Tetrahedral DNA loaded siCCR2 restrains M1 macrophage polarization to ameliorate pulmonary fibrosis in chemoradiation-induced murine model.

Idiopathic pulmonary fibrosis (IPF) is a chronic lethal disease in the absence of demonstrated efficacy for preventing progression. Although macrophage-mediated alveolitis is determined to participate in myofibrotic transition during disease development, the paradigm of continuous macrophage polarization is still under-explored due to lack of proper animal models. Here, by integrating 2.5 U/kg intratracheal Bleomycin administration and 10 Gy thorax irradiation at day 7, we generated a murine model with continuous alveolitis-mediated fibrosis, which mimics most of the clinical features of our involved IPF patients. In combination with data from scRNA-seq of patients and a murine IPF model, a decisive role of CCL2/CCR2 axis in driving M1 macrophage polarization was revealed, and M1 macrophage was further confirmed to boost alveolitis in leading myofibroblast activation. Multiple sticky-end tetrahedral framework nucleic acids conjunct with quadruple ccr2-siRNA (FNA-siCCR2) was synthesized in targeting M1 macrophages. FNA-siCCR2 successfully blocked macrophage accumulation in pulmonary parenchyma of the IPF murine model, thus preventing myofibroblast activation and leading to the disease remitting. Overall, our studies lay the groundwork to develop a novel IPF murine model, reveal M1 macrophages as potential therapeutic targets, and establish new treatment strategy by using FNA-siCCR2, which are highly relevant to clinical scenarios and translational research in the field of IPF.

Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression.

BACKGROUND: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing-remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS. METHODS: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively. RESULTS: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + TEMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy. CONCLUSIONS: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + TEMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.

Secretome of human umbilical cord mesenchymal stem cell maintains skin homeostasis by regulating multiple skin physiological function.

Skin is the largest organ in the body and the first defense to resist various diseases and external stimuli that easily cause infection and inflammation. Aseptic inflammation, barrier damage, and foreign aid pressure induce the destruction and damage to the skin microenvironment. Subsequently, it destroys the skin's physiological function, leading to the maintenance and circulation of steady-state imbalance and aggravating the process of skin disorders. Our study evaluated the therapeutic potential of the secretome of human umbilical cord mesenchymal stem cells (UC-CM) for dermatological diseases in adult human skin cells, ex vivo skin tissue, and a 3D skin model. Our data suggested several advantages of UC-CM due to (1) their low cytotoxicity and sensitization properties; (2) their anti-inflammatory capacity for treating inflammatory chronic cutaneous diseases; (3) their enhanced capacity of the skin barrier for treating abnormal barrier metabolism; and (4) their positive impact on restoring skin homeostasis due to effective regulation ability of skin physiological function including cell apoptosis, detoxification, and anti-aging. We thus envisage that the possibility of harnessing the therapeutic potential of UC-CM might benefit patients suffering from inflammatory skin disorders such as atopic dermatitis, acne, and psoriasis.

Anticoagulation medication in nontraumatic intracranial hemorrhage survivors with atrial fibrillation.

BACKGROUND: The relative effectiveness of anticoagulation agents in patients with atrial fibrillation (AF) who survive an intracranial hemorrhage (ICH) is unknown. This study was performed to examine the comparative effectiveness of different oral anticoagulation (OAC) on clinical outcomes in this group of patients. METHODS: We performed a Bayesian network meta-analysis of randomized controlled trials (RCTs) and observational studies comparing different OAC (direct oral anticoagulant [DOAC] and warfarin) for the treatment of patients with AF who sustained ICH. Outcomes included repeat ICH, thromboembolic events, and all-cause mortality. The values derived from the surface under the cumulative ranking curve were obtained to rank the treatment hierarchy. RESULTS: We identified 12 studies (two RCTs and ten observational studies) involving 23,265 patients; 346 patients were treated with any OAC agents; 5,006 received DOAC; 5,271 received warfarin; 12,007 received antiplatelet or no therapy, and 635 did not received relevant therapy. Both DOAC and warfarin (RR, 0.58; 95% CI, 0.45-0.74; RR, 0.83; 95% CI, 0.69-0.98) were superior to antiplatelet or no therapy in preventing thromboembolic events. Moreover, DOAC also showed superiority in preventing thromboembolic events (RR, 0.70; 95% CI, 0.58-0.83), repeat ICH (RR, 0.52; 95% CI, 0.40-0.67), and all-cause mortality (RR, 0.51; 95% CI, 0.46-0.56) than warfarin. CONCLUSIONS: Our study suggests DOACs may be a reasonable alternative to anti-platelet therapy and warfarin for patients with AF who experienced ICH. However, given the available evidence is primarily observational, further validation by ongoing trials directly comparing these two classes of drugs are needed.

MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes.

BACKGROUND: Astrocytes are the most numerous glial cell type with important roles in maintaining homeostasis and responding to diseases in the brain. Astrocyte function is subject to modulation by microRNAs (miRs), which are short nucleotide strands that regulate protein expression in a post-transcriptional manner. Understanding the miR expression profile of astrocytes in disease settings provides insight into the cellular stresses present in the microenvironment and may uncover pathways of therapeutic interest. METHODS: Laser-capture microdissection was used to isolate human astrocytes surrounding stroke lesions and those from neurological control tissue. Astrocytic miR expression profiles were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Primary human fetal astrocytes were cultured under in vitro stress conditions and transfection of a miR mimic was used to better understand how altered levels of miR-210 affect astrocyte function. The astrocytic response to stress was studied using qPCR, enzyme-linked immunosorbent assays (ELISAs), measurement of released lactate, and Seahorse. RESULTS: Here, we measured miR expression levels in astrocytes around human ischemic stroke lesions and observed differential expression of miR-210 in chronic stroke astrocytes compared to astrocytes from neurological control tissue. We also identified increased expression of miR-210 in mouse white matter tissue around middle cerebral artery occlusion (MCAO) brain lesions. We aimed to understand the role of miR-210 in primary human fetal astrocytes by developing an in vitro assay of hypoxic, metabolic, and inflammatory stresses. A combination of hypoxic and inflammatory stresses was observed to upregulate miR-210 expression. Transfection with miR-210-mimic (210M) increased glycolysis, enhanced lactate export, and promoted an anti-inflammatory transcriptional and translational signature in astrocytes. Additionally, 210M transfection resulted in decreased expression of complement 3 (C3) and semaphorin 5b (Sema5b). CONCLUSIONS: We conclude that miR-210 expression in human astrocytes is modulated in response to ischemic stroke disease and under in vitro stress conditions, supporting a role for miR-210 in the astrocytic response to disease conditions. Further, the anti-inflammatory and pro-glycolytic impact of miR-210 on astrocytes makes it a potential candidate for further research as a neuroprotective agent.

PCSK9 inhibitors for secondary prevention in patients with cardiovascular diseases: a bayesian network meta-analysis.

BACKGROUND: The Food and Drug Administration has approved Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors for the treatment of dyslipidemia. However, evidence of the optimal PCSK9 agents targeting PCSK9 for secondary prevention in patients with high-risk of cardiovascular events is lacking. Therefore, this study was conducted to evaluate the benefit and safety of different types of PCSK9 inhibitors. METHODS: Several databases including Cochrane Central, Ovid Medline, and Ovid Embase were searched from inception until March 30, 2022 without language restriction. Randomized controlled trials (RCTs) comparing administration of PCSK9 inhibitors with placebo or ezetimibe for secondary prevention of cardiovascular events in patients with statin-background therapy were identified. The primary efficacy outcome was all-cause mortality. The primary safety outcome was serious adverse events. RESULTS: Overall, nine trials totaling 54,311 patients were identified. Three types of PCSK9 inhibitors were evaluated. The use of alirocumab was associated with reductions in all-cause mortality compared with control (RR 0.83, 95% CrI 0.72-0.95). Moreover, evolocumab was associated with increased all-cause mortality compared with alirocumab (RR 1.26, 95% CrI 1.04-1.52). We also found alirocumab was associated with decreased risk of serious adverse events (RR 0.94, 95% CrI 0.90-0.99). CONCLUSIONS: In consideration of the fact that both PCSK9 monoclonal antibody and inclisiran enable patients to achieve recommended LDL-C target, the findings in this meta-analysis suggest that alirocumab might provide the optimal benefits regarding all-cause mortality with relatively lower SAE risks, and evolocumab might provide the optimal benefits regarding myocardial infarction for secondary prevention in patients with high-risk of cardiovascular events. Further head-to-head trials with longer follow-up and high methodologic quality are warranted to help inform subsequent guidelines for the management of these patients.

Clinical characteristics of intracranial aneurysms in elderly patents over 70 years old: a retrospective observational study.

