凉血通瘀方干预高血压大鼠急性脑出血模型对脑组织中差异miRNA表达的影响＊

目的 研究凉血通瘀方对高血压大鼠急性脑出血模型脑组织miRNA表达的影响，对差异表达的miRNA靶基因进行分析，探索凉血通瘀方可能的药效机制。方法 将自发性高血压大鼠随机分成对照组（B）和实验组（C）。适应性饲养一周后，C组灌胃凉血通瘀方，B组灌胃等体积生理盐水，连续5天，每天1次。构建脑出血模型后收集脑组织，借助全转录组测序技术获得miRNA表达量，与miRBase数据库比对获取已知miRNA，使用miRDeep2预测新miRNA。差异分析软件为DESeq2，筛选阈值为|log₂FC| ≥1 并且P <0.05。对显著差异表达的miRNA进行靶基因预测，对靶基因进行GO功能、KEGG通路富集和PPI网络分析。结果 实验组和对照组对比，共发现21个显著差异表达的miRNA，上调有9个，下调有12个，共预测得到1243个有统计学意义的靶基因。GO富集分析发现，生物过程中突触囊泡分泌的调节、神经递质分泌的调节和神经递质运输的调节占前三位，神经元投射终点、全膜、质膜区域和细胞投射则是主要的细胞成分。分子功能分别为小GTPase绑定、底物特异性跨膜转运蛋白活性和离子跨膜转运体活性。通路分析结果显示，靶基因在癌证通路、pI3K-Akt信号通路、人类乳头瘤病毒感染、神经活性配体-受体相互作用和MAPK通路等分布广泛。采用STRING网站和Cytoscape软件，根据MCC算法筛选出ADRA2C、CASR、CCL28、CCR1、DRD2、GNAT3、GRM2、DYNC1LI1、GABBR1、GNAI1等核心靶基因。结论 凉血通瘀方对脑出血急性期鼠脑组织内miRNA的表达有重要影响；显著差异表达miRNAs可能通过靶向核心基因调控凉血通瘀方干预急性脑出血的病理过程及预后。     

Glycaemic control for patients with severe acute brain injury: Protocol for a systematic review

Background

Hyperglycaemia is common in patients with acute brain injury admitted to an intensive care unit (ICU). Many studies have found associations between development of hyperglycaemia and increased mortality in hospitalised patients. However, the optimal target for blood glucose control is unknown. We want to conduct a systematic review with meta-analysis and trial sequential analysis to explore the beneficial and harmful effects of restrictive versus liberal glucose control on patient outcomes in adults with severe acute brain injury.

Methods

We will systematically search medical databases including CENTRAL, Embase, MEDLINE and trial registries. We will search the following websites for ongoing or unpublished trials: http://www.controlled-trials.com/ , http://www.clinicaltrials.gov/ , www.eudraCT.com , http://centerwatch.com/ , The Cochrane Library's CENTRAL, PubMed, EMBASE, Science Citation Index Expanded and CINAHL. Two authors will independently review and select trials and extract data. We will include randomised trials comparing levels of glucose control in our analyses and observational studies will be included to address potential harms. The primary outcomes are defined as all-cause mortality, functional outcome and health-related quality of life. Secondary outcomes include serious adverse events including hypoglycaemia, length of ICU stay and duration of mechanical ventilation, and explorative outcomes including intracranial pressure and infection. Trial Sequential Analysis will be used to investigate the risk of type I error due to repetitive testing and to further explore imprecision. Quality of trials will be evaluated using the Cochrane Risk of Bias tool, and quality of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.

Discussion

The results of the systematic review will be disseminated through peer-reviewed publication. With the review, we hope to inform future randomised clinical trials and improve clinical practice.     

慢性高原病脑部多体素1H-MRS研究

目的利用多体素氢质子磁共振波谱成像(hydrogen proton magnetic resonance spectroscopy,¹H-MRS)探讨慢性高原病(chronic mountain sickness,CMS)长期缺氧状态下脑部代谢物的特点,并比较各代谢物与血液指标之间的相关性。材料与方法前瞻性纳入青海大学附属医院经临床确诊为CMS的17例男性患者作为实验组,年龄(53.29±9.03)岁,居住海拔(3989.12±937.45)m,血红蛋白(hemoglobin,HGB)(224.35±11.81)g/mL,并招募与实验组年龄及居住海拔相匹配的18名健康男性志愿者作为对照组,年龄(48.61±8.76)岁,居住海拔(3674.94±634.27)m,HGB(156.67±9.46)g/mL。采用Siemens Prisma 3.0 T MR扫描仪20通道头颅线圈对所有受试者行常规头颅MRI及多体素;H-MRS检查,通过Syngo.via后处理软件获得;H-MRS图,ROI选取双侧额叶及海马区,并获得相应脑区N-乙酰天门冬氨酸/肌酸(NAA/Cr)、胆碱/肌酸CHo/Cr、乙酰天门冬氨酸/胆碱(NAA/CHo)、乳酸/肌酸(Lac/Cr)的比值。结合独立样本t检验及非参数曼-惠特尼U检验以比较两组间代谢物相对浓度差异,然后将CMS组双侧额叶及海马区各代谢物比值与血液生化指标作相关性分析。结果(1)两组受试者年龄、长期居住海拔差异均无统计学意义(P>0.05),而与对照组相比,CMS组HGB、红细胞计数(red blood cell count,RBC)、血细胞比容(hematocrit,HCT)增高,血小板(blood platelet,简称PLT)减低,差异均有统计学意义(P<0.01);(2)与对照组相比,CMS组双侧额叶及海马区NAA/Cr及NAA/CHo均减低(P<0.05),Lac/Cr增高(P<0.05),差异均具有统计学意义;(3)与对照组相比,CMS组双侧额叶及双侧海马区CHo/Cr均增高(P>0.05),差异无统计学意义;(4)CMS组右侧额叶及左侧海马CHo/Cr与RBC明显正相关,左侧额叶CHo/Cr与HCT低度正相关,右侧额叶及左侧海马Lac/Cr与HCT低度正相关。结论CMS长期缺氧状态下脑组织局部代谢物改变,神经元受损,无氧代谢增加,且这些代谢物的改变与血液指标呈一定的相关性,可为临床后续进一步预防或干预CMS患者脑损害提供影像学证据及监测指标。     

