Sublobar resection reduces the risk of postoperative cognitive dysfunction compared with lobectomy.

OBJECTIVES: Sublobar resection, including wedge resection and segmentectomy, is non-inferior to lobectomy in early-stage non-small cell lung cancer treatment. We aimed to compare the risk of postoperative cognitive dysfunction (POCD) between sublobar resection and lobectomy. METHODS: We conducted a prospective cohort study. Patients with sublobar resection or lobectomy were divided into the sublobar group or the lobar group, respectively. Cognition was assessed before and after surgery with Montreal Cognitive Assessment and Minimum Mental State Examination tests. POCD is defined as Z score of Montreal Cognitive Assessment change ≤-1.96. Propensity score matching (PSM) was performed to make demographics well-balanced between the 2 groups. RESULTS: A total of 335 patients were enrolled. Both the postoperative 1-day POCD rate (sublobar 5.5% vs lobar 18.2%, P < 0.001) and the postoperative 1-month POCD rate (sublobar 7.9% vs lobar 21.8%, P < 0.001) were significantly lower in the sublobar group compared with lobar group, with demographics unbalanced between the 2 groups. In the 133 demographics-matched pairs obtained by PSM, both the postoperative 1-day POCD rate (sublobar 5.3% vs lobar 17.3%, P = 0.005) and the postoperative 1-month POCD rate (sublobar 8.3% vs lobar 18.8%, P = 0.018) remained significantly lower in the sublobar group than in the lobar group. The incidences of postoperative 1-day (P = 0.109) and postoperative 1-month (P = 0.026) Minimum Mental State Examination abnormity were also lower in the sublobar group than in the lobar group but only the latter was with statistical significance after PSM. CONCLUSIONS: Sublobar resection has an advantage over lobectomy in preventing POCD. Our findings might be a reference for selecting the most suitable type of resection for non-small-cell lung cancer patients.

Glibenclamide Directly Prevents Neuroinflammation by Targeting SUR1-TRPM4-Mediated NLRP3 Inflammasome Activation In Microglia.

Glibenclamide (GLB) reduces brain edema and improves neurological outcome in animal experiments and preliminary clinical studies. Recent studies also suggested a strong anti-inflammatory effect of GLB, via inhibiting nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation. However, it remains unknown whether the anti-inflammatory effect of GLB is independent of its role in preventing brain edema, and how GLB inhibits the NLRP3 inflammasome is not fully understood. Sprague-Dawley male rats underwent 10-min asphyxial cardiac arrest and cardiopulmonary resuscitation or sham-operation. The Trpm4 siRNA and GLB were injected to block sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel in rats. Western blotting, quantitative real-time polymerase chain reaction, behavioral analysis, and histological examination were used to evaluate the role of GLB in preventing NLRP3-mediated neuroinflammation through inhibiting SUR1-TRPM4, and corresponding neuroprotective effect. To further explore the underlying mechanism, BV2 cells were subjected to lipopolysaccharides, or oxygen-glucose deprivation/reperfusion. Here, in rat model of cardiac arrest with brain edema combined with neuroinflammation, GLB significantly alleviated neurocognitive deficit and neuropathological damage, via the inhibition of microglial NLRP3 inflammasome activation by blocking SUR1-TRPM4. Of note, the above effects of GLB could be achieved by knockdown of Trpm4. In vitro under circumstance of eliminating distractions from brain edema, SUR1-TRPM4 and NLRP3 inflammasome were also activated in BV2 cells subjected to lipopolysaccharides, or oxygen-glucose deprivation/reperfusion, which could be blocked by GLB or 9-phenanthrol, a TRPM4 inhibitor. Importantly, activation of SUR1-TRPM4 in BV2 cells required the P2X7 receptor-mediated Ca2+ influx, which in turn magnified the K+ efflux via the Na+ influx-driven opening of K+ channels, leading to the NLRP3 inflammasome activation. These findings suggest that GLB has a direct anti-inflammatory neuroprotective effect independent of its role in preventing brain edema, through inhibition of SUR1-TRPM4 which amplifies K+ efflux and promotes NLRP3 inflammasome activation.

Incidence and outcome of refeeding syndrome in neurocritically ill patients.