BACKGROUND: Although the characteristics of intracranial aneurysms (IAs) in different age groups have been well documented, they remain relatively unclear in elderly patients due to a lack of large sample studies. METHODS: Data from IA patients aged more than 70 years who were treated in our centre from January 2016 to January 2020 were retrospectively collected. RESULTS: A total of 290 elderly patients (75.9% female) with a mean age of 74.0 ± 4.7 years were analysed. Rupture occurred in 60.7% of patients, 38.6% of whom presented with meningeal irritation, and seizures were noted in 2.3%. A total of 48.9% of the patients with ruptured IAs had initial symptoms presenting with slow development, and the mean delay from ictus was prolonged to 264.2 ± 914.0 hours. In addition, 61.9% of the patients with ruptured IAs had lesions with a maximum diameter of less than 5 mm. A total of 30.3% of the patients had multiple aneurysms, 35.5% had aneurysms with irregular shapes and 54.8% had cerebrovascular atherosclerotic stenosis (CAS). Pulmonary infection (n = 138, 47.6%), hydrocephalus (n = 72, 24.8%), and thrombosis (n = 35, 12.1%) were common complications during hospitalization. By the end of the 1-year follow-up, 22.1% of the patients had unfavourable clinical outcomes, and the mortality rate was 23.4%. CONCLUSIONS: Several characteristics regarding IAs in elderly patients were reported, including an obvious female predominance; mild, slow initial symptom development causing prolonged admission delay; a low incidence of meningeal irritation and seizures due to decreased electrophysiological activity of the neurons; increased percentages of CAS, multiple aneurysms, and aneurysms with daughter sacs causing a high risk of rupture even for small lesions; a high risk of complications during hospitalization; and relatively poor clinical outcomes.

The prognostic value of the Charlson comorbidity index in aged patients with intracerebral hemorrhage.

BACKGROUND: Comorbidities are common in aged intracerebral hemorrhage patients. The purpose of this study was to assess whether the Charlson Comorbidity Index (CCI) was associated with in-hospital death and short-term functional outcome in elderly patients (age ≥ 70) with intracerebral hemorrhage (ICH). METHODS: This was a retrospective cohort of aged ICH patients (≥70 years old) admitted within 24 hours of ICH onset. The CCI was derived using hospital discharge ICD-9 CM codes and patient history obtained from standardized case report forms. Multivariable logistic regression was used to determine the independent effect of the CCI score on clinical outcomes. RESULTS: In this cohort of 248 aged ICH patients, comorbid conditions were common, with CCI scores ranging from 2 to 12. Logistic regression showed that the CCI score was independently predictive of 1-month functional outcome (OR = 1.642, P < 0.001) and in-hospital death (OR = 1.480, P = 0.003). Neither ICH volume nor the presence of IVH was an independent predictive factor for 1-month functional outcome or in-hospital mortality (P < 0.05). CONCLUSION: Comorbid medical conditions as assessed by the CCI independently influence short-term outcomes in aged ICH patients. The characteristics of the hematoma itself, such as ICH volume and the presence of IVH, seem to have a reduced effect on it.

Efficacy and safety of erenumab in migraine prevention: evidences from direct and indirect comparisons.

BACKGROUND: To date, it remains challenging for clinicians to make informed decisions about which dosage of erenumab is more effective for treating adult patients with migraine. Thus, we sought to examine the safety and efficacy of different doses of erenumab in this group of patients. METHODS: We searched several databases from inception to May 31, 2021, irrespective of language. We included only RCTs that compared erenumab 70 mg, erenumab 140 mg, and placebo in migraine patients. The primary efficacy outcome was change in monthly migraine days (MMDs). The primary safety outcome was defined as treatment-emergent adverse events (TEAEs). We reported relative risks (RRs) with 95% credible intervals (CrIs) from the analysis. RESULTS: Overall, eight trials comprising 4281 participants were included in this study. Network meta-analysis showed that both erenumab 70 mg (MD: - 1.43, 95% CrI: - 1.71 to - 1.16) and erenumab 140 mg (MD: - 1.78, 95% CrI: - 2.21 to - 1.45) were associated with decreased MMDs. Also, erenumab 140 mg was associated with significantly lower MMDs than erenumab 70 mg (MD: - 0.34, 95% CrI: - 0.68 to - 0.01). In terms of primary safety outcome, neither erenumab 70 mg (RR: 0.98, 95% CrI: 0.92 to 1.05) nor erenumab 140 mg (RR: 0.99, 95% CrI: 0.91 to 1.07) was associated with increased risk of TEAEs. CONCLUSIONS: The results from this study suggested erenumab 140 mg might provide better efficacy than 70 mg among adult patients with migraine, without increasing TEAEs. Future elaborated RCTs with a larger number of participants are warranted to validate these discoveries.

A propensity score-matched study on the short-term outcome of ruptured blood blister-like aneurysm treated by microsurgery or endovascular surgery: a single-center study of 155 cases.