Optical coherence tomography angiography in the evaluation of vascular patterns of ocular surface squamous neoplasia during topical medical treatment

PurposeOptical coherence tomography angiography (OCTA) was utilized to examine changes in ocular surface squamous neoplasia (OSSN) vascular patterns over time in individuals treated with topical medical therapy.MethodsTen individuals with OSSN diagnosed by clinical examination and high resolution (HR)-optical coherence tomography (OCT) were recruited. All individuals received topical immuno- or chemotherapy. OCTA images were obtained and analyzed at three points: presentation, mid-treatment and tumor resolution. Tumor metrics including tumor area (TA), tumor volume (TV), tumor depth (TD), and total tumor density (TTD) were calculated. Vessel area density (VAD) was also quantified within the OSSN, the subepithelium under and adjacent to the OSSN and the subepithelium of the uninvolved, contralateral eye. Vascular network changes were also subjectively evaluated.ResultsTA, TV, TD and TTD all significantly decreased with time (p < 0.001). The mean VAD within the OSSN significantly decreased (p < 0.001) between visits (presentation: 26.52 ± 6.8%, mid-treatment: 7.19 ± 5.88%, tumor resolution: 0.11 ± 0.34%). The mean subepithelial VAD under the OSSN also decreased with time (23.22 ± 11.03%, 20.99 ± 5.99% and 19.58 ± 7.08%), and after resolution the sub-tumor VAD (19.58 ± 7.08%) was comparable to the subepithelial VAD in the contralateral eye (15.47 ± 4.37%, p > 0.05). The mean VAD in the subepithelium adjacent to the OSSN increased with treatment, then decreased significantly between mid-treatment and resolution (23.26 ± 4.54, 28.30 ± 7.43% and 21.68 ± 6.10%, p = 0.009). Qualitatively, the tumor subepithelial vascular network was complex and dense but with tumor resolution appeared less tortuous and similar to the uninvolved eye.ConclusionOCTA provided insight into the pathophysiology of tumor angiogenesis, showing decreased vascular density and normalization of vascular networks associated with tumor resolution.     

The association between sport-related concussion and musculoskeletal injury in university rugby athletes

ObjectivesThe study aimed to analyse the association between Sports-Related Concussion (SRC) and Subsequent Musculoskeletal Injury (MSK) in United Kingdom university-aged rugby union players whilst considering the effects of sex, athlete playing position and injury location.DesignRetrospective cohort study. A period of 365 days with 0–90, 91–180 and 181–365 days sub-periods was analysed for the following variables; MSK injury incidence, occurrence, severity, injury location, playing position and sex.SettingInjury data was collected from the Sports Development Centre database at Loughborough University.ParticipantsA total of 408 injuries in 181 athletes (55 females and 126 males) were included.ResultsThe MSK injury incidence of SRC group was significantly higher than control and higher post-SRC than pre-SRC period over a 365-day period (p=0.012 and p=0.034, respectively). The odds ratios of MSK injury incidence between groups and between periods were 1.62 (95% CI, 1.10–2.25) and 1.57 (95% CI ,1.08–2.29). A SRC was not associated with a greater time loss from a subsequent MSK injury or a specific MSK injury location.ConclusionsAthletes with a second recorded injury were more likely to sustain a MSK injury if they had experienced SRC, however, there was no indication a SRC resulted in greater time loss from a MSK injury.     

Selecting patients for early interdisciplinary rehabilitation during neurointensive care after moderate to severe traumatic brain injury

Background

Early interdisciplinary rehabilitation (EIR) in neurointensive care is a limited resource reserved for patients with moderate to severe traumatic brain injury (TBI) believed to profit from treatment. We evaluated how key parameters related to injury severity and patient characteristics were predictive of receiving EIR, and whether these parameters changed over time.

Methods

Among 1003 adult patients with moderate to severe TBI admitted over 72 h to neurointensive care unit during four time periods between 2005 and 2020, EIR was given to 578 and standard care to 425 patients. Ten selection criteria thought to best represent injury severity and patient benefit were evaluated (Glasgow Coma Scale, Head Abbreviated Injury Scale, New-Injury-Severity-Scale, intracranial pressure monitoring, neurosurgery, age, employment, Charlson Comorbidity Index, severe psychiatric disease, and chronic substance abuse).

Results

In multivariate regression analysis, patients who were employed (adjOR 1.99 [95% CI 1.41, 2.80]), had no/mild comorbidity (adjOR 3.15 [95% CI 1.72, 5.79]), needed neurosurgery, had increasing injury severity and were admitted by increasing time period were more likely to receive EIR, whereas receiving EIR was less likely with increasing age (adjOR 0.97 [95% CI 0.96, 0.98]) and chronic substance abuse. Overall predictive ability of the model was 71%. Median age and comorbidity increased while employment decreased from 2005 to 2020, indicating patient selection became less restrictive with time.

Conclusion

Injury severity and need for neurosurgery remain important predictors for receiving EIR, but the importance of age, employment, and comorbidity have changed over time. Moderate prediction accuracy using current clinical criteria suggest unrecognized factors are important for patient selection.     

Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.