Journal of Investigative Medicine最新文献

{"title":"Tenecteplase thrombolysis for stroke up to 24 hours after onset with perfusion imaging selection: the umbrella phase IIa CHABLIS-T randomised clinical trial.","authors":"Xin Cheng, Lan Hong, Leonid Churilov, Longting Lin, Yifeng Ling, Jin Zhang, Jianhong Yang, Yu Geng, Danhong Wu, Xueyuan Liu, Xiaoyu Zhou, Yuwu Zhao, Qijin Zhai, Liandong Zhao, Yangmei Chen, Ying Guo, Xiaofei Yu, Fan Gong, Yi Sui, Gang Li, Lumeng Yang, Hong-Qiu Gu, Yilong Wang, Mark Parsons, Qiang Dong","doi":"10.1136/svn-2023-002820","DOIUrl":"10.1136/svn-2023-002820","url":null,"abstract":"<p><strong>Background: </strong>The performance of intravenous tenecteplase in patients who had an acute ischaemic stroke with large/medium vessel occlusion or severe stenosis in an extended time window remains unknown. We investigated the promise of efficacy and safety of different doses of tenecteplase manufactured in China, in patients who had an acute ischaemic stroke with large/medium vessel occlusion beyond 4.5-hour time window.</p><p><strong>Methods: </strong>The CHinese Acute tissue-Based imaging selection for Lysis In Stroke-Tenecteplase was an investigator-initiated, umbrella phase IIa, open-label, blinded-endpoint, Simon's two-stage randomised clinical trial in 13 centres across mainland China. Participants who had salvageable brain tissue on automated perfusion imaging and presented within 4.5-24 hours from time of last seen well were randomised to receive 0.25 mg/kg tenecteplase or 0.32 mg/kg tenecteplase, both with a bolus infusion over 5-10 s. The primary outcome was proportion of patients with promise of efficacy and safety defined as reaching major reperfusion without symptomatic intracranial haemorrhage at 24-48 hours after thrombolysis. Assessors were blinded to treatment allocation. All participants who received tenecteplase were included in the analysis.</p><p><strong>Results: </strong>A total of 86 patients who had an acute ischaemic stroke identified with anterior large/medium vessel occlusion or severe stenosis were included in this study from November 2019 to December 2021. All of the 86 patients enrolled either received 0.25 mg/kg (n=43) or 0.32 mg/kg (n=43) tenecteplase, and were available for primary outcome analysis. Fourteen out of 43 patients in the 0.25 mg/kg tenecteplase group and 10 out of 43 patients in the 0.32 mg/kg tenecteplase group reached the primary outcome, providing promise of efficacy and safety for both doses based on Simon's two-stage design.</p><p><strong>Discussion: </strong>Among patients with anterior large/medium vessel occlusion and significant penumbral mismatch presented within 4.5-24 hours from time of last seen well, tenecteplase 0.25 mg/kg and 0.32 mg/kg both provided sufficient promise of efficacy and safety.</p><p><strong>Trial registration number: </strong>ClinicalTrials.gov Registry (NCT04086147, https://clinicaltrials.gov/ct2/show/NCT04086147).</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"551-559"},"PeriodicalIF":2.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139576626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trendelenburg position for acute anterior circulation ischaemic stroke with large artery atherosclerosis aetiology (HOPES 3): rationale and design.","authors":"Xiaoqiu Li, Zhenni Guo, Lu Wang, Yue Wang, Thanh Nguyen, Yi Yang, Hui-Sheng Chen","doi":"10.1136/svn-2023-002868","DOIUrl":"10.1136/svn-2023-002868","url":null,"abstract":"<p><strong>Rationale: </strong>The effect of the head position as a non-pharmacological therapy on acute ischaemic stroke (AIS) remains inconclusive. Our recent Head dOwn-Position for acutE moderate ischaemic Stroke with large artery atherosclerosis (HOPES 2) suggested the safety, feasibility and potential benefit of the head-down position (HDP) in AIS.</p><p><strong>Aim: </strong>To investigate the benefit of HDP in acute moderate ischaemic stroke patients with large artery atherosclerosis (LAA).