Treating blood blister-like aneurysms (BBA) is a major neurosurgical challenge. Whether endovascular repair serves as a better strategy than microsurgery remains controversial. We aim to perform a propensity score-matched (PSM) retrospective study to analyze the short-term outcome in BBA patients who received microsurgery and endovascular treatment. One hundred fifty-five eligible patients with internal carotid artery BBA were retrospectively collected with demographic and angiographic baseline in a single center. Three-month outcome and adverse events were set as outcome endpoints. PSM was used to match the microsurgery and endovascular group. Matching effect was evaluated by distribution variation analysis and love plot. The outcome of neurosurgery and endovascular treatment was then compared before and after PSM. Better WFNS levels (p = .017) and modified Fisher grade (p = .027) were noted in endovascular group before matching. Other baseline including angiographic features were comparable between two groups. Before matching, the 3-month outcome of endovascular repair surgery was more favorable than microsurgery (p < .0001). The occurrence of adverse events was also higher in the microsurgery group (p = .0079). In PSM-adjusted groups, the superior outcome effect of endovascular treatment still existed but with a reduced significance (p = .004). Similar trend was also observed in the adverse event rate (p = .038). Fatality rate was comparable between two adjusted groups regardless of PSM adjustment. Endovascular surgery of BBAs exhibits overall more favorable short-term outcome regardless of PSM matching. Microsurgery does not cause a higher fatality rate, hence it could be considered a salvage plan for those high-grade BBA patients.

Efficacy and safety of monoclonal antibody against calcitonin gene-related peptide or its receptor for migraine patients with prior preventive treatment failure: a network meta-analysis.

OBJECTIVE: The relative effects of monoclonal antibody against calcitonin gene-related peptide (CGRP) or its receptor for adult migraine patients with prior treatment failure remains uncertain. Therefore, this study systematically assessed the comparative effectiveness of different CGRP binding monoclonal antibodies (mAbs) for these patients. METHODS: Several online databases including Ovid MEDILNE, Ovid EMBASE, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception to June 15, 2022. We included randomized clinical trials (RCT) of adult migraine patients with previous treatment failure that assessed any CGRP monoclonal antibody. The primary efficacy outcome was change in monthly migraine days (MMDs), and the primary safety outcome was treatment-emergent adverse events (TEAEs). RESULTS: Overall, seven studies totaling 3, 052 patients were included. Three-node analysis showed that CGRP mAbs was superior to CGRP receptor mAbs in reducing MMDs (MD: -1.55, 95% CrI: - 2.43 to - 0.44) and improving at least 50% response rates (RR: 1.52, 95% CrI: 1.04 to 2.21). Nine-node analysis showed galcanezumab 240 mg ranked first in reducing MMDs (MD -4.40, 95% CrI - 7.60 to - 1.19) and improving 50% response rates (RR: 4.18, 95% CrI: 2.63 to 6.67). Moreover, treatment with fremanezumab or eptinezumab 300 mg provides a significant advantage over erenumab 140 mg regarding an improved response rate of at least 50%. The analysis did not show difference in incidences of TEAEs and serious adverse events in any of the comparisons. CONCLUSIONS: It appears that CGRP mAbs, especially galcanezumab 240 mg, monthly fremanezumab, and eptinezumab 300 mg, seem to be the best choice for the treatment of migraine patients with previous treatment failures. This finding also calls for future research that examine the associations between these medications in migraine therapy among the same patient group to testify the present findings.

Comparison of clinical and histopathological characteristics of short-term progressive and non-progressive blood blister-like aneurysms.

BACKGROUND: Many blood blister aneurysms (BBAs) have been documented with a rapid progression history in repeated angiography. The underlying mechanism and clinical significance remained elusive. This current study aims to clarify the clinical and histopathological differences between short-term progressive BBA and non-progressive BBAs. METHODS AND MATERIALS: Eighty-one patients with BBAs were consecutively included for this single-center retrospective analysis. Clinical and radiological data on these patients were retrieved from 2017 to 2019. BBAs were defined as either progressive or non-progressive based on observed growth based on repeated imaging. Histopathological examinations of a saccular aneurysm, a progressive BBA, and a non-progressive BBA were conducted using representative aneurysm samples. RESULTS: Among all enrolled patients, 26 of the them were identified with progressive BBAs, while the other 55 with non-progressive BBAs. Progressive BBAs were diagnosed significantly earlier in angiography (3.36 ± 0.61 vs. 6.53 ± 1.31 days, p < 0.05) and showed a higher presence rate of daughter sacs (61.5 vs. 38.2%, p < 0.05). Three different progression patterns were identified. BBAs that developed daughter sac enlargement are diagnosed significantly later than BBAs exhibiting other progression patterns. Patients with progressive and non-progressive BBAs exhibited similar overall clinical outcomes and incidence for complications. For patients with non-progressive BBAs, microsurgery appears to be inferior to endovascular treatment, while for patients with progressive BBAs, the short-term outcomes between microsurgery and endovascular treatment were identical. Histopathological analysis revealed that both subtypes shared a similar pseudoaneurysms structure, but non-progressive BBAs had more histologically destructed aneurysm wall with less remