Objectives: The objective of this study is to determine whether transient spinal cord ischemia activates small ubiquitin-like modifier (SUMO1-3) conjugation, a post-translational protein modification that protects neurons from ischemia-like conditions. Methods: Mice were subjected to 8-12 min of spinal cord ischemia and 3-24 h of recovery using a newly developed experimental model. To characterize the model, activation of stress response pathways induced after spinal cord ischemia, previously observed in other experimental models, was verified by western blot analysis. Levels and subcellular localization of SUMO-conjugated proteins in spinal cords were evaluated by western blot analysis and immunohistochemistry, respectively. Results: Following transient spinal cord ischemia, stress responses were activated as indicated by increased phosphorylation of eukaryotic initiation factor 2 (eIF2a), extracellular signal-regulated kinases (ERK1/2) and Akt. SUMO1 conjugation was not altered, but a selective rise in levels of SUMO2/3-conjugated proteins occurred, peaking at 6 h reperfusion. The marked activation of SUMO2/ 3 conjugation was a neuronal response to ischemia, as indicated by co-localization with the neuronal marker NeuN, and was associated with nuclear accumulation of SUMO2/3-conjugated proteins. Conclusion: Our study suggests that spinal cord neurons respond to ischemic stress by activation of SUMO2/3 conjugation. Many of the identified SUMO target proteins are transcription factors and other nuclear proteins involved in gene expression and genome stability. It is therefore concluded that the post-ischemic activation of SUMO2/3 conjugation may define the fate of neurons exposed to a transient interruption of blood supply, and that this pathway could be a therapeutic target to increase the resistance of spinal cord neurons to transient ischemia.
Background: Xenon has been proven to be neuroprotective in experimental brain injury. The authors hypothesized that xenon would improve outcome from focal cerebral ischemia with a delayed treatment onset and prolonged recovery interval. Methods: Rats were subjected to 70 min temporary focal ischemia. Ninety minutes later, rats were treated with 0, 15, 30, or 45% Xe for 20 h or 0 or 30% Xe for 8, 20, or 44 h. Outcome was measured after 7 days. In another experiment, after ischemia, rats were maintained at 37.5° or 36.0°C for 20 h with or without 30% Xe. Outcome was assessed 28 days later. Finally, mice were subjected to intracerebral hemorrhage with or without 30% Xe for 20 h. Brain water content, hematoma volume, rotarod function, and microglial activation were measured.Results: Cerebral infarct sizes (mean ± SD) for 0, 15, 30, and 45% Xe were 212 ± 27, 176 ± 55, 160 ± 32, and 198 ± 54 mm 3 , respectively (P = 0.023). Neurologic scores (median ± interquartile range) followed a similar pattern (P = 0.002). Infarct size did not vary with treatment duration, but neurologic score improved (P = 0.002) at all xenon exposure durations (8, 20, and 44 h). Postischemic treatment with either 30% Xe or subtherapeutic hypothermia (36°C) had no effect on 28-day outcome. Combination of these interventions provided long-term benefit. Xenon improved intracerebral hemorrhage outcome measures. Conclusion: Xenon improved focal ischemic outcome at 7, but not 28 days postischemia. Xenon combined with subtherapeutic hypothermia produced sustained recovery benefit. Xenon improved intracerebral hemorrhage outcome. Xenon may have potential for clinical stroke therapy under carefully defined conditions.
Background Octogenarians have low physiologic reserve and may benefit more from transcatheter aortic valve replacement ( TAVR ) than surgical aortic valve replacement ( SAVR ). Methods and Results This retrospective cohort study based on the National Inpatient Sample included octogenarians who underwent TAVR or SAVR from 2012 to 2015. Crude and standardized‐morbidity‐ratio‐weighted regression models were used to compare in‐hospital outcomes. Among 19 145 TAVR and 9815 SAVR hospitalizations, TAVR patients had higher Charlson Comorbidity Index ( CCI ) scores (2.0 versus 0.8, P <0.0001) than SAVR patients. Before weighting, TAVR was associated with significantly shorter length of stay, more home discharges, and lower incidences of acute kidney injury, bleeding, and cardiogenic shock. Associations were consistent across Charlson Comorbidity Index, except for TAVR being associated with greater length of stay reductions among patients with Charlson Comorbidity Index ≥2, compared with Charlson Comorbidity Index <2 (change in estimate −3.56 versus −2.61 days, P =0.004). After weighting, TAVR patients had significantly shorter length of stay (change in estimate −3.29 days, 95% CI −3.82, −2.75) and lower odds of transfer to skilled nursing facility (odds ratio 0.34, 95% CI 0.29, 0.41), acute kidney injury (odds ratio 0.55, 95% CI 0.45, 0.68), bleeding (odds ratio 0.44, 95% CI 0.37, 0.53), and cardiogenic shock (odds ratio 0.55, 95% CI 0.33, 0.92), compared with SAVR patients. Odds of permanent pacemaker implantation, transient ischemic attack/stroke, vascular complications, and in‐hospital mortality were not significantly different. Conclusions TAVR may be preferred over SAVR in high‐risk octogenarians because of shorter length of stay, better discharge disposition, and less acute kidney injury, and bleeding. All octogenarians may benefit more from TAVR , irrespective of comorbidity burden, but additional research is needed to confirm our findings.
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