BACKGROUND & AIM: Neurocritically ill patients are more likely to be comatose and suffer from dysphagia, conditions that inevitably require nutritional support. Inappropriate nutritional support may lead to refeeding syndrome (RFS). This study aimed to explore the incidence and outcome of RFS in neurocritically ill patients. METHODS: We conducted a retrospective study among neurocritically ill patients who received total enteral nutrition for >72 h in a university-affiliated hospital. RFS was defined as the occurrence of new-onset hypophosphatemia (<0.65 mmol/L) within 72 h of the commencement of nutritional support. The primary outcome was 6-month mortality. The secondary outcomes included 30-day mortality, neurocritical care unit (NCU) stay, and hospital length of stay. RESULTS: A total of 328 patients were enrolled, and 56 (17.1%) of them developed RFS within 72 h of nutrition support. Significantly, we found that patients with high malnutrition universal screening tool (MUST) and sequential organ failure assessment (SOFA) scores were more likely to develop RFS. The occurrence of RFS was associated with a longer NCU stay, higher 30-day mortality and 6-month mortality, and poorer 6-month functional outcome. Moreover, RFS was identified as an independent risk factor for 6-month mortality. CONCLUSION: RFS is not rare in neurocritically ill patients and is more likely to occur in patients with nutritional risk and more severe conditions. RFS is an independent risk factor for 6-month mortality in neurocritically ill patients.

Trimethylamine N-Oxide increases soluble fms-like tyrosine Kinase-1 in human placenta via NADPH oxidase dependent ROS accumulation.

BACKGROUNDS: Preeclampsia (PE) is characterized as placental vascular disturbance and excessive secretion of soluble fms-like tyrosine kinase 1 (sFlt-1) into the maternal circulation. Trimethylamine N-oxide (TMAO, a gut microbe-derived metabolite) is strongly associated with various cardiovascular and cerebrovascular diseases. Recently, we observe that higher maternal circulating TMAO and sFlt-1 in patients with PE. The aims of the present study are to explore the effects of TMAO on placental sFlt-1 production and the underlying mechanism in human placenta. METHODS: Human placental explants, human placental primary trophoblasts and the extravillous trophoblasts (EVT) cell line (HRT-8/SVneo) were exposured to various concentrations of TMAO (100, 150, 300, and 600 µM). The mRNA expression and protein secretion of sFlt-1 in placental explants, primary trophoblasts and HRT-8/SVneo cells were determined with qPCR and ELISA, respectively. The levels of intracellular reactive oxygen species (ROS) production in primary trophoblasts and HRT-8/SVneo cells were measured by peroxide-sensitive fluorescent probe dichlorofluorescein diacetate. RESULTS: Exposure of placental explants, primary trophoblasts and HRT-8/SVneo cells to TMAO significantly enhanced sFlt-1 at both mRNA and protein levels in a dose dependent manner. Moreover, inhibition of NADPH oxidase with apocynin significantly attenuated TMAO-induced ROS production in primary trophoblasts and HRT-8/SVneo, and suppressed sFlt-1 secretion in placental explants, primary trophoblasts and HRT-8/SVneo. CONCLUSIONS: Our findings indicated the NADPH oxidase dependent ROS pathway played a critical role in mediating TMAO-induced sFlt-1 generation in human placenta. TMAO may become a potential novel target for pharmacological or dietary interventions to reduce the risk of developing PE.

Biomarkers of Unfavorable Outcome in Acute Ischemic Stroke Patients with Successful Recanalization by Endovascular Thrombectomy.

BACKGROUND: We aimed to identify plasma markers of unfavorable outcomes for patients with acute ischemic stroke (AIS) after recanalization by endovascular thrombectomy (EVT). METHODS: From November 2017 to May 2019, we prospectively collected 61 AIS patients due to anterior large vessel occlusion who achieved recanalization by EVT. Plasma samples were obtained between 18 and 24 h after recanalization. Unfavorable outcomes included futile recanalization at 90 days and overall early complications within 7 days after EVT. RESULTS: After adjustment for age and initial National Institute of Health Stroke Scale (NIHSS), matrix metalloproteinase-9 (MMP-9), tenascin-C, thioredoxin, ADAMTS13, and gelsolin were independently associated with both futile recanalization and overall early complications significantly (all p < 0.05), while C-reactive protein (CRP) was independently associated with overall early complications (p = 0.031) but at the limit of significance for futile recanalization (p = 0.051). The baseline clinical model (BCM) (including age and initial NIHSS) demonstrated discriminating ability to indicate futile recanalization (area under the curve [AUC] 0.807, 95% confidence interval [CI] 0.693-0.921) and overall early complications (AUC 0.749, 95% CI 0.611-0.887). BCM+MMP-9+thioredoxin enhanced discrimination (AUC 0.908, 95% CI 0.839-0.978, p = 0.043) and reclassification (net reclassification improvement [NRI] 67.2%, p < 0.001) to indicate futile recanalization. With respect to overall early complications, BCM+MMP-9+tenascin-C, BCM+MMP-9+CRP, BCM+MMP-9+ADAMTS13, BCM+tenascin-C+ADAMTS13, and BCM+CRP+ADAMTS13, all improved discrimination (AUC [95% CI]: 0.868 [0.766-0.970], 0.882 [0.773-0.990], 0.886 [0.788-0.984], 0.880 [0.783-0.977], and 0.863 [0.764-0.962], respectively, all p < 0.05 by the DeLong method) and reclassification (NRI 59.1%, 71.8%, 51.1%, 67.4%, and 38.3%, respectively, all p < 0.05). CONCLUSIONS: The increased levels of MMP-9, tenascin-C, CRP, thioredoxin, and decreased levels of ADAMTS13 and gelsolin were independent predictors of futile recanalization in AIS patients after recanalization by EVT.

