Exosomes derived from bone marrow mesenchymal stem cells protect the injured spinal cord by inhibiting pericyte pyroptosis

Mesenchymal stem cell (MSC) transplantation is a promising treatment strategy for spinal cord injury, but immunological rejection and possible tumor formation limit its application. The therapeutic effects of MSCs mainly depend on their release of soluble paracrine factors. Exosomes are essential for the secretion of these paracrine effectors. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-EXOs) can be substituted for BMSCs in cell transplantation. However, the underlying mechanisms remain unclear. In this study, a rat model of T10 spinal cord injury was established using the impact method. Then, 30 minutes and 1 day after spinal cord injury, the rats were administered 200 μL exosomes via the tail vein (200 μg/mL; approximately 1 × 10⁶ BMSCs). Treatment with BMSC-EXOs greatly reduced neuronal cell death, improved myelin arrangement and reduced myelin loss, increased pericyte/endothelial cell coverage on the vascular wall, decreased blood-spinal cord barrier leakage, reduced caspase 1 expression, inhibited interleukin-1β release, and accelerated locomotor functional recovery in rats with spinal cord injury. In the cell culture experiment, pericytes were treated with interferon-γ and tumor necrosis factor-α. Then, Lipofectamine 3000 was used to deliver lipopolysaccharide into the cells, and the cells were co-incubated with adenosine triphosphate to simulate injury in vitro. Pre-treatment with BMSC-EXOs for 8 hours greatly reduced pericyte pyroptosis and increased pericyte survival rate. These findings suggest that BMSC-EXOs may protect pericytes by inhibiting pyroptosis and by improving blood-spinal cord barrier integrity, thereby promoting the survival of neurons and the extension of nerve fibers, and ultimately improving motor function in rats with spinal cord injury. All protocols were conducted with the approval of the Animal Ethics Committee of Zhengzhou University on March 16, 2019.

Chinese Library Classification No. R456; R745.4; R363     

Patterns of attendances to the hospital emergency eye care service: a multicentre study in England

Background/ObjectivesTo characterise the patterns of presentation and diagnostic frequencies in Hospital Emergency Eye Care Services (HEECS) across 13 hospitals in England.MethodsRetrospective, cross-sectional, observational multi-centre (n = 13) study to assess HEECS attendances over a 28-day study period. Data derived included: number of consecutive attendances, patient demographics and diagnoses. Age and gender variations, the impact of day of the week on attendance patterns, diagnostic frequencies and estimates of the annual incidence and attendance rates were evaluated.ResultsA total of 17,667 patient (mean ± standard deviation age = 49.6 ± 21.8 years) attendances were identified with an estimated HEECS annual new attendance rate of 31.0 per 1,000 population. Significantly more females (53%) than males (47%) attended HEECS (p < 0.001). Female attendances were 13% higher in those ≥50 years of age. Weekends were associated with a significant reduction in attendances compared to weekdays (χ² = 6.94, p < 0.001). Among weekdays, Mondays and Fridays were associated with significantly higher attendances compared with midweek (χ² = 2.20, p = 0.032). Presenting pathologies involving the external eye, cornea and conjunctiva accounted for 28.6% of the caseload.ConclusionThis is the largest multicentre study assessing attendance patterns in HEECS in England. We have, for the first time, observed a “weekend effect” in relation to attendance to HEECS. Differences in health-seeking behaviour and lack of awareness of HEECS weekend services may be partly attributed to the differences observed. Our findings, along with the type of presentations, have the potential to guide commissioners with future planning of HEECS.Subject terms: Epidemiology, Epidemiology     

Original research: Widespread gaps in the quality of care for primary biliary cholangitis in UK

ObjectivePrimary biliary cholangitis (PBC) is a progressive, autoimmune, cholestatic liver disease affecting approximately 15 000 individuals in the UK. Updated guidelines for the management of PBC were published by The European Association for the Study of the Liver (EASL) in 2017. We report on the first national, pilot audit that assesses the quality of care and adherence to guidelines.DesignData were collected from 11 National Health Service hospitals in England, Wales and Scotland between 2017 and 2020. Data on patient demographics, ursodeoxycholic acid (UDCA) dosing and key guideline recommendations were captured from medical records. Results from each hospital were evaluated for target achievement and underwent χ² analysis for variation in performance between trusts.Results790 patients’ medical records were reviewed. The data demonstrated that the majority of hospitals did not meet all of the recommended EASL standards. Standards with the lowest likelihood of being met were identified as optimal UDCA dosing, assessment of bone density and assessment of clinical symptoms (pruritus and fatigue). Significant variations in meeting these three standards were observed across UK, in addition to assessment of biochemical response to UDCA (all p<0.0001) and assessment of transplant eligibility in high-risk patients (p=0.0297).ConclusionOur findings identify a broad-based deficiency in ‘real-world’ PBC care, suggesting the need for an intervention to improve guideline adherence, ultimately improving patient outcomes. We developed the PBC Review tool and recommend its incorporation into clinical practice. As the first audit of its kind, it will be used to inform a future wide-scale reaudit.     

Cell death mechanisms induced by synergistic effects of halofuginone and artemisinin in colorectal cancer cells

Our previous study found that the combination of halofuginone (HF) and artemisinin (ATS) synergistically arrest colorectal cancer (CRC) cells at the G1/G0 phase of the cell cycle; however, it remains unclear whether HF-ATS induces cell death. Here we report that HF-ATS synergistically induced caspase-dependent apoptosis in CRC cells. Specifically, both in vitro and in vivo experiments showed that HF or HF-ATS induces apoptosis via activation of caspase-9 and caspase-8 while only caspase-9 is involved in ATS-induced apoptosis. Furthermore, we found HF or HF-ATS induces autophagy; ATS can''t induce autophagy until caspase-9 is blocked. Further analyzing the crosstalk between autophagic and caspase activation in CRC cells, we found autophagy is essential for activation of caspase-8, and ATS switches to activate capase-8 via induction of autophagy when caspase-9 is inhibited. When apoptosis is totally blocked, HF-ATS switches to induce autophagic cell death. This scenario was then confirmed in studies of chemoresistance CRC cells with defective apoptosis. Our results indicate that HF-ATS induces cell death via interaction between apoptosis and autophagy in CRC cells. These results highlight the value of continued investigation into the potential use of this combination in cancer therapy.     

Streptococcus pneumoniae Serotypes Associated with Death,South Africa, 2012–2018

The Streptococcus pneumoniae polysaccharide capsule plays a role in disease severity. We assessed the association of serotype with case-fatality ratio (CFR) in invasive pneumococcal disease (IPD) and meningitis in South Africa, 2012–2018 (vaccine era), using multivariable logistic regression by manual backward elimination. The most common serotypes causing IPD were 8 and 19A. In patients <15 years of age, serotypes associated with increased CFR in IPD, compared with serotype 8 and controlling for confounding factors, were 11A, 13, 19F, 15A, and 6A. None of these serotypes were associated with increased CFR in meningitis. Among IPD patients >15 years of age, serotype 15B/C was associated with increased CFR. Among meningitis patients of all ages, serotype 1 was associated with increased CFR. PCV13 serotypes 1, 3, 6A, 19A, and 19F should be monitored, and serotypes 8, 12F, 15A, and 15B/C should be considered for inclusion in vaccines to reduce deaths caused by S. pneumoniae.     

孕期活动能量消耗与分娩进展的关系探讨

目的探讨孕期活动能量消耗与分娩进展的关系。方法自行设计问卷对140例经阴道分娩单胎产妇进行调查,记录孕期活动方式和时间、妊娠终止时间和分娩进展等。结果孕期活动能量消耗多者引产、催产及需人工破膜者少(P<0．05),第一产程宫缩强度大和时间短(P<0．01)。结论孕期进行适当活动和延长坚持工作时间有助于自然分娩进展。     

经皮冠状动脉支架介入治疗患者行非心脏手术抗血小板治疗的困惑与思考

冠状动脉粥样硬化性心脏病患者日益增多,其中有相当比例的患者接受了经皮冠状动脉介入治疗及术后双联抗血小板治疗。这些患者如果短期内需要接受非心脏手术将面临失血增加的危害,但是如果停止抗血小板治疗,围手术期支架内血栓形成的风险和心肌梗死的发生率将增加。文章针对上述问题就冠状动脉支架植入患者术后抗凝治疗的主要药物、有效性及安全...     