</p><p><strong>Sample size estimates: </strong>Based on a two-sided 0.05 level of significance, 600 patients are expected to yield the superiority hypothesis with 80% power, stratified by age, sex, history of diabetes, baseline systolic blood pressure, location of index vessel, National Institutes of Health Stroke Scale Score at randomisation, onset to randomisation time, progression to moderate neurological deficit due to early neurological deterioration and degree of responsible vessel stenosis.</p><p><strong>Design: </strong>Head dOwn-Position for acutE moderate ischaemic Stroke with large artery atherosclerosis(HOPES 3) is a prospective, randomised, open-label, blinded endpoint and multicentre study. Eligible patients who had an ischaemic stroke will be randomly assigned (1:1) into the HDP group receiving -20° Trendelenburg plus standard medical care in compliance with national guidelines, or control group only receiving standard medical care in compliance with national guidelines.</p><p><strong>Outcome: </strong>The primary outcome is favourable functional outcome, defined as modified Rankin Scale 0-2 at 90 days. Safety outcomes are HDP-related adverse events. All outcomes will have blinded assessment and will be analysed on the intention-to-treat basis.</p><p><strong>Conclusions: </strong>The results of HOPES 3 will provide evidence for the effect of HDP in acute moderate ischaemic stroke patients with LAA within 24 hours of onset or in patients with progression from mild neurological deficit within 24 hours.</p><p><strong>Trial registration number: </strong>NCT06010641.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"574-579"},"PeriodicalIF":2.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139724556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characteristics, temporal trends and outcomes of intravenous thrombolysis in Chinese patients aged>80 years who had a stroke.","authors":"Changsheng Li, Yingyu Jiang, Hong-Qiu Gu, Meng Wang, Zimo Chen, Xin Yang, Qi Zhou, Xia Meng, Chunjuan Wang, Zixiao Li","doi":"10.1136/svn-2024-003427","DOIUrl":"https://doi.org/10.1136/svn-2024-003427","url":null,"abstract":"<p><strong>Background and purpose: </strong>To date, no large cohort study has investigated the effects of intravenous thrombolysis (IVT) in Chinese patients aged over 80 years who had a stroke. This study aimed to assess the trends in the use of alteplase, the clinical characteristics and the outcomes of Chinese patients aged above 80 years who had an acute ischaemic stroke.</p><p><strong>Methods: </strong>Data for this analysis were obtained from the China Stroke Center Alliance programme, a nationwide, multicentre, prospective registry encompassing 1751 hospitals across 31 provinces, covering the period from 1 January 2018 to 14 December 2022. The primary outcome was defined as a modified Rankin Scale (mRS) Score of 0-2 at discharge. Secondary outcomes included an mRS Score of 0-1 and independent ambulation on discharge. Safety outcomes assessed were in-hospital mortality and symptomatic intracranial haemorrhage (sICH).</p><p><strong>Results: </strong>Out of 30 902 patients over 80 years old who qualified for thrombolysis, 8673 (median age (IQR), 84 (82-87) years) received alteplase treatment. Patients administered alteplase demonstrated improved short-term functional outcomes, such as an mRS Score of 0-2 (adjusted OR (aOR) 1.12, 95% CI, 1.06 to 1.18, p<0.001), an mRS Score of 0-1 (aOR 1.14, 95% CI, 1.08 to 1.19, p<0.001) and independent ambulation at discharge (aOR 1.14, 95% CI, 1.08 to 1.20, p<0.001). Moreover, no significant increase was observed in the risk of in-hospital mortality (aOR 1.12, 95% CI, 0.93 to 1.35; p=0.23). However, the risk of sICH was significantly higher among patients treated with alteplase (aOR 3.22, 95% CI, 2.77 to 3.75; p<0.001).</p><p><strong>Conclusions: </strong>IVT with alteplase in elderly patients who had a stroke resulted in improved short-term functional outcomes without elevating the risk of in-hospital mortality. Nonetheless, this population remains at a higher risk of sICH.