STING mediates neuroinflammatory response by activating NLRP3-related pyroptosis in severe traumatic brain injury.

Long-term neurological deficits after severe traumatic brain injury (TBI), including cognitive dysfunction and emotional impairments, can significantly impair rehabilitation. Glial activation induced by inflammatory response is involved in the neurological deficits post-TBI. This study aimed to investigate the role of the stimulator of interferon genes (STING)-nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) signaling in a rodent model of severe TBI. Severe TBI models were established using weight-drop plus blood loss reinfusion model. Selective STING agonist ADU-S100 or antagonist C-176 was given as a single dose after modeling. Further, NLRP3 inhibitor MCC950 or activator nigericin, or caspase-1 inhibitor VX765, was given as an intracerebroventricular injection 30 min before modeling. After that, a novel object recognition test, open field test, force swimming test, western blot, and immunofluorescence assays were used to assess behavioral and pathological changes in severe TBI. Administration of C-176 alleviated TBI-induced cognitive dysfunction and emotional impairments, neuronal loss, and inflammatory activation of glia cells. However, the administration of STING agonist ADU-S100 exacerbated TBI-induced behavioral and pathological changes. In addition, STING activation exacerbated pyroptosis-associated neuroinflammation via promoting glial activation, as evidenced by increased cleaved caspase-1 and GSDMD N-terminal expression. In contrast, the administration of C-176 showed anti-pyroptotic effects. The neuroprotective effects of C-176 were partially reversed by the NLRP3 activator, nigericin. Collectively, glial STING is responsible for neuroinflammation post-TBI. However, pharmacologic inhibition of STING led to a remarkable improvement of neuroinflammation partly through suppressing NLRP3 signaling. The STING-NLRP3 signaling is a potential therapeutic target in TBI-induced neurological dysfunction.

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

Overexpression of hSNF2H in glioma promotes cell proliferation, invasion, and chemoresistance through its interaction with Rsf-1.

hSNF2H partners with Rsf-1 to compose the Rsf complex to regulate gene expression. Recent studies indicated that hSNF2H was overexpressed in several human cancers. However, its expression pattern and biological mechanism in glioma remain unexplored. In this study, we found that hSNF2H was overexpressed in 32 % of glioma specimens. hSNF2H overexpression correlated with advanced tumor grade (p = 0.0338) and Rsf-1 positivity in glioma tissues (p = 0.016). Small interfering RNA (siRNA) knockdown was performed in A172 and U87 cell lines. MTT, colony formation assay, and cell cycle analysis showed that knockdown of hSNF2H inhibited cell proliferation, colony formation ability, and cell cycle transition. Matrigel invasion assay showed that hSNF2H depletion inhibited invasive ability of glioma cells. In addition, we demonstrated that hSNF2H depletion decreased temozolomide resistance of A172 and U87 cell lines and increased temozolomide induced apoptosis. Furthermore, hSNF2H depletion decreased cyclin D1, cyclin E, p-Rb, MMP2, cIAP1, Bcl-2 expression, and phosphorylation of IκBα and p65, suggesting hSNF2H regulates apoptosis through NF-κB pathway. Immunoprecipitation showed that hSNF2H could interact with Rsf-1 in both cell lines. To validate the involvement of Rsf-1, we checked the change of its downstream targets in Rsf-1 depleted cells. In Rsf-1 depleted cells, changes of cyclin E, Bcl-2, and p-IκBα were not significant using hSNF2H siRNA treatment. In conclusion, our study demonstrated that hSNF2H was overexpressed in human gliomas and contributed to glioma proliferation, invasion, and chemoresistance through regulation of cyclin E and NF-κB pathway, which is dependent on its interaction with Rsf-1.

Icariin mitigates anxiety-like behaviors induced by hemorrhagic shock and resuscitation via inhibiting of astrocytic activation.

BACKGROUND: Abnormal activation of astrocytes in the amygdala contributes to anxiety after hemorrhagic shock and resuscitation (HSR). Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-associated epigenetic reprogramming of astrocytic activation is crucial to anxiety. A bioactive monomer derived from Epimedium icariin (ICA) has been reported to modulate NF-κB signaling and astrocytic activation. PURPOSE: The present study aimed to investigate the effects of ICA on post-HSR anxiety disorders and its potential mechanism of action. METHODS: We first induced HSR in mice through a bleeding and re-transfusion model and selectively inhibited and activated astrocytes in the amygdala using chemogenetics. Then, ICA (40 mg/kg) was administered by oral gavage once daily for 21 days. Behavioral, electrophysiological, and pathological changes were assessed after HSR using the light-dark transition test, elevated plus maze, recording of local field potential (LFP), and immunofluorescence assays. RESULTS: Exposure to HSR reduced the duration of the light chamber and attenuated open-arm entries. Moreover, HSR exposure increased the theta oscillation power in the amygdala and upregulated NF-κB p65, H3K27ac, and H3K4me3 expression. Contrarily, chemogenetic inhibition of astrocytes significantly reversed these changes. Chemogenetic inhibition in astrocytes was simulated by ICA, but chemogenetic activation of astrocytes blocked the neuroprotective effects of ICA. CONCLUSION: ICA mitigated anxiety-like behaviors induced by HSR in mice via inhibiting astrocytic activation, which is possibly associated with NF-κB-induced epigenetic reprogramming.

Propofol increases expression of basic fibroblast growth factor after transient cerebral ischemia in rats.

Anesthetics such as propofol can provide neuroprotective effects against cerebral ischemia. However, the underlying mechanism of this beneficial effect is not clear. Therefore, we subjected male Sprague-Dawley rats to 2 h of middle cerebral artery occlusion and investigated how post-ischemic administration of propofol affected neurologic outcome and the expression of basic fibroblast growth factor (bFGF). After 2 h of ischemia, just before reperfusion, the animals were randomly assigned to receive either propofol (20 mg kg(-1) h(-1)) or vehicle (10 % intralipid, 2 ml kg(-1) h(-1)) intravenously for 4 h. Neurologic scores, infarct volume, and brain water content were measured at different time points after reperfusion. mRNA level of bFGF was measured by real-time PCR, and the protein expression level of bFGF was analyzed by immunohistochemistry and Western blot. At 6, 24, 72 h, and 7 days of reperfusion, infarct volume was significantly reduced in the propofol-treated group compared to that in the vehicle-treated group (all P < 0.05). Propofol post-treatment also attenuated brain water content at 24 and 72 h and reduced neurologic deficit score at 72 h and 7 days of reperfusion (all P < 0.05). Additionally, in the peri-infarct area, bFGF mRNA and protein expression were elevated at 6, 24, and 72 h of reperfusion compared to that in the vehicle-treated group (all P < 0.05). These results show that post-ischemic administration of propofol provides neural protection from cerebral ischemia-reperfusion injury. This protection may be related to an early increase in the expression of bFGF.

The Effect of the Magnesium Sulfate in Ultrasound-Guided Quadratus Lumborum Block on Postoperative Analgesia: A Randomized Controlled Trial.

INTRODUCTION: Quadratus lumborum block (QLB) has proven to be an effective analgesic technique in various abdominal surgeries. Magnesium sulfate as an adjuvant in different nerve blocks has been reported. The aim of this study was to assess the efficacy of magnesium sulfate as an adjuvant to ropivacaine in an ultrasound-guided QLB for postoperative analgesia in laparoscopic gynecologic surgery. METHODS: Ninety patients belonging to American Society of Anesthesiologists (ASA) physical status I or II, aged between 40 and 60 years, scheduled for laparoscopic gynecologic surgery were enrolled. Patients were divided into three groups and received bilateral quadratus lumborum block: ropivacaine group (group N, 0.375% ropivacaine 40 ml + normal saline 4 ml), magnesium sulfate group (group M, 0.375% ropivacaine 40 ml + 10% magnesium sulfate 4 ml), and control group (group C, normal saline 44 ml). Visual analogue scale (VAS) at rest and during activity at 4, 6, 12, 24, and 48 h postoperatively, consumption of morphine, the time of first analgesic request, frequency of rescue analgesia, satisfaction with postoperative analgesia, and any side effects were recorded. RESULTS: VAS scores in groups M and N were significantly lower than in group C at 4 and 6 h postoperatively (P < 0.001). VAS scores were lower in group M at 12 and 24 h postoperatively compared to groups N and C (P < 0.05). The mean total morphine consumption was significantly lower in group M than in groups N and C (P < 0.001). The mean time to the first patient-controlled analgesia (PCA) bolus was significantly prolonged in group M compared to group C (P < 0.05). The satisfaction with postoperative analgesia of group M was superior to that of groups N and C (P < 0.05). There was no significant difference in side effects among the three groups. CONCLUSION: Magnesium sulfate as an adjuvant to ropivacaine in ultrasound-guided QLB prolongs the duration of analgesia, decreases analgesic requirements, and improves patient satisfaction without significant side effects. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900027066.

