Mitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InsP(3)R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP(3)R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InsP(3)R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP(3)R, resulting in sustained, oscillatory cytosolic calcium increases. These calcium events are linked to the coordinate release of cytochrome c from all mitochondria. Our findings identify a feed-forward mechanism whereby early cytochrome c release increases InsP(3)R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.

A fundamental question in developmental biology is how a limited number of growth factors and their cognate receptors coordinate the formation of tissues and organs endowed with enormous morphological complexity. We report that the related neurotrophins NGF and NT-3, acting through a common receptor, TrkA, are required for sequential stages of sympathetic axon growth and, thus, innervation of target fields. Yet, while NGF supports TrkA internalization and retrograde signaling from distal axons to cell bodies to promote neuronal survival, NT-3 cannot. Interestingly, final target-derived NGF promotes expression of the p75 neurotrophin receptor, in turn causing a reduction in the sensitivity of axons to intermediate target-derived NT-3. We propose that a hierarchical neurotrophin signaling cascade coordinates sequential stages of sympathetic axon growth, innervation of targets, and survival in a manner dependent on the differential control of TrkA internalization, trafficking, and retrograde axonal signaling.

The precise coordination of the many events in nervous system development is absolutely critical for the correct establishment of functional circuits. The postganglionic sympathetic neuron has been an amenable model for studying peripheral nervous system formation. Factors that control several developmental events, including multiple stages of axon extension, neuron survival and death, dendritogenesis, synaptogenesis, and establishment of functional diversity, have been identified in this neuron type. This knowledge allows us to integrate the various intricate processes involved in the formation of a functional sympathetic nervous system and thereby create a paradigm for understanding neuronal development in general.

The neurotrophin nerve growth factor (NGF) plays a crucial role in the development of the sympathetic nervous system. In addition to being required for sympathetic neuron survival in vivo and in vitro, NGF has been shown to mediate axon growth in vitro. The role of NGF in sympathetic axon growth in vivo, however, is not clear because of its requirement for survival. This requirement can be circumvented by a concomitant deletion of Bax, a pro-apoptotic Bcl-2 family member, thus allowing an examination of the role of neurotrophins in axon growth independently of their function in cell survival. Here, we analyzed peripheral sympathetic target organ innervation in mice deficient for both NGF and Bax. In neonatal NGF Ϫ/Ϫ ; Bax Ϫ/Ϫ mice, sympathetic target innervation was absent in certain organs (such as salivary glands), greatly reduced in others (such as heart), somewhat diminished in a few (such as stomach and kidneys), but not significantly different from control in some (such as trachea). At embryonic day 16.5, peripheral target sympathetic innervation was also reduced in NGF Ϫ/Ϫ ; Bax Ϫ/Ϫ mice, with analogous variability for different organs. Interestingly, in some organs such as the spleen the precise location at which sympathetic axons become NGF-dependent for growth was evident. We thus show that NGF is required for complete peripheral innervation of both paravertebral and prevertebral sympathetic ganglia targets in vivo independently of its requirement for cell survival. Remarkably, target organs vary widely in their individual NGF requirements for sympathetic innervation.

Summary NGF and NT3 collaborate to support development of sympathetic neurons. Although both neurotrophins activate TrkA-dependent axonal extension, NGF is unique in its ability to promote retrograde transport of TrkA endosomes and retrograde survival. Here, we report that actin depolymerization is essential for initiation of NGF/TrkA endosome trafficking and that a Rac1–cofilin signaling module associated with TrkA early endosomes supports their maturation to retrograde transport-competent endosomes. Moreover, the actin-regulatory endosomal components are absent from NT3-formed TrkA endosomes, explaining the failure of NT3 to support retrograde TrkA transport and survival. The inability of NT3 to activate Rac1-GTP–cofilin signaling is likely due to the labile nature of NT3/TrkA complexes within the acidic environment of TrkA early endosomes. Thus, TrkA endosomes associate with actin-modulatory proteins to promote F-actin disassembly enabling their maturation into transport-competent signaling endosomes. Differential control of this process explains how NGF in final targets, but not NT3 from intermediate targets, supports retrograde survival of sympathetic neurons.

