demonstrated good mid-term results, focusing on the unique features of VCA grafts may enable additional, more specific treatment strategies in the future and improved long-term graft outcomes.
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