不同剂量乌司他丁联合微量推注泵美罗培南对重症肺炎患者的疗效及血管生成素2的影响

摘要 目的：探讨与分析不同剂量乌司他丁联合微量推注泵美罗培南对重症肺炎患者的疗效及血管生成素-2的影响。方法：2019年1月到2022年2月选择在本院诊治的重症肺炎患者78例作为研究对象,将其分为研究组与对照组各39例,两组都给予美罗培南微量推注治疗,研究组与对照组分别给予高剂量与低剂量的乌司他丁治疗,连续应用7 d,观察患者的疗效及血清血管生成素2表达变化情况。结果：研究组的ICU住院时间、退热时间、炎症吸收时间与痰液颜色改变时间较对照组少（P<0.05）。研究组的治疗总有效率较对照组高（P<0.05）。两组治疗后的血清白细胞介素-6（IL-6）、白细胞介素-17（IL-17）含量明显低于治疗前(P<0.05),研究组治疗后的血清IL-6、IL-17含量也明显低于对照组（P<0.05）。两组治疗后的血清血管生成素-2含量低于治疗前,治疗后研究组血清血管生成素-2含量低于对照组（P<0.05）。结论：高剂量乌司他丁联合微量推注泵美罗培南在重症肺炎患者的应用能抑制血清血管生成素-2的表达,也可抑制血清IL-6、IL-17的表达,从而能提高治疗效果,促进改善患者的临床症状,有利于患者康复。     

重症肺炎患儿俯卧位与仰卧位机械通气的临床效果比较及其脱机结局的影响因素分析

摘要 目的：比较重症肺炎患儿俯卧位与仰卧位机械通气的临床效果,并分析其脱机结局的影响因素。方法：选择2020年5月~2021年12月期间在我院重症监护室（ICU）住院的重症肺炎患儿120例作为研究对象。根据机械通气体位方式的不同将患儿分为仰卧组（n=52）和俯卧组（n=68）,对比仰卧组、俯卧组的临床症状改善时间和血气分析指标[动脉血氧分压（PaO₂）、动脉血二氧化碳分压（PaCO₂）、平均动脉压（MAP）]。记录仰卧组、俯卧组的死亡例数、脱机成功和脱机失败例数,计算死亡率、脱机失败发生率。采用单因素及多因素Logistic回归分析脱机失败的影响因素。结果：俯卧组的发热消失时间、肺部啰音消失时间、呼吸改善时间短于仰卧组（P<0.05）。两组治疗5 d后 PaO₂、MAP较治疗前升高,PaCO₂较治疗前下降（P<0.05）;俯卧组的PaO₂、MAP高于仰卧组,PaCO2低于仰卧组（P<0.05）。两组患儿死亡率组间对比未见统计学差异（P>0.05）。俯卧组的脱机失败率低于仰卧组（P<0.05）。在120例患儿中,死亡7例,根据重症肺炎患儿脱机结局将剩余113例分为脱机成功组（n=72）和脱机失败组（n=41）,脱机失败组、脱机成功组在年龄、急性生理与慢性健康评分系统II（APACHE II）评分、病程、先天性病史、D-二聚体（D-D）、白蛋白（ALB）、血乳酸、脑尿钠肽（BNP）方面对比有统计学差异（P<0.05）。多因素Logistic回归分析结果显示：年龄偏小、APACHE II评分偏高、D-D偏高、ALB偏低、先天性病史均是重症肺炎患儿脱机结局的影响因素（P<0.05）。结论：与仰卧位相比,俯卧位机械通气用于重症肺炎患儿可获得更好的临床效果和脱机成功率,且患儿的脱机结局受到年龄、APACHE II评分、D-D、ALB、先天性病史的影响。     

研究报告: 急性缺血性卒中患者血清脑红蛋白的动态变化及临床意义

目的 脑红蛋白（neuroglobin,Ngb）又称神经球蛋白,是一种携氧球蛋白。有研究证明Ngb在脑缺血缺氧疾病中具有神经保护作用,对氧具有高亲和力,有助于预防缺氧缺血性脑损伤,并影响急性缺血性卒中（acute ischemic stroke,AIS）的预后。本研究观察了AIS后血清Ngb水平的变化,并评估了Ngb与卒中严重程度及预后的关系。方法 前瞻性地募集AIS患者和健康对照者进行研究。在AIS患者起病后不同时间点（脑梗死发病后72 h内和第14天）及对照组中分别检测血清Ngb水平,并比较AIS患者与对照组之间的血清Ngb水平。对合并与不合并糖尿病的AIS患者的血清Ngb水平进行比较。分析患者血清Ngb水平与梗死体积及国家卫生研究院卒中量表（NIHSS）评分之间的相关性。应用受试者操作特征（ROC）曲线评估Ngb对AIS预后的预测价值。结果 AIS患者的血清Ngb水平在脑梗死后72 h内和第14天时分别为105.7（88.3,123.1）μg/L和72.8（58.7,86.9）μg/L。对照组血清Ngb水平为58.2（35.0,81.6）μg/L。AIS发病后72 h内血清Ngb水平较对照组显著升高（P<0.05）。合并与不合并糖尿病的AIS患者血清Ngb水平在发病后72 h内及第14天均无显著差异（P>0.05）。AIS发病72 h内的血清Ngb水平与NIHSS评分显著相关（Spearman相关系数=0.232,P=0.038）。在各时间点,大体积脑梗死组患者血清Ngb水平与中小体积脑梗死组相比无显著性差异（P>0.05）。ROC曲线分析表明,血清Ngb水平对AIS患者的预后具有良好的预测能力。结论 AIS发病后72 h内血清Ngb水平升高。合并与不合并糖尿病的AIS患者血清Ngb水平无显著差异。发病后72 h内的血清Ngb水平与NIHSS评分显著相关。Ngb可能作为卒中严重程度和预后的预测因子。     

Hypoxic conditioned medium derived from bone marrow mesenchymal stromal cells protects against ischemic stroke in rats

In recent years, studies have shown that the secretome of bone marrow mesenchymal stromal cells (BMSCs) contains many growth factors, cytokines, and antioxidants, which may provide novel approaches to treat ischemic diseases. Furthermore, the secretome may be modulated by hypoxic preconditioning. We hypothesized that conditioned medium (CM) derived from BMSCs plays a crucial role in reducing tissue damage and improving neurological recovery after ischemic stroke and that hypoxic preconditioning of BMSCs robustly improves these activities. Rats were subjected to ischemic stroke by middle cerebral artery occlusion and then intravenously administered hypoxic CM, normoxic CM, or Dulbecco modified Eagle medium (DMEM, control). Cytokine antibody arrays and label-free quantitative proteomics analysis were used to compare the differences between hypoxic CM and normoxic CM. Injection of normoxic CM significantly reduced the infarct area and improved neurological recovery after stroke compared with administering DMEM. These outcomes may be associated with the attenuation of apoptosis and promotion of angiogenesis. Hypoxic preconditioning significantly enhanced these therapeutic effects. Fourteen proteins were significantly increased in hypoxic CM compared with normoxic CM as measured by cytokine arrays. The label-free quantitative proteomics analysis revealed 163 proteins that were differentially expressed between the two groups, including 107 upregulated proteins and 56 downregulated proteins. Collectively, our results demonstrate that hypoxic CM protected brain tissue from ischemic injury and promoted functional recovery after stroke in rats and that hypoxic CM may be the basis of a potential therapy for stroke patients.     