Background and purpose The purpose is to determine whether patching during carotid endarterectomy (CEA) affects the perioperative and long-term risks of restenosis, stroke, death, and MI as compared to primary closure. Methods We identified all patients who were randomized and underwent CEA in CREST. CEA patients who received a patch were compared to patients who underwent CEA with primary closure without a patch. We compared peri-procedural and 4-year event rates, 2-year restenosis rates, and rates of reoperation between the two groups. We further analyzed results by surgeon specialty. Results There were 1,151 patients who underwent CEA (753 (65%) with patch; 329 (29%) with primary closure). We excluded 44 patients who underwent eversion CEA and 25 patients missing CEA data (5%). Patch use differed by surgeon specialty: 89% of vascular surgeons, 6% of neurosurgeons, and 76% of thoracic surgeons patched. Comparing patients who received a patch versus those who did not, there was a significant reduction in the two-year risk of restenosis, and this persisted after adjustment by surgeon specialty (HR 0.35, 95% CI 0.16–0.74, P=.006). There were no significant differences in the rates of periprocedural stroke and death (HR 1.58, 95% CI 0.33–7.58, P=.57), in immediate re-operation (HR 0.6, 95% CI 0.16–2.27, P=.45), or in the four-year risk of ipsilateral stroke (HR 1.23, 95% CI 0.42–3.63, P=.71). Conclusions Patch closure in CEA is associated with reduction in restenosis though it is not associated with improved clinical outcomes. Thus, more widespread use of patching should be considered to improve long-term durability. Clinical Trial Registration http://clinicaltrials.gov/show/NCT00004732

Open anatomic lung resections for primary lung cancer had nearly twice the complication rate but only a slightly higher readmission rate than thoracoscopic resection. More complications occurred after discharge after thoracoscopic than open resections. Most readmissions occurred within 2 weeks after both thoracoscopic and open resections. Risk-adjusted comparison identified no statistically significant difference in risk of related, unplanned readmission after thoracoscopic versus open resections. Future studies should focus on identification of processes of care to decrease complications and unplanned readmissions after lung cancer resection.

Objective: Postoperative readmissions are frequent in vascular surgery patients, but it is not clear which factors are the main drivers of readmissions. Specifically, the relative contributions of patient comorbidities vs those of operative factors and postoperative complications are unknown. We sought to study the multiple potential drivers of readmission and to create a model for predicting the risk of readmission in vascular patients. Methods: The 2012-2013 American College of Surgeons National Surgical Quality Improvement Program data set was queried for unplanned readmissions in 86,238 vascular patients. Multivariable forward selection logistic regression analysis was used to model the relative contributions of patient comorbidities, operative factors, and postoperative complications for readmission. Results: The unplanned readmission rate was 9.3%. The preoperative model based on patient demographics and comorbidities predicted readmission risk with a low C index of .67; the top five predictors of readmission were American Society of Anesthesiologists class, preoperative open wound, inpatient operation, dialysis dependence, and diabetes mellitus. The postoperative model using operative factors and postoperative complications predicted readmission risk better (C index, .78); postoperative complications were the most significant predictor of readmission, overpowering patient comorbidities. Importantly, postoperative complications identified before discharge from the hospital were not a strong predictor of readmission as the model using predischarge postoperative complications had a similar C index to our preoperative model (.68). However, the inclusion of complications identified after discharge from the hospital appreciably improved the predictive power of the model (C index, .78). The top five predictors of readmission in the final model based on patient comorbidities and postoperative complications were postdischarge deep space infection, superficial surgical site infection, pneumonia, myocardial infection, and sepsis. Conclusions: Readmissions in vascular surgery patients are mainly driven by postoperative complications identified after discharge. Thus, efforts to reduce vascular readmissions focusing on inpatient hospital data may prove ineffective. Our study suggests that interventions to reduce vascular readmissions should focus on prompt identification of modifiable postdischarge complications.