Bradykinin postconditioning protects rat hippocampal neurons after restoration of spontaneous circulation following cardiac arrest via activation of the AMPK/mTOR signaling pathway

Bradykinin(BK)is an active component of the kallikrein-kinin system that has been shown to have cardioprotective and neuroprotective effects.We previously showed that BK postconditioning strongly protects rat hippocampal neurons upon restoration of spontaneous circulation(ROSC)after cardiac arrest.However,the precise mechanism underlying this process remains poorly understood.In this study,we treated a rat model of ROSC after cardiac arrest(induced by asphyxiation)with 150μg/kg BK via intraperitoneal injection 48 hours after ROSC following cardiac arrest.We found that BK postconditioning effectively promoted the recovery of rat neurological function after ROSC following cardiac arrest,increased the amount of autophagosomes in the hippocampal tissue,inhibited neuronal cell apoptosis,up-regulated the expression of autophagy-related proteins LC3 and NBR1 and down-regulated p62,inhibited the expression of the brain injury marker S100βand apoptosis-related protein caspase-3,and affected the expression of adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway-related proteins.Adenosine monophosphate-activated protein kinase inhibitor compound C clearly inhibited BK-mediated activation of autophagy in rats after ROSC following cardiac arrest,which aggravated the injury caused by ROSC.The mechanistic target of rapamycin inhibitor rapamycin enhanced the protective effects of BK by stimulating autophagy.Our findings suggest that BK postconditioning protects against injury caused by ROSC through activating the adenosine monophosphate-activated protein kinase/mechanistic target of the rapamycin pathway.

Bone marrow-derived mesenchymal stem cell transplantation attenuates overexpression of inflammatory mediators in rat brain after cardiopulmonary resuscitation

Emerging evidence suggests that bone marrow-derived mesenchymal stem cell transplantation improves neurological function after cardiac arrest and cardiopulmonary resuscitation;however, the precise mechanisms remain unclear. This study aimed to investigate the effect of bone marrow-derived mesenchymal stem cell treatment on expression profiles of multiple cytokines in the brain after cardiac arrest and cardiopulmonary resuscitation. Cardiac arrest was induced in rats by asphyxia and cardiopulmonary resuscitation was initiated 6 minutes after cardiac arrest. One hour after successful cardiopulmonary resuscitation, rats were injected with either phosphate-buffered saline(control) or 1 × 10~6 bone marrow-derived mesenchymal stem cells via the tail vein. Serum S100 B levels were measured by enzyme-linked immunosorbent assay and neurological deficit scores were evaluated to assess brain damage at 3 days after cardiopulmonary resuscitation. Serum S100 B levels were remarkably decreased and neurological deficit scores were obviously improved in the mesenchymal stem cell group compared with the phosphate-buffered saline group. Brains were isolated from the rats and expression levels of 90 proteins were determined using a RayBio Rat Antibody Array, to investigate the cytokine profiles. Brain levels of the inflammatory mediators tumor necrosis factor-α, interferon-γ, macrophage inflammatory protein-1α, macrophage inflammatory protein-2, macrophage inflammatory protein-3α, macrophage-derived chemokine, and matrix metalloproteinase-2 were decreased ≥ 1.5-fold, while levels of the anti-inflammatory factor interleukin-10 were increased ≥ 1.5-fold in the mesenchymal stem cell group compared with the control group. Donor mesenchymal stem cells were detected by immunofluorescence to determine their distribution in the damaged brain, and were primarily observed in the cerebral cortex. These results indicate that bone marrow-derived mesenchymal stem cell transplantation attenuates brain damage induced by cardiac arrest and cardiopulmonary resuscitation, possibly via regulation of inflammatory mediators. This experimental protocol was approved by the Institutional Animal Care and Use Committee of Fujian Medical University, China in January 2016(approval No. 2016079).

Therapeutic benefits of mild hypothermia in patients successfully resuscitated from cardiac arrest:A meta-analysis

BACKGROUND:Good neurological outcome after cardiac arrest(CA) is hard to achieve for clinicians.Experimental and clinical evidence suggests that therapeutic mild hypothermia is beneficial.This study aimed to assess the effectiveness and safety of therapeutic mild hypothermia in patients successfully resuscitated from CA using a meta-analysis.METHODS:We searched the MEDLINE(1966 to April 2012),OVID(1980 to April 2012),EMBASE(1980 to April 2012),Chinese bio-medical literature & retrieval system(CBM)(1978 to April 2012),Chinese medical current contents(CMCC)(1995 to April 2012),and Chinese medical academic conference(CMAC)(1994 to April 2012).Studies were included if 1) the study design was a randomized controlled trial(RCT);2) the study population included patients successfully resuscitated from CA,and received either standard post-resuscitation care with normothermia or mild hypothermia;3) the study provided data on good neurologic outcome and survival to hospital discharge.Relative risk(RR) and 95%confidence interval(CI) were used to pool the effect.RESULTS:The study included four RCTs with a total of 417 patients successfully resuscitated from CA.Compared to standard post-resuscitation care with normothermia,patients in the hypothermia group were more likely to have good neurologic outcome(RR=1.43,95%CI 1.14-1.80,P=0.002) and were more likely to survive to hospital discharge(RR=1.32,95%CI 1.08-1.63,P=0.008).There was no significant difference in adverse events between the normothermia and hypothermia groups(P>0.05),nor heterogeneity and publication bias.CONCLUSION:Therapeutic mild hypothermia improves neurologic outcome and survival in patients successfully resuscitated from CA.

Water-filled balloon in the postoperative resection cavity improves dose distribution to target volumes in radiotherapy of maxillary sinus carcinoma

Postoperative radiotherapy is a major treatment for patients with maxillary sinus carcinoma. However, the irregular resection cavity poses a technical difficulty for this treatment, causing uneven dose distribution to target volumes. In this study, we evaluated the dose distribution to target volumes and normal tissues in postoperative intensity-modulated radiotherapy (IMRT) after placing a water-filled balloon into the resection cavity. Three postoperative patients with advanced maxillary sinus carcinoma were selected in this trial. Water-filled balloons and supporting dental stents were fabricated according to the size of the maxillary resection cavity. Simulation CT scans were performed with or without water-filled balloons, IMRT treatment plans were established, and dose distribution to target volumes and organs at risk were evaluated. Compared to those in the treatment plan without balloons, the dose (D98) delivered to 98% of the gross tumor volume (GTV) increased by 2.1 Gy (P = 0.009), homogeneity index (HI) improved by 2.3% (P = 0.001), and target volume conformity index (TCI) of 68 Gy increased by 18.5% (P = 0.011) in the plan with balloons. Dosimetry endpoints of normal tissues around target regions in both plans were not significantly different (P > 0.05) except for the optic chiasm. In the plan without balloons, 68 Gy high-dose regions did not entirely cover target volumes in the ethmoid sinus, posteromedial wall of the maxillary sinus, or surgical margin of the hard palate. In contrast, 68 Gy high-dose regions entirely covered the GTV in the plan with balloons. These results suggest that placing a water-filled balloon in the resection cavity for postoperative IMRT of maxillary sinus c arcinoma can reduce low-dose regions and markedly and simultaneously increase dose homogeneity and conformity of target volumes.