Role of acute-phase protein ORM in a mice model of ischemic stroke

The only Food and Drug Administration-approved treatment for acute ischemic stroke is tissue plasminogen activator, and the discovery of novel therapeutic targets is critical. Here, we found orosomucoid (ORM), an acute-phase protein mainly produced by the liver, might act as a treatment candidate for an ischemic stroke. The results showed that ORM2 is the dominant subtype in mice normal brain tissue. After middle cerebral artery occlusion (MCAO), the level of ORM2 is significantly increased in the ischemic penumbra compared with the contralateral normal brain tissue, whereas ORM1 knockout did not affect the infarct size. Exogenous ORM could significantly decrease infarct size and neurological deficit score. Inspiringly, the best administration time point was at 4.5 and 6 hr after MCAO. ORM could markedly decrease the Evans blue extravasation, and improve blood–brain barrier-associated proteins expression in the ischemic penumbra of MACO mice and oxygen–glucose deprivation (OGD)-treated bEnd3 cells. Meanwhile, ORM could significantly alleviate inflammation by inhibiting the production of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α), reduce oxidative stress by improving the balance of malondialdehyde (MDA) and superoxide dismutase (SOD), inhibit apoptosis by decreasing caspase-3 activity in ischemic penumbra of MCAO mice and OGD-treated bEnd.3 cells. Because of its protective role at multiple levels, ORM might be a promising therapeutic target for ischemic stroke.     

X-box binding protein l splicing attenuates brain microvascular endothelial cell damage induced by oxygen-glucose deprivation through the activation of phosphoinositide 3-kinase/protein kinase B,extracellular signal-regulated kinases,and hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathways

Angiogenesis is positively correlated with the survival rate of stroke patients. Therefore, studying factors that initiate and promote angiogenesis after ischemic stroke is crucial for finding novel and effective treatment targets that improve the prognosis of stroke. X-box binding protein l splicing (XBP1s) plays a positive regulatory role in cell proliferation and angiogenesis. However, the role and mechanism of XBP1s on the proliferation of brain microvascular endothelial cells (BMECs) and angiogenesis after cerebral ischemia remains unclear. In the current study, we investigated the role XBP1s plays in BMEC proliferation and angiogenesis following cerebral ischemia. In this study, the roles of XBP1s on cell survival, apoptosis, cycle migration, and angiogenesis were determined in oxygen-glucose deprivation (OGD) treated BMECs. The expression of XBP1s in BMECs, which were exposed to OGD at 0, 2, 4, and 6 hr, increased in a time-dependent manner. The overexpression of XBP1s promoted cell survival, cell cycle, migration, and angiogenesis of BMECs, and inhibited the apoptosis in OGD-treated BMECs. In addition, the overexpression of XBP1s promoted the expression of cyclin D1, matrix metalloproteinase (MMP-2), and MMP-9, but inhibited cleaved Caspase-3 and cleaved Caspase-9 expression in OGD-treated BMECs. The overexpression of XBP1s also promoted the expression of hypoxia-inducible factor 1-alpha, vascular endothelial growth factor, phosphatidylinositol-4,5-bisphosphate 3-kinase, p-AKT, p-mTOR, p-GSK3β, and p-extracellular signal-regulated kinase1/2 in OGD-treated BMECs. The effect of XBP1s silencing was opposite to that of XBP1s overexpression. In conclusion, using an in vitro OGD model, we demonstrated that XBP1s may be a promising target for ischemic stroke therapy to maintain BMECs survival and induce angiogenesis.     

Silencing of PTGS2 exerts promoting effects on angiogenesis endothelial progenitor cells in mice with ischemic stroke via repression of the NF-κB signaling pathway