Interleukin-1α leads to growth hormone deficiency in adamantinomatous craniopharyngioma by targeting pericytes: implication in pituitary fibrosis.

BACKGROUND: The incidence of growth hormone deficiency (GHD) in adamantinomatous craniopharyngioma (aCP) is significantly higher than in other sellar region tumors, but the possible mechanism is still elusive. A high level of inflammatory responses is another feature of aCP. We investigated the internal connection between interleukin-1α (IL-1α) and GHD, while focusing on its biological activities in pituitary fibrosis. MATERIALS AND METHODS: To diagnosis of GHD, the Body Mass Index (BMI), Insulin Like Growth Factor-1(IGF-1) and peak growth hormone (GH) values after insulin stimulation test of 15 aCP patients were recorded. Histological staining was performed on the aCP samples. Levels of 9 proinflammatory cytokines in tumor tissue and cell supernatant were detected using Millipore bead arrays. The effect of IL-1α on GH secretion was evaluated in vivo and in vitro. Western blot, qRT-PCR and cell functional assays were used to explore the potential mechanism through which IL-1α acts on GH secretion. The stereotactic ALZET osmotic pump technique was used to simulate aCP secretion of proinflammatory cytokines in rats. Recombinant IL-1α (rrIL-1α) and conditioned media (CM) prepared from the supernatant of aCP cells was infused directly into the intra-sellar at a rate of 1 µl/h over 28 days, and then the effects of IL-1α treatment on pathological changes of pituitary gland and GH secretion were measured. To further confirm whether IL-1α affects GH secretion through IL-1R1, an IL-1R1 blocker (IL-1R1a, 10 mg/kg body weight, once daily) was administered subcutaneously from the first day until day 28. RESULTS: There was a significant positive correlation between pituitary fibrosis and GHD (rS = 0.756, P = 0.001). A number of cytokines, in particular IL-1α, interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), were elevated in tumor tissue and cell supernatant. Only IL-1α showed a significant difference between the GHD group and the No-GHD group (P < 0.001, F = 6.251 in tumor tissue; P = 0.003, F = 1.529 in cell supernatant). IL-1α significantly reduced GH secretion in coculture of GH3 and pericytes. The activation of pericytes induced by IL-1α was mediated by the IL-1R1 signaling pathway. In vivo, IL-1α induces pituitary fibrosis, further leading to a decreased level of GH. This pathological change was antagonized by IL-1R1a. CONCLUSION: This study found that the cross talk between aCP cells and stroma cells in the pituitary, i.e. pericytes, is an essential factor in the formation of GHD, and we propose that neutralization of IL-1α signaling might be a potential therapy for GHD in aCP.

Maternal serum trimethylamine-N-oxide is significantly increased in cases with established preeclampsia.

PURPOSE: To compare the levels of trimethylamine-N-oxide (TMAO) in sera of normal and preeclamptic pregnancies and to explore whether serum TMAO level was associated with the severity of preeclampsia. MATERIALS AND METHODS: Eighty-six pregnant women in the third trimester were enrolled in this case control study. Levels of TMAO were quantified by a novel liquid chromatography/tandem mass spectrometry-based method in fasting serum samples from 43 preeclamptic women and 43 normotensive controls. Clinical characteristics, serum biomarkers of inflammation (IL-1ß) and biomarkers of endothelial dysfunction (sVCAM-1, sFlt-1) were assessed. RESULTS: TMAO levels were significantly higher in women with preeclampsia than those with normal pregnancy. The serum levels of TMAO were positively correlated with systolic blood pressure (r = 0.602, P < 0.001), urinary protein levels (r = 0.557, P < 0.001) and the serum levels of IL-1ß (r = 0.633, P < 0.001), sVCAM-1 (r = 0.719, P < 0.001) as well as sFlt-1 (r = 0.763, P < 0.001) in patients with PE. CONCLUSIONS: Elevated TMAO levels are associated with higher risk of preeclampsia and correlate with increased systemic inflammation and endothelial dysfunction. Further validation of these findings with more robust multicenter prospective and longitudinal characterization of maternal serum TMAO in pregnancy may be carried out in subsequent investigations to determine its suitability as a predictive biomarker for preeclampsia.