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stenting for symptomatic intracranial arterial stenosis with different qualifying arteries: a preplanned pooled individual patient data analysis.","authors":"Tianhua Li, Jichang Luo, Xuesong Bai, Eyad Almallouhi, Peng Gao, Delin Liu, Ran Xu, Wenlong Xu, Guangdong Lu, Haozhi Gong, Xiao Zhang, Taoyuan Lu, Jie Wang, Renjie Yang, Zixuan Xing, Guangjie Liu, Yufu Dai, Colin P Derdeyn, Liqun Jiao, Tao Wang","doi":"10.1136/svn-2024-003532","DOIUrl":"https://doi.org/10.1136/svn-2024-003532","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of percutaneous transluminal angioplasty and stenting (PTAS) relative to medical management in treating symptomatic intracranial arterial stenosis (ICAS) varies based on the qualifying artery. This study aims to evaluate PTAS compared with medical therapy alone in cases of ICAS involving the internal carotid artery (ICA), middle cerebral artery (MCA), vertebral artery (VA) and basilar artery (BA).</p><p><strong>Methods: </strong>This study involves a thorough pooled analysis of individual patient data from two randomised controlled trials, evaluating the efficacy of PTAS in comparison to medical management for symptomatic ICAS with different qualifying arteries. The primary outcome was stroke or death within 30 days postenrolment, or stroke in the region of the qualifying artery beyond 30 days through 1 year. A methodology based on intention-to-treat was employed, and HR accompanied by 95% CIs were used to convey risk estimates.</p><p><strong>Results: </strong>The data of 809 individuals were collected from Stenting vs Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial and China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis trial. Four hundred were designated for PTAS, while 409 were assigned to medical therapy alone. For the primary outcome, patients with symptomatic BA stenosis had a significantly higher risk of receiving PTAS compared with medical therapy (17.17% vs 7.77%; 9.40; HR, 2.38 (1.03 to 5.52); p=0.04). However, PTAS had no significant difference in patients with symptomatic ICA (26.67% vs 16.67%; HR, 1.68 (0.78 to 3.62); p=0.19), MCA (8.28% vs 9.79%; HR, 0.85 (0.42 to 1.74); p=0.66) and VA stenosis (9.52% vs 10.71%; HR, 0.91 (0.32 to 2.62); p=0.86) compared with medical therapy.</p><p><strong>Conclusions: </strong>PTAS significantly increases the risk of both short-term and long-term stroke in patients with symptomatic BA stenosis. Without significant technological advancements to mitigate these risks, PTAS offers limited benefits. For symptomatic ICA, MCA and VA stenosis, PTAS provided no significant advantage.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding external carotid artery collateralisation after cerebral revascularisation in moyamoya disease: insights from quantitative analysis.","authors":"Wenjie Li, Meng Zhao, Xingju Liu, Peijiong Wang, Huan Zhu, Qihang Zhang, Chenyu Zhu, Qian Zhang, Xun Ye, Jizong Zhao, Yan Zhang","doi":"10.1136/svn-2024-003336","DOIUrl":"https://doi.org/10.1136/svn-2024-003336","url":null,"abstract":"<p><strong>Background: </strong>This study aims to quantitatively evaluate collateralisation angiogenesis ratio (CAR) of external carotid artery and intracranial arterial residual volumes (ARV) postcerebral revascularisation in moyamoya disease (MMD) and elucidate the factors influencing external carotid artery collateralisation.</p><p><strong>Methods: </strong>The study retrospectively analysed 297 patients diagnosed with MMD who underwent cerebral revascularisation at our University's Hospital, between January 2015 and May 2023. The clinical data, imaging results and surgical specifics for the patients were collected. Using a newly proposed digital subtraction angiography-based evaluation system, the CAR of external carotid artery and the intracranial ARV were evaluated quantitatively following standardised protocols.</p><p><strong>Results: </strong>The study included 136 male and 161 female patients. The severity of ischaemic (r=-0.297) and haemorrhagic (r=-0.270) MMD, as assessed by the Suzuki stage, demonstrated a significant negative correlation with intracranial ARV (p<0.001). However, no significant correlation was observed between the intracranial ARV and the modified Rankin Scale scores. Patients with fetal-type posterior cerebral arteries exhibited greater intracranial ARV compared with those without (p=0.003). Additionally, a positive correlation was observed between external carotid artery collateralisation and intracranial ARV post-revascularisation (r=0.340, p<0.001). The CAR of external carotid artery following cerebral revascularisation in patients with MMD remained independent correlation of the intracranial ARV (β=0.385, 95% CI (0.921 to 1.669), p<0.001) and Suzuki stage (β=0.211, 95% CI (0.009 to 0.030), p<0.001).</p><p><strong>Conclusions: </strong>This study showed a complex association between ARV, the Suzuki stage and the collateralisation of the external carotid artery in patients with MMD who are undergoing revascularisation. These findings provide insights into MMD progression and revascularisation outcomes and may guide clinical decision-making to improve patient care.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone marrow-derived mesenchymal stem cell ameliorates post-stroke enterobacterial translocation through liver-gut axis.","authors":"Xiaotao Su, Tiemei Li, Yuge Wang, Lei Wei, Banghao Jian, Xinmei Kang, Mengyan Hu, Chunyi Li, Shisi Wang, Danli Lu, Shishi Shen, Huipeng Huang, Yuxin Liu, Xiaohui Deng, Bingjun Zhang, Wei Cai, Zhengqi Lu","doi":"10.1136/svn-2024-003494","DOIUrl":"10.1136/svn-2024-003494","url":null,"abstract":"<p><strong>Background: </strong>Enterobacterial translocation is a leading contributor to fatal infection among patients with acute ischaemic stroke (AIS). Accumulative evidence suggests that mesenchymal stem cell (MSC) effectively ameliorates stroke outcomes. Whether MSC could inhibit post-stroke enterobacterial translocation remains elusive.</p><p><strong>Methods: </strong>Patients with AIS and healthy individuals were enrolled in the study. Mice subjected to transient middle cerebral artery occlusion were treated with bone marrow-derived MSC (BM-MSC) right after reperfusion. Enterobacterial translocation was evaluated with Stroke Dysbiosis Index and circulating endotoxin. Thickness of mucus was assessed with Alcian blue staining. Hepatic glucocorticoid (GC) metabolism was analysed with expression of HSD11B2, HSD11B1 and SRD5A1.</p><p><strong>Results: </strong>We report that the gut mucus layer was attenuated after the stroke leading to pronounced enterobacterial translocation. The attenuation of the gut mucus was attributed to diminished mucin production by goblet cells in response to the elevated systemic GC after cerebral ischaemia. Transferred-BM-MSC restored the mucus thickness, thus preserving gut microbiota homeostasis and preventing enterobacterial invasion. Mechanistically, the transferred-BM-MSC stationed in the liver and enhanced peroxisome proliferator-activated receptor γ signalling in hepatocytes. Consequently, expression of HSD11B2 and SRD5A1 was increased while HSD11B1 expression was downregulated which promoted GC catabolism and subsequently restored mucin production.</p><p><strong>Conclusions: </strong>Our findings reveal that MSC transfer improves post-stroke gut barrier integrity and inhibits enterobacterial translocation by enhancing the hepatic GC metabolism thus representing a protective modulator of the liver-gut-brain axis in AIS.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Definitions of white matter hyperintensity change: impact on estimates of progression and regression.","authors":"Angela C C Jochems, Susana Muñoz Maniega, Una Clancy, Carmen Arteaga Reyes, Daniela Jaime Garcia, Maria Del C Valdés Hernández, Francesca M Chappell, Gayle Barclay, Charlotte Jardine, Donna McIntyre, Iona Gerrish, Stewart Wiseman, Michael S Stringer, Michael J Thrippleton, Fergus Doubal, Joanna M Wardlaw","doi":"10.1136/svn-2024-003300","DOIUrl":"https://doi.org/10.1136/svn-2024-003300","url":null,"abstract":"<p><strong>Background: </strong>White matter hyperintensity (WMH) progression is well documented; WMH regression is more contentious, which might reflect differences in defining WMH change. We compared four existing WMH change definitions in one population to determine the effect of definition on WMH regression.