Gender-based differences in neuroprotective effects of hydrogen gas against intracerebral hemorrhage-induced depression.

BACKGROUND: Post-stroke depression (PSD) severely affects recovery in patients with intracerebral hemorrhage (ICH). Although hydrogen gas (H2) exerts excellent neuroprotective effects in patients with ICH, there are sex-based differences in H2 efficacy in several diseases. Herein, we determined whether estrogen increases susceptibility to the neuroprotective effects of H2 in males with ICH-induced depression. METHODS: A rodent model of ICH in the basal ganglia was established using autologous blood injection (30 µL). Mice were treated with 2.9% H2 for 2 h daily for 3 days post-ICH. Estrogen (1 mg/kg) was administered by subcutaneous injection daily for 3 days to male mice post-ICH. Thirty days post-ICH, PSD was evaluated by sucrose preference, forced swimming, and 3-chamber social tests. Following the completion of behavioral tests, levels of superoxide dismutase (SOD) and reactive oxygen species (ROS), astrocytic activation, phosphorylated (p)-NF-κB-positive astrocytes, p-NF-κB, p-IKKß, IL-1ß, and IL-6 expression were determined. RESULTS: Compared with female mice, H2 administration post-ICH exhibited fewer neuroprotective effects, including decreased sucrose consumption and time spent sniffing a novel mouse, increased immobility time, downregulated total SOD content, upregulated ROS content and p-NF-κB levels, and elevated astrocyte branches, whereas estrogen enhanced the neuroprotective effects of H2 in male mice. A reduced number of p-NF-κB-positive astrocytes, downregulated expression of p-NF-κB, p-IKKß, IL-1ß, and IL-6 in the amygdala were demonstrated in ICH-males treated with estrogen plus H2. CONCLUSIONS: Estrogen was responsible for increased H2 sensitivity in male mice with ICH. The underlying mechanism may be associated with the suppression of NF-κB signaling in astrocytes.

Dexmedetomidine prevents hemorrhagic brain injury by reducing damage induced by ferroptosis in mice.

Intracerebral hemorrhage (ICH) is a devastating condition with significant morbidity and mortality for which few effective treatments are clinically available. After ICH, iron overload within the perihaematomal region can induce lethal reactive oxygen species (ROS) production and lipid peroxidation, which contribute to secondary brain injury. An iron-dependent form of non-apoptotic cell death known as ferroptosis was recently identified. Ferroptosis plays an important role in ICH pathology. It is characterized by an accumulation of iron-induced lipid ROS, which leads to intracellular oxidative stress. Dexmedetomidine (DEX), an α2-adrenergic agonist, is widely used for anesthesia, pain control, and intensive care unit sedation. DEX has numerous beneficial activities, including anti-inflammatory, anti-oxidative, and anti-cell death activities. Here, we established a mouse model of ICH using collagenase VII and evaluated the effect of DEX in preventing ICH-induced brain injury. Our study showed that administering DEX reduced the damage induced by ferroptosis after ICH by regulating iron metabolism, amino acid metabolism and lipid peroxidation processes.

Dexmedetomidine Alleviates Intracerebral Hemorrhage-Induced Anxiety-Like Behaviors in Mice Through the Inhibition of TRPV4 Opening.