An evaluation of a national mass media campaign to raise public awareness of possible lung cancer symptoms in England in 2016 and 2017

Background A two-phase ‘respiratory symptoms’ mass media campaign was conducted in 2016 and 2017 in England raising awareness of cough and worsening shortness of breath as symptoms warranting a general practitioner (GP) visit.Method A prospectively planned pre–post evaluation was done using routinely collected data on 15 metrics, including GP attendance, GP referral, emergency presentations, cancers diagnosed (five metrics), cancer stage, investigations (two metrics), outpatient attendances, inpatient admissions, major lung resections and 1-year survival. The primary analysis compared 2015 with 2017. Trends in metrics over the whole period were also considered. The effects of the campaign on awareness of lung cancer symptoms were evaluated using bespoke surveys.Results There were small favourable statistically significant and clinically important changes over 2 years in 11 of the 15 metrics measured, including a 2.11% (95% confidence interval 1.02–3.20, p < 0.001) improvement in the percentage of lung cancers diagnosed at an early stage. However, these changes were not accompanied by increases in GP attendances. Furthermore, the time trends showed a gradual change in the metrics rather than steep changes occurring during or after the campaigns.Conclusion There were small positive changes in most metrics relating to lung cancer diagnosis after this campaign. However, the pattern over time challenges whether the improvements are wholly attributable to the campaign. Given the importance of education on cancer in its own right, raising awareness of symptoms should remain important. However further research is needed to maximise the effect on health outcomes.Subject terms: Translational research, Epidemiology     

神经内镜治疗脑积水的适应证与并发症

目的研究神经内镜治疗脑积水的适应证、效果和并发症。方法采用神经内镜治疗脑积水30例,其中神经内镜三脑室造瘘术(ETV)22例,神经内镜透明膈造瘘术2例,因室间孔狭小或视野不清改行脑室-腹腔分流术5例。分析其临床和影像学结果,总结其效果、适应证和并发症。结果行ETV的22例术后颅内压210~240mmH2O,平均(226±28)mmH2O。并发脑膜炎2例,发热4例,1例切口愈合不良,4例ETV术后并发头皮下少量积液。出血3例,无死亡和永久后遗症。结论对于因导水管狭窄、后颅窝和中脑占位引起的梗阻性脑积水患者ETV有很好的效果。慎重选择造瘘部位和器械对于避免出血等严重并发症有重要意义。     

阻断内毒素胞内信号转导通路对大鼠移植肝脏再灌注损伤的影响

目的 探讨以白细胞介素-1受体相关激酶-4（IRAK-4）为靶点,阻断内毒素胞内信号转导后对大鼠移植肝脏再灌注损伤（I／RI）的影响并探索肝移植时可行的RNA干扰（RNAi）治疗途径。方法 两袖套法建立SD大鼠同种异体原位肝移植模型,随机分为冷缺血转染组、活体转染组及对照组。冷缺血转染组于冷缺血期经门静脉灌注转染携带IRAK-4-shRNA的质粒pSIIRAK-4;活体转染组在门静脉袖套吻合完成后,经门静脉分支注入pSIIRAK-4;对照组不予任何处理。按门静脉血流恢复后第0min、60min及180min分为三个亚组,RT—PCR及Western—blot测定肝组织的IRAK-4mRNA和蛋白表达水平;ELISA法测定受体血清TNF-α含量。采用TUNEL法检测肝细胞凋亡状态,透射电镜观察肝组织超微结构的病理形态学变化。结果 再灌注后冷缺血转染组的IRAK-4表达明显低于同时点的活体转染组及对照组（P〈0．01）;同时,肝细胞凋亡指数、血清TNF-α含量及肝细胞、血窦内皮细胞损伤程度也明显低于后者。结论 以IRAK-4为靶点的冷缺血期shRNAs转染途径能有效阻断内毒素胞内信号转导,进而减轻肝移植时的I／RI程度。