Background Intralipid, a brand name for the first safe fat emulsion for human use, has been shown to be cardioprotective. However, the mechanism of this protection is not known. Here we investigated the molecular mechanism(s) of Intralipid-induced cardioprotection against ischemia/reperfusion injury, particularly the role of GSK-3β and mitochondiral permeability transition pore in this protective action. Methods In-vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with Intralipid (1% in ex-vivo and one bolus of 20% in in-vivo) or vehicle. The hemodynamic function, infarct size, threshold for the opening of mitochondiral permeability transition pore and phosphorylation levels of Akt/ERK/GSK-3β were measured. Results Administration of Intralipid at the onset of reperfusion resulted in ~70% reduction in infarct size in the in-vivo rat model. Intralipid also significantly improved functional recovery of isolated Langendorff-perfused mouse hearts as the rate pressure product was increased from 2999±863mmHg*beats/min in control to 13676±611 mmHg*beats/min (Mean±SEM) and the infarct size was markedly smaller (18.3±2.4% vs. 54.8±2.9% in control, P<0.01). The Intralipid-induced cardioprotection was fully abolished by LY294002, a specific inhibitor of PI3K, but only partially by PD98059, a specific ERK inhibitor. Intralipid also increased the phosphorylation levels of Akt/ERK1/GSK-3β by 8, 3 and 9 fold, respectively. The opening of mitochondiral permeability transition pore was inhibited by Intralipid as calcium retention capacity was higher in Intralipid group (274.3±8.4nM/mg vs. 168.6±9.6nM/mg control). Conclusions Postischemic treatment with Intralipid inhibits the opening of mitochondiral permeability transition pore and protects the heart through GSK-3β via PI3K/Akt/ERK pathways.

Introduction First described in 1927, a Schmorl's node (SN) is the herniation of nucleus pulposus (NP) through the cartilaginous and bony end plate into the body of the adjacent vertebra. SNs are common findings on imaging, and although most SNs are asymptomatic, some have been shown to become painful lesions. In this manuscript, we review the literature regarding the epidemiology, clinical presentation, pathogenesis, imaging, and management of SNs. Materials and methods Using databases from the US National Library of Medicine and the National Institutes of Health, relevant articles were identified. Results While several theories regarding the pathogenesis of SNs have been proposed, an axial load model appears to have the greatest supporting evidence. Symptomatic SNs are thought to be due to the inflammatory response solicited by the herniation of NP into the wellvascularized vertebral body. Management options for symptomatic SNs vary, ranging from medical management to surgical fusion. Conclusion SNs are common lesions that are often asymptomatic. In certain cases, SNs can cause back pain. No consensus on pathogenesis exists. There is no established treatment modality for symptomatic SNs.

This study is the first to report discharge opioid prescribing practices in an ERAS setting. Although an ERAS intervention for colorectal surgery led to an increase in opioid-free anesthesia and multimodal analgesia, we did not observe an impact on discharge opioid prescribing practices. The majority of patients were discharged with an opioid prescription, including those with a combination of low discharge pain scores, no preoperative opioid use, and low morphine milligram equivalents consumption before discharge. This observation in the setting of an ERAS pathway that promotes multimodal analgesia suggests that our findings are very likely to also be observed in non-ERAS settings and offers an opportunity to modify opioid prescribing practices on discharge after surgery. For opioid-free anesthesia and multimodal analgesia to influence the opioid epidemic, the dose and quantity of the opioids prescribed should be modified based on the information gathered by in-hospital pain scores and opioid use as well as pain history before admission.

OBJECTIVES Lipid Emulsion (LE) has been shown to be effective in resuscitating bupivacaine-induced cardiac arrest but its mechanism of action is not clear. Here we investigated whether fatty acid oxidation is required for rescue of bupivacaine induced cardiotoxicity by LE in rats. We also compared the mitochondrial function and calcium threshold for triggering of mitochondrial permeability transition pore (mPTP) opening in bupivacaine-induced cardiac arrest before and after resuscitation with LE. DESIGN Prospective, randomized, animal study. SETTING University Research Laboratory. SUBJECTS Adult male Sprague-Dawley rats. INTERVENTIONS Asystole was achieved with a single dose of bupivacaine (10mg/kg over 20seconds, i.v.) and 20% LE infusion (5ml/kg bolus, and 0.5ml/kg/min maintenance) with cardiac massage started immediately. The rats in CVT group were pretreated with a single dose of fatty acid oxidation inhibitor CVT (0.5, 0.25, 0.125 or 0.0625mg/kg bolus i.v.) 5min prior to inducing asystole by bupivacaine overdose. Heart rate (HR), ejection fraction (EF), fractional shortening (FS), the threshold for opening of mPTP, oxygen consumption and membrane potential were measured. The values are Mean±SEM. MEASUREMENTS AND MAIN RESULTS Administration of bupivacaine resulted in asystole. ILP infusion improved the cardiac function gradually as the EF was fully recovered within 5min (EF=64±4% and FS=36±3%, n=6) and heart rate increased to 239±9 beats/min (71% recovery, n=6) within 10min. LE was only able to rescue rats pretreated with low dose of CVT (0.0625mg/kg) (HR=~181±11 beats/min at 10 min, recovery of 56%; EF=50±1%; FS=26±0.6% at 5min, n=3) but was unable to resuscitate rats pretreated with higher doses of CVT (0.5, 0.25 or 0.125mg/kg). The calcium retention capacity in response to Ca2+ overload was significantly higher in cardiac mitochondria isolated from rats resuscitated with 20% LE compared to the group that did not receive ILP after bupivacaine-overdose (330±42 vs. 180±8.2 nmol/mg-mitochondrial protein, p<0.05, n=3 in each group). The mitochondrial oxidative rate and membrane potential were similar in bupivacaine group before and after resuscitation with LE infusion. CONCLUSIONS Fatty acid oxidation is required for successful rescue of bupivacaine induced cardiotoxicity by LE. This rescue action is associated with inhibition of mitochondrial permeability transition pore opening.

Background We have recently shown that postischemic administration of intralipid protects the heart against ischemia-reperfusion injury. Here we compared the cardioprotective effects of intralipid with cyclosporine-A, a potent inhibitor of the mitochondrial permeability transition pore opening. Methods In vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with intralipid (0.5%, 1% and 2% ex-vivo, and 20% in vivo), cyclosporine-A (0.2 μM, 0.8 μM, and 1.5 μM ex- vivo and 10 mg/kg in vivo), or vehicle. The hemodynamic function, infarct size, calcium retention capacity, mitochondrial superoxide production, and phosphorylation levels of protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) were measured. The values are mean ± SEM. Results Administration of intralipid at reperfusion significantly reduced myocardial infarct size compared with cyclosporine-A in vivo (infarct size/area at risk)%: 22.9 ± 2.5% vs. 35.2 ± 3.5%; P = 0.030, n = 7/group). Postischemic administration of intralipid at its optimal dose (1%) was more effective than cyclosporine-A (0.8 μM) in protecting the ex vivo heart against ischemia-reperfusion injury, as the rate pressure product at the end of reperfusion was significantly higher (mmHg · beats/min: 12,740 ± 675 [n = 7] vs. 9,203 ± 10,781 [n = 5], P = 0.024), and the infarct size was markedly smaller (17.3 ± 2.9 [n = 7] vs. 29.2 ± 2.7 [n = 5], P = 0.014). Intralipid was as efficient as cyclosporine-A in inhibiting the mitochondrial permeability transition pore opening (calcium retention capacity = 280 ± 8.2 vs. 260.3 ± 2.9 nmol/mg mitochondria protein in cyclosporine-A, P = 0.454, n = 6) and in reducing cardiac mitochondrial superoxide production. Unlike intralipid, which increased phosphorylation of Akt (6-fold) and GSK-3β (5-fold), cyclosporine-A had no effect on the activation of these prosurvival kinases. Conclusions Although intralipid inhibits the opening of the mitochondrial permeability transition pore as efficiently as cyclosporine-A, intralipid is more effective in reducing the infarct size and improving the cardiac functional recovery.

Having reported that traumatic brain injury (TBI), produced by moderate lateral controlled cortical impact (CCI), causes long-term dysregulation of the neuroendocrine stress response, the aim of this study was to assess short- and long-term effects of both moderate and mild CCI on stress-induced hypothalamic-pituitary-adrenal (HPA) function. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths to produce either a moderate or mild CCI. Controls underwent sham surgery without injury. Commencing at one week after recovery from surgery, rats were exposed to stressors: 30-min restraint (days 7, 34, and 70) or 15-min forced swim (days 21 and 54). Tail vein blood was analyzed for corticosterone (CORT) content by radioimmunoassay. On days 7 and 21, the stress-induced HPA responses were significantly attenuated by both mild and moderate CCI. Significant attenuation of the CORT response to stress persisted through day 70 after moderate CCI. In contrast, stress-induced CORT levels on days 34, 54, and 70 were significantly enhanced after mild CCI. Differential effects of injury severity were also observed on motor function in a forelimb test on post-injury day 12 and on cortical lesion volume and hippocampal cell loss at day 70, but not on working memory in a radial maze on day 15. The differing short- and long-term stress-induced HPA responses may be mediated by differential effects of moderate and mild CCI on the efficiency of glucocorticoid negative feedback or signaling among hypothalamic and extrahypothalamic components of the neuroendocrine stress-response system.

BackgroundNovel therapies aimed at modulating the autonomic nervous system, including thoracic epidural anesthesia (TEA), have been shown in small case series to be beneficial in treating medically refractory ventricular tachycardia (VT) storm. However, it is not clear when these options should be considered. We reviewed a multicenter experience with TEA in the management of VT storm to determine its optimal therapeutic use.Methods and ResultsData for 11 patients in whom TEA was instituted for VT storm between July 2005 and March 2016 were reviewed to determine the clinical characteristics, outcomes, and role in management. The clinical presentation was incessant VT in 7 (64%), with polymorphic VT in 3 (27%) and monomorphic VT in 8 (73%). The underlying conditions were nonischemic cardiomyopathy in 5 (45%), ischemic cardiomyopathy in 3 (27%), and hypertrophic cardiomyopathy, Brugada syndrome, and cardiac lipoma in 1 (9%) each. Five (45%) had a complete and 1 (9%) had a partial response to TEA; 4 of the complete responders had incessant VT. All 4 patients with a documented response to deep sedation demonstrated a complete response to TEA.ConclusionsMore than half of the patients with VT storm in our series responded to TEA. TEA may be effective and should be considered as a therapeutic option in patients with VT storm, especially incessant VT, who are refractory to initial management. Improvement in VT burden with deep sedation may suggest that sympathoexcitation plays a key role in perpetuating VT and predict a positive response to TEA.

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