Post-stroke anxiety severely affects recovery in patients with intracerebral hemorrhage (ICH). Dexmedetomidine (Dex), a highly selective alpha 2 adrenal receptor (α2-AR) agonist, was recently found to exert an excellent protective effect against mental disorders including anxiety. The transient receptor potential vanilloid 4 (TRPV4) channel is involved in a series of diseases such as asthma, cancer, anxiety, and cardiac hypertrophy. This study examines whether Dex improved ICH-induced anxiety via the inhibition of TRPV4 channel opening. A rodent model of moderate ICH in the basal ganglia was established using autologous blood injection (20 µl). Mice were treated with Dex (25 µg/kg, intraperitoneal injection) every day for 3 days post-ICH. GSK1016790A (1 µmol/2 µl), an agonist of TRPV4, was administered via the left lateral ventricle. Thirty days post-ICH, post-stroke anxiety was evaluated by elevated plus-maze and open-field tests. Following behavioral tests, superoxide dismutase (SOD), malondialdehyde (MDA), astrocytic activation, and A1-and A2-type astrocytes were determined. Primary astrocytes were exposed to hemin to simulate ICH in vitro. Compared with sham-treated mice, Dex administration ameliorates ICH-induced decreases of distance and time in the open-arm, reduces distance and time in the central zone, increases astrocytic activation and A1-type astrocytes, elevates MDA content, downregulates total SOD contents, and decreases A2-type astrocytes. However, GSK1016790A partially reversed the neuroprotective effects of Dex. In addition, Dex significantly inhibited hemin-induced astrocytic activation in vitro. Dex improves ICH-induced anxiety-like behaviors in mice, and the mechanism might be associated with the inhibition of TRPV4-channel opening.

Regulation of melanoma malignancy by the RP11-705C15.3/miR-145-5p/NRAS/MAPK signaling axis.

Melanoma is a common lethal skin cancer. Dissecting molecular mechanisms driving the malignancy of melanoma may uncover potential therapeutic targets. We previously identified miR-145-5p as an important tumor-suppressive microRNA in melanoma. Here, we further investigated the roles of long non-coding RNAs (lncRNAs) in melanoma. We identified RP11-705C15.3, a regulator of miR-145-5p, as an oncogenic lncRNA in melanoma. RP11-705C15.3 competitively bound miR-145-5p, relieved the repressive roles of miR-145-5p on its target NRAS, upregulated NRAS expression, and activated MAPK signaling. In vitro functional assays revealed that ectopic expression of RP11-705C15.3 promoted melanoma cell proliferation, inhibited apoptosis, and promoted migration and invasion. Silencing of RP11-705C15.3 repressed melanoma cell proliferation, induced apoptosis, and repressed migration and invasion. Notably, the roles of RP11-705C15.3 in melanoma cell proliferation, apoptosis, migration and invasion are reversed by miR-145-5p overexpression. In vivo functional assays revealed that RP11-705C15.3 promoted melanoma tumor growth and metastasis, which were also reversed by miR-145-5p overexpression. Furthermore, we investigated the expression of RP11-705C15.3 in clinical melanoma tissues and found that RP11-705C15.3 was increased in melanoma tissues. High expression of RP11-705C15.3 was positively correlated with thickness, ulceration, metastasis, and inferior overall survival. Taken together, our findings suggest RP11-705C15.3 as a novel oncogene in melanoma, and highlight that the RP11-705C15.3/miR-145-5p/NRAS/MAPK signaling axis may be potential therapeutic targets for melanoma.

FUT8-AS1 Inhibits the Malignancy of Melanoma Through Promoting miR-145-5p Biogenesis and Suppressing NRAS/MAPK Signaling.