[Maternal neutrophil-to-lymphocyte ratio as a prognostic biomarker for placental inflammatory response in late pregnancy].

OBJECTIVE: To investigate the association between maternal serum neutrophil-lymphocyte ratio (NLR) and placental inflammatory response (PIR) in late pregnancy. METHODS: We retrospectively analyzed the clinical and follow-up data of 478 pregnant women undergoing routine prenatal examination and delivery in our hospital in the year 2016. According to the placental pathological results, the women were divided into PIR group (238 cases) and control group (240 cases). The levels of serum inflammatory makers including leukocytes, neutrophils, lymphocytes, C-reactive protein (CRP) and NLR were compared between the two groups to analyze the association of these markers with PIR. Multivariate analysis was performed to identify the independent risk factors of PIR. Logistic regression model was established and the area under the receiver operating characteristic curve (ROC) was used for analyzing the prognostic value of these makers in late pregnancy. RESULTS: The areas under the curve (AUC) of leukocytes, neutrophils, lymphocytes, CRP and NLR were 0.698 (95%CI: 0.485-0.766), 0.716 (95%CI: 0.453-0.783), 0.329 (95%CI: 0.228-0.431), 0.725 (95%CI: 0.677-0.765) and 0.801 (95%CI: 0.742-0.856), respectively. After adjusting the confounders, multivariate logistic regression analysis showed that preterm labor (OR=2.446, 95%CI: 1.003-4.590), premature rupture of membranes (OR=2.304, 95%CI: 1.049-4.161), NLR > 7 (OR=3.268, 95%CI: 2.071-6.920), and CRP > 15 mg/L (OR=2.137, 95%CI: 1.412-8.236) were independent risk factors for PIR. CONCLUSIONS: An increased NLR in late pregnancy can serve as an effective indicator for predicting the risk of PIR.

Cell permeable HMGB1-binding heptamer peptide ameliorates neurovascular complications associated with thrombolytic therapy in rats with transient ischemic stroke.

BACKGROUND: Blood-brain barrier (BBB) breakdown and inflammatory responses are the major causes of tissue-type plasminogen activator (tPA)-induced hemorrhagic transformation (HT), while high-mobility group box 1 (HMGB1) exacerbates inflammatory damage to BBB during the process of brain ischemia/reperfusion. This study aimed to investigate the change of HMGB1 after thrombolytic therapy and whether blocking HMGB1 could ameliorate the neurovasculature complications secondary to tPA treatment in stroke rats. METHODS: Sera from acute stroke patients and rats with thrombolytic therapy were collected to investigate HMGB1 secretion. Male Sprague-Dawley rats with 2 h or 4.5 h middle cerebral artery occlusion were continuously infused with tPA followed by administration of membrane permeable HMGB1-binding heptamer peptide (HBHP). The mortality rate, neurological score, HT, brain swelling, BBB permeability, and inflammatory factors were determined. RESULTS: The results revealed that HMGB1 levels were elevated in both stroke patients and rats after tPA treatment. Blocking HMGB1 signaling by HBHP in the rat model of 4.5 h brain ischemia significantly attenuated tPA-related complications, including mortality rate, the degree of hemorrhage, brain swelling, neurological deficits, BBB impairment, microglia activation, and the expressions of inflammatory cytokines. CONCLUSIONS: tPA treatment might induce HMGB1 secretion while blocking HMGB1 with HBHP could markedly reduce the risk of thrombolysis-associated brain hemorrhage and mortality through attenuating BBB damage and inflammatory reactions. These results indicate that HMGB1 may potentiate the risk of HT in tPA administration and that blocking HMGB1 signaling would be helpful in preventing complications brought by thrombolysis in ischemic stroke. TRIAL REGISTRATION: http://www.chictr.org.cn . Unique identifier: ChiCTR-OOC-16010052. Registered 30 November 2016.