</p><p><strong>Methods: </strong>We recruited patients with minor non-disabling ischaemic stroke who underwent MRI 1-3 months after stroke and 1 year later. We assessed WMH volume (in absolute mL and % intracranial volume) and applied four different definitions, including two thresholds (based on SD or mL), percentile and quintile approaches.</p><p><strong>Results: </strong>In 198 participants, mean age 65.5 (SD=11.13), baseline WMH volume was 15.46 mL (SD=19.2), the mean net WMH volume change was 0.98 mL (SD=2.84), range -7.98 to +12.84 mL. Proportion regressing/stable/progressing WMH were threshold 1 (SD), 29.8%/55.6%/14.6%; threshold 2(mL), 29.8%/16.7%/53.5%; percentile approach, 28.3%/21.2%/50.5%. The quintile approach includes five groups with quintile 3 reflecting no change (N=40), quintiles 1 and 2 any WMH decrease (N=80) and quintiles 4 and 5 any WMH increase (N=78).</p><p><strong>Conclusions: </strong>Different WMH change definitions cause big differences in how participants are categorised; additionally, non-normal WMH distribution precludes use of some definitions. Consistent use of an appropriate definition would facilitate data comparisons, particularly in clinical trials of potential WMH treatments.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advance Consent for participation in Acute Stroke Trials (ACTION): protocol for a feasibility study.","authors":"Ubong Udoh, Rena Seeger, Brian Dewar, Emma Cummings, Sophia Gocan, Stuart Nicholls, Mark Fedyk, Victoria Shepherd, Jeff Perry, Robert Fahed, Tim Ramsay, Jamie Brehaut, Michael D Hill, Alexandre Y Poppe, Bijoy K Menon, Richard H Swartz, Dar Dowlatshahi, Michel Shamy","doi":"10.1136/svn-2023-003029","DOIUrl":"https://doi.org/10.1136/svn-2023-003029","url":null,"abstract":"<p><strong>Introduction: </strong>Obtaining informed consent for research from patients in medical emergencies remains a challenge, particularly in acute stroke care as treatment must be administered quickly and patients often arrive in the hospital in a state of incapacitation. Adaptations to standard consenting approaches-such as the use of surrogate consent or deferral of consent-have significant limitations. This feasibility study aims to test a new consenting approach in acute stroke care that we call advance consent. Advance consent has the potential to render emergency trial enrolment faster, fairer and more transparent, leading to more generalisable results.</p><p><strong>Methods and design: </strong>We will conduct a five-part study at The Ottawa Hospital, a quaternary care stroke centre: (1) administering questionnaires in the Ottawa Hospital Stroke Prevention Clinic that will examine patients' perspectives on research participation and advance consent; (2) inviting participants to consent in advance to any or both currently enrolling acute stroke trials; (3) tracking patient enrolment into these trials over 1 year; (4) administering a follow up questionnaire to participants at 1 year and (5) administering a questionnaire to participating hospital staff in order to interrogate their experiences with advance consent. Outcomes include but are not limited to eligibility rate, recruitment rate, withdrawal rate and the proportion of patients whose advance consent results in trial enrolment.</p><p><strong>Conclusion: </strong>This study will test the feasibility of enrolling patients at risk of stroke into acute stroke trials using advance consent.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomes-mediated delivery of miR-486-3p alleviates neuroinflammation via SIRT2-mediated inhibition of mitophagy after subarachnoid hemorrhage.","authors":"Bin Sheng, Sen Gao, XiangXin Chen, Yang Liu, Niansheng Lai, Jin Dong, Jiaqing Sun, Yan Zhou, Lingyun Wu, Chun-Hua Hang, Wei Li","doi":"10.1136/svn-2024-003509","DOIUrl":"https://doi.org/10.1136/svn-2024-003509","url":null,"abstract":"<p><strong>Background: </strong>Neuroinflammation participates in the pathogenesis of subarachnoid haemorrhage (SAH); however, no effective treatments exist. MicroRNAs regulate several aspects of neuronal dysfunction. In a previous study, we found that exosomal miR-486-3p is involved in the pathophysiology of SAH. Targeted delivery of miR-486-3p without blood-brain barrier (BBB) restriction to alleviate SAH is a promising neuroinflammation approach.</p><p><strong>Methods: </strong>In this study, we modified exosomes (Exo) to form an RVG-miR-486-3p-Exo (Exo/miR) to achieve targeted delivery of miR-486-3p to the brain. Neurological scores, brain water content, BBB damage, flow cytometry and FJC staining were used to determine the effect of miR-486-3p on SAH. Western blot analysis, ELISA and RT-qPCR were used to measure relevant protein and mRNA levels. Immunofluorescence staining and laser confocal detection were used to measure the expression of mitochondria, lysosomes and autophagosomes, and transmission electron microscopy was used to observe the level of mitophagy in the brain tissue of mice after SAH.</p><p><strong>Results: </strong>Tail vein injection of Exo/miR improved targeting of miR-486-3p to the brains of SAH mice. The injection reduced levels of neuroinflammation-related factors by changing the phenotype switching of microglia, inhibiting the expression of sirtuin 2 (SIRT2) and enhancing mitophagy. miR-486-3p treatment alleviated neurobehavioral disorders, brain oedema, BBB damage and neurodegeneration. Further research found that the mechanism was achieved by regulating the acetylation level of peroxisome proliferator-activated receptor γ coactivator l alpha (PGC-1α) after SIRT2 enters the nucleus.</p><p><strong>Conclusion: </strong>Exo/miR treatment attenuates neuroinflammation after SAH by inhibiting SIRT2 expression and stimulating mitophagy, suggesting potential clinical applications.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles bearing serum amyloid A1 exacerbate neuroinflammation after intracerebral haemorrhage.","authors":"Huimin Zhu, Ningning Wang, Yingying Chang, Ying Zhang, Shihe Jiang, Xiaoping Ren, Meng Yuan, Haoxiao Chang, Wei-Na Jin","doi":"10.1136/svn-2024-003525","DOIUrl":"https://doi.org/10.1136/svn-2024-003525","url":null,"abstract":"<p><strong>Introduction: </strong>Intracerebral haemorrhage (ICH) elicits a robust inflammatory response, which significantly contributes to secondary brain damage. Extracellular vesicles (EVs) play a pivotal role in intercellular communication by transporting immune-regulatory proteins. However, the precise contribution of these EV-carried proteins to neuroinflammation following ICH remains elusive. Here, we identified proteins dysregulated in EVs and further studied the EVs-enriched Serum amyloid A 1 (SAA1) to understand its role in neuroinflammation and ICH injury.</p><p><strong>Methods: </strong>We used mass spectrometry to analyse the EV protein cargo isolated from plasma samples of 30 ICH patients and 30 healthy controls. To validate the function of the dysregulated protein SAA1, an ICH mouse model was conducted to assess the effects of SAA1 neutralisation on brain oedema, neurological function and infiltration of peripheral leucocytes.</p><p><strong>Results: </strong>49 upregulated proteins and 12 downregulated proteins were observed in EVs from ICH patients compared with controls. Notably, SAA1 demonstrated a significant increase in EVs associated with ICH. We observed that exogenous SAA1 stimulation led to an augmentation in the population of microglia and astrocytes, exacerbating neuroinflammation. Neutralising SAA1 with an anti-SAA1 monoclonal antibody (mAb) diminished the prevalence of proinflammatory microglia and the infiltration of peripheral leucocytes, which ameliorates brain oedema and neurological function in ICH mice.</p><p><strong>Conclusion: </strong>Our findings provide compelling evidence implicating EVs and their cargo proteins in ICH pathogenesis. SAA1 emerges as a potential therapeutic target for mitigating neuroinjury and neuroinflammation following ICH.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}