Melanoma is the major lethal skin malignancy. However, the critical molecular drivers governing melanoma progression and prognosis are still not clear. By analyzing The Cancer Genome Atlas (TCGA) data, we identified FUT8-AS1 as a prognosis-related long non-coding RNA (lncRNA) in melanoma. We further confirmed that FUT8-AS1 is downregulated in melanoma. Reduced expression of FUT8-AS1 is correlated with aggressive clinical factors and inferior overall survival. Using in vitro functional assays, our findings demonstrated that ectopic expression of FUT8-AS1 represses melanoma cell proliferation, migration, and invasion. FUT8-AS1 silencing promotes melanoma cell proliferation, migration, and invasion. Furthermore, in vivo functional assays demonstrated that FUT8-AS1 represses melanoma growth and metastasis. Mechanistically, FUT8-AS1 was found to bind NF90, repress the interaction between NF90 and primary miR-145 (pri-miR-145), relieve the repressive roles of NF90 on mature miR-145-5p biogenesis, and thus promote miR-145-5p biogenesis and upregulate mature miR-145-5p level. The expression of FUT8-AS1 is positively correlated with miR-145-5p in melanoma tissues. Via upregulating miR-145-5p, FUT8-AS1 reduces the expression of NRAS, a target of miR-145-5. FUT8-AS1 further represses MAPK signaling via downregulating NRAS. Functional rescue assays demonstrated that inhibition of miR-145-5p reverses the tumor suppressive roles of FUT8-AS1 in melanoma. The oncogenic roles of FUT8-AS1 silencing are also blocked by MAPK signaling inhibitor MEK162. In conclusion, these findings demonstrate that FUT8-AS1 exerts tumor suppressive roles in melanoma via regulating NF90/miR-145-5p/NRAS/MAPK signaling axis. Targeting FUT8-AS1 and its downstream molecular signaling axis represent promising therapeutic strategies for melanoma.

The Relationship Between Colloid Transfusion During Surgical Decompression Hemicraniectomy Period and Postoperative Pneumonia or Long-Term Outcome After Space-Occupying Cerebral Infarction: A Retrospective Study.

BACKGROUND: Colloid transfusion during surgical decompressive hemicraniectomy (DHC) to treat space-occupying cerebral infarction induced by middle cerebral artery (MCA) is controversial. A multicenter retrospective study was conducted to determine whether an increased colloid transfusion during surgery is associated with a lower incidence of postoperative pneumonia and better long-term outcomes after space-occupying cerebral infarction. METHODS: Data from surgical DHC within 48 hours to treat space-occupying cerebral infarction that took place between November 30, 2013, and March 30, 2016, were collected in a multicenter chart. Univariate analysis, Spearman correlation, χ2 test, and bivariate and multivariate logistic regression were performed to account for the associations between colloid transfusion and postoperative pneumonia or long-term outcomes (indicated by modified Rankin Scale [mRS] scores). RESULTS: Univariate analysis showed that surgical duration and mRS were significantly different between the subjects older and younger than 60 years who underwent surgical DHC (P < 0.05). In the entire population studied, increased National Institutes of Health Stroke Scale was associated with a greater incidence of postoperative pneumonia (odds ratio [OR] 1.255, P = 0.003) and increased mRS (OR 1.229, P = 0.014). In the population older than 60 years, it was revealed that increased colloid transfusion was associated with a lower incidence of postoperative pneumonia (OR 0.761, P = 0.030) or better outcomes, as indicated with lower mRS (OR 0.837, P = 0.045). CONCLUSIONS: Our retrospective study demonstrated that there is a robust association between increased perioperative colloid transfusion and lower incidence of postoperative pneumonia and better outcomes among the patients older than 60 years after space-occupying cerebral infarction.

Decreased Tidal Volume With Increased Height, but not Colloid Transfusion, is Associated With Worse Outcomes and Postoperative Pneumonia After Coil Embolization of Aneurysmal Subarachnoid Hemorrhage: A Retrospective Study.

BACKGROUND: The tidal volume setting as well as colloid transfusion during the peri-operative period after intracranial aneurysm is controversial. A multicenter retrospective study was conducted to determine whether or not an increased tidal volume setting and colloid transfusion are associated with poor outcomes and postoperative pulmonary complications after intracranial aneurysm. METHOD: Data from endovascular coiling to treat intracranial aneurysms that took place between 30 March 2014 and 30 March 2016 were collected in a multicenter chart. The primary outcomes were better (defined as a Modified Rankin scores [MRS] ≤2) and worse outcomes (MRS ≥3). Secondary outcomes included pneumonia and non-pneumonia in patients with intracranial aneurysms. Univariate analysis, bivariate logistic regression, Spearman correlation, and a linear regression model were performed to account for the association between peri-operative risk factors and different outcomes. RESULTS: Bivariate logistic analysis showed that worse outcomes were correlated with height, Hunt and Hess scores (HHS), and Fisher grade (P < 0.05). There was no significant association between colloid transfusion and worse outcomes and postoperative pneumonia (P > 0.05). Postoperative pneumonia incidence was associated with increased height in a population with intracranial aneurysms (P < 0.05). The Spearman correlation and a linear regression model suggested that increased height was significantly correlated with lower tidal volume setting (per unit of body weight; P < 0.05). CONCLUSION: Decreased tidal volume with increased height, but not colloid transfusion, was independently associated with worse outcomes and postoperative pneumonia across a spectrum of risk profiles. These findings may help to improve practice decisions regarding tidal volume settings.

Neuroprotective effects of erythropoietin against sevoflurane-induced neuronal apoptosis in primary rat cortical neurons involving the EPOR-Erk1/2-Nrf2/Bach1 signal pathway.

OBJECTIVE: Erythropoietin (EPO)-induced activation of the EPO receptor (EPOR) against sevoflurane-induced neuronal apoptosis is an effective intervention, but the underlying mechanism is poorly understood. Previous studies have shown that alteration of the nuclear factor erythroid 2-related factor (Nrf2)/BTB-to-CNC homology 1 (Bach1) ratio by extracellular signal-related kinases (Erk) 1/2 ameliorates the oxidative stress which occurs in human macrophages. In this study, we determined whether or not EPO attenuates sevoflurane-induced neuronal apoptosis via the EPOR-Erk1/2-Nrf2/Bach1 signal pathway. METHODS: Primary rat cortical neurons were exposed to 4% sevoflurane for 6h. Neuronal viability, injury, apoptosis, and oxidative stress were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), propidium iodide uptake (PI), malondialdehyde (MDA), and superoxide dismutase (SOD) assays. A real-time PCR assay was used to measure EPOR expression. Western blotting was used to assess Nrf2, Bach1, and heme oxygenase-1 (HO-1) expression. RESULTS: Sevoflurane exposure increased cell apoptosis, injury, and MDA (P<0.05), but decreased cell viability and the Nrf2:Bach1 ratio (P<0.05), and down-regulated superoxide dismutase (SOD; P<0.05), while EPO partially rescued the neurotoxicity induced by sevoflurane (P<0.05). Inhibition of EPOR via EPO-specific monoclonal antibody or Erk1/2 phosphorylation via PD98059 reversed the protective effect of EPO (P<0.05). CONCLUSION: The neuroprotective effects of EPO against sevoflurane-induced neuronal apoptosis in primary rat cortical neurons involves the EPOR-Erk1/2-Nrf2/Bach1 signal pathway.

Increased Perioperative Crystalloid Transfusion Is Associated with Better Outcomes After Spontaneous Hypertensive Putamen Hemorrhage: A Retrospective Study.

BACKGROUND: The appropriate amount of transfused fluids, and which types of fluids should be transfused during the peri-operative period, is a matter of controversy among neurosurgeons. Thus, a retrospective study was conducted to assess whether crystalloid transfusion is associated with better outcomes after spontaneous hypertensive putamen hemorrhage (HPH). METHODS: Data from acute spontaneous HPH surgeries performed between December 2013 and June 2016 were collected in a multi-center chart. The primary outcome was prognosis, with better outcome defined as a Glasgow outcome score (GOS) of 4 or greater. The secondary outcome was survival, with survival defined as a GOS score of 2 or greater. Univariate analysis and bivariate logistic regression were performed to account for the association between perioperative HPH and different outcomes. We also used Spearman rank correlation and linear regression to determine the correlation between length of stay (LOS) and the univariate analysis significant factors in patients with a GOS score of 4 or greater. RESULTS: Bivariate logistic regression showed a marked correlation between better outcome and age (odds ratio [OR], 0.927; 95% confidence interval [CI], 0.851-0.995), Glasgow Coma Scale (GCS; OR, 1.162; 95% CI, 1.049-1.356), and crystalloid transfusion (OR, 1.083; 95% CI, 1.005-1.142). In addition, bivariate logistic regression also revealed a significant correlation between survival and GCS score (OR, 1.097; 95% CI, 1.056-1.199). In patients with a GOS of 4 or greater, Spearman rank correlation and linear regression suggested that a higher GCS score was more likely to prolong the LOS. CONCLUSION: Increased perioperative crystalloid transfusion was independently associated with better outcome across a spectrum of surgical risk profiles after spontaneous HPH.

Increased Transfusion of Fresh Frozen Plasma is Associated with Mortality or Worse Functional Outcomes After Severe Traumatic Brain Injury: A Retrospective Study.

BACKGROUND: The fresh frozen plasma (FFP) transfusion threshold and timing for traumatic brain injury (TBI)-associated coagulopathy are controversial. Thus, a multicenter retrospective study was conducted to determine whether or not FFP transfusion is associated with poor outcomes after severe TBI. METHODS: Data from decompressive craniotomy after blunt force trauma that took place between December 2013 and June 2016 were collected in a multicenter chart. The primary outcomes were mortality and survival, as well as worse outcomes (defined as a Glasgow Outcome Scale [GOS] score ≤3) and better outcomes (GOS score ≥4). Secondary outcomes included 90-day survival rates in all patients with or without FFP transfusion, as well as length of hospital stay in patients with a better prognosis (GOS score ≥4). Univariate analysis, bivariate logistic regression, Spearman rank correlation, and Kaplan-Meier analysis were performed to account for the association between perioperative FFP transfusion and different outcomes. RESULTS: Bivariate logistic analysis showed that mortality and worse outcomes were correlated with FFP transfusion and Glasgow Coma Scale score (P < 0.05). Kaplan-Meier analysis suggested that mortality was statistically higher in the FFP transfusion groups compared with the no FFP transfusion groups, regardless of the severity of TBI (P < 0.05). The overall complications, acute respiratory distress syndrome, and pneumonia rate were significantly higher for patients receiving FFP transfusion (P < 0.05). CONCLUSIONS: Increased perioperative FFP infusion was independently associated with mortality or worse outcomes across a spectrum of surgical risk profiles.

Sevoflurane pre-conditioning increases phosphorylation of Erk1/2 and HO-1 expression via inhibition of mPTP in primary rat cortical neurons exposed to OGD/R.

BACKGROUND: As an indispensable clinical inhalation anesthetic, sevoflurane is widely used for peri-operative sedation. The neuroprotective effect of sevoflurane pre-conditioning against cerebral ischemia/reperfusion has been gradually realized, but the underlying mechanism during the early reperfusion period has not been established. METHOD: Primary cultured cortical neurons were treated with 2% sevoflurane pre-conditioning for 30min, exposed to oxygen-glucose deprivation for 90min, and followed by 60min of reperfusion (OGD/R). Additionally, neuronal cells were treated with an inhibitor of extracellular signal-related kinases 1 and 2 (Erk1/2) phosphorylation (PD98059), a mPTP opener (atractyloside), or a mPTP opening inhibitor (cyclosporine A) before sevoflurane pre-conditioning. RESULT: Sevoflurane pre-conditioning decreased neuronal apoptosis (assessed by TUNEL), oxidative stress (assessed by malondialdehyde [MDA], superoxide dismutase [SOD], and heme oxygenase [HO]-1), and opening of mitochondrial permeability transition pores [mPTPs] (assessed by calcein-cobalt), but increased neuronal viability (assessed by MTT) and mitochondrial membrane potential (assessed by JC-1) after OGD/R exposure compared with OGD/R treatment alone. Pre-treatment with the mPTP opener and inhibitor of Erk1/2 phosphorylation abolished the protective effect induced by sevoflurane pre-conditioning. Pre-treatment with the mPTP opener attenuated the phosphorylation of Erk1/2 in mitochondria of neuronal cultures exposed to OGD/R induced by sevoflurane pre-conditioning. The mPTP opening inhibitor, like sevoflurane pre-conditioning, increased phosphorylation of Erk1/2 after OGD/R exposure, while PD98059 failed to reverse inhibition of mPTP opening in cultures exposed to OGD/R induced by sevoflurane pre-conditioning. CONCLUSION: The neuroprotective mechanism of sevoflurane pre-conditioning might be associated with increased Erk1/2 phosphorylation in mitochondria via inhibition of mPTP opening in the early reperfusion period.