The objective of the current study is to investigate the effect of PTGS2 on proliferation, migration, angiogenesis and apoptosis of endothelial progenitor cells (EPCs) in mice with ischemic stroke through the NF-κB signaling pathway. Middle cerebral artery occlusion (MCAO) model was established in mice. EPCs were identified, in which ectopic expression and depletion experiments were conducted. The mRNA and protein expression of related factors in tissues and cells were measured. Besides, proliferation, migration, angiogenesis, and apoptosis, as well as cell cycle distribution, of cells were determined. MCAO mice showed overexpression of interleukin-6 (IL-6), IL-17, and IL-23, and increased positive protein expression of PTGS2, as well as expression of PTGS2, nuclear factor-κB (NF-κB), tumor suppressor region 1 (TSP-1) and Bcl-2-associated X protein (Bax), but underexpression of vascular endothelial growth factor (VEGF), S-phase kinase associated protein 2 (Skp2), and B-cell lymphoma 2 (Bcl-2). Moreover, ectopic expression of tumor necrosis factor-α significantly elevated the expression of PTGS2, NF-κB, TSP-1, and Bax, as well as cell apoptosis and cell cycle arrest, but decreased the expression of VEGF, Skp2, and Bcl-2, as well as proliferation, migration and angiogenesis of EPCs, and the PTGS2-siRNA group showed an opposite trend. Taken together, we conclude that the specific knockdown of PTGS2 expression could repress the NF-κB signaling pathway, thereby inhibits apoptosis and promotes proliferation, migration and angiogenesis of EPCs, providing protective effect on mice with ischemic stroke.     

The ventilation mechanism of the Pacific hagfish Eptatretus stoutii

We made anatomical and physiological observations of the breathing mechanisms in Pacific hagfish Eptatretus stoutii, with measurements of nostril flow and pressure, mouth and pharyngo-cutaneous duct (PCD) pressure and velum and heart impedance and observations of dye flow patterns. Resting animals frequently exhibit spontaneous apnea. During normal breathing, water flow is continuous at a high rate (~125 ml kg⁻¹ min⁻¹ at 12°C) powered by a two-phase unidirectional pumping system with a fast suction pump (the velum, ~22 min⁻¹) for inhalation through the single nostril and a much slower force pump (gill pouches and PCD ~4.4 min⁻¹) for exhalation. The mouth joins the pharynx posterior to the velum and plays no role in ventilation at rest or during swimming. Increases in flow up to >400 ml kg⁻¹ min⁻¹ can be achieved by increases in both velum frequency and stroke volume and the ventilatory index (product of frequency x nostril pressure amplitude) provides a useful proxy for ventilatory flow rate. Two types of coughing (flow reversals) are described. During spontaneous swimming, ventilatory pressure and flow pulsatility becomes synchronised with rhythmic body undulations.     

Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease

The present study investigated a joint contribution of matrix metalloproteinases (MMPs) genes to ischemic stroke (IS) development and analyzed interactions between MMP genes and genome-wide associated loci for IS. A total of 1288 unrelated Russians (600 IS patients and 688 healthy individuals) from Central Russia were recruited for the study. Genotyping of seven single nucleotide polymorphisms (SNPs) of MMP genes (rs1799750, rs243865, rs3025058, rs11225395, rs17576, rs486055, and rs2276109) and eight genome-wide associated loci for IS were done using Taq-Man–based assays and MALDI-TOF mass spectrometry iPLEX platform, respectively. Allele − 799T at rs11225395 of the MMP8 gene was significantly associated with a decreased risk of IS after adjustment for sex and age (OR = 0.82; 95%CI, 0.70-0.96; P = 0.016). The model-based multifactor dimensionality reduction method has revealed 21 two-order, 124 three-order, and 474 four-order gene-gene (G×G) interactions models meaningfully (P_perm < 0.05) associated with the IS risk. The bioinformatic analysis enabled establishing the studied MMP gene polymorphisms possess a clear regulatory potential and may be targeted by gene regulatory networks driving molecular and cellular pathways related to the pathogenesis of IS. In conclusion, the present study was the first to identify an association between polymorphism rs11225395 of the MMP8 gene and IS risk. The study findings also indicate that MMPs deserve special attention as a potential class of genes influencing the multistep mechanisms of cerebrovascular disease including atherosclerosis in cerebral arteries, acute cerebral artery occlusion as well as the ischemic injury of the brain and its recovery.