Sevoflurane post-conditioning protects primary rat cortical neurons against oxygen-glucose deprivation/resuscitation via down-regulation in mitochondrial apoptosis axis of Bid, Bim, Puma-Bax and Bak mediated by Erk1/2.

Temporal post-conditioning helps provide neuroprotection against brain injury secondary to ischemia-reperfusion and is considered an effective intervention, but the exact mechanism of sevoflurane post-conditioning is unclear. The essential axis involves activator Bid, Bim, Puma (BH3s), Bax, and Bak; activates the mitochondrial death program; and might be involved in a cell death signal. Extracellular signal-related kinases 1/2 (Erk1/2) play a pivotal role in cell growth and proliferation. We hypothesized that sevoflurane post-conditioning might inhibit Bid, Bim, Puma, Bax, and Bak expression and is activated by phosphor-Erk1/2 to decrease neuronal death. To test this hypothesis, we exposed primary cortical neuron cultures to oxygen-glucose deprivation for 1h, along with resuscitation for 24h (OGD/R). MTT assays, propidium iodide uptake (PI), JC-1 fluorescence, and Western blot indicated the following: decreased cell viability (P<0.05); increased cell death (P<0.05); decreased mitochondrial membrane potential (P<0.05); and decreased Bid, Bim, Puma, Bax, and Bak expression with OGD/R exposure. Inhibition of Erk1/2 phosphorylation could attenuate sevoflurane post-conditioning that mediated an increase in neuronal viability and mitochondrial membrane potential, as well as a decrease in cell death and Bid, Bim, Puma, Bax, and Bak expression after OGD/R treatment. The results demonstrated that sevoflurane post-conditioning caused a marked decrease in cortical neuronal death secondary to OGD/R exposure through the downregulation of the mitochondrial apoptosis axis involving Bid, Bim, Puma, Bax, and Bak that was mediated by the phosphorylation/activation of Erk1/2.

Three-dimensional digitalized virtual planning for retrograde sural neurovascular island flaps: a comparative study.

BACKGROUND: The purpose of this study was to explore the effectiveness and safety of three-dimensional (3D) digitalized planning for the sural neurovascular island flap in repair of soft tissue defects in the ankle and foot. METHODS: This study included 40 patients with soft tissue defects of the ankle and foot who underwent soft tissue reconstruction between October 2008 and June 2012. The patients were randomly assigned into two groups: 3D-reconstruction group (Group A, n=20) and control group (Group B, n=20). Three-dimensional, digitalized virtual planning was performed in the patients in Group A, who underwent computed topographic angiography. The survival rate, operation time, and surgical accuracy were compared between the two groups. RESULTS: All flaps in Group A survived and the recipient site primarily healed, but 4 flaps in Group B had marginal necrosis after the operation. During the 6-12 month follow-up period, all flaps in Group A had good skin quality. In Group B, hard scarring and mild contracture occurred in 4 cases, and the patients experienced pain when walking. The survival rate of the flap in Group A (100%) was significantly higher than in Group B (70%). The operation time in Group A was significantly less than in Group B. The surgical accuracy in Group A was significantly better than in Group B. CONCLUSION: The preoperative use of 3D digitalized virtual planning for the sural neurovascular island flap improves the surgical accuracy, decreases the operation time, and increases the survival rate of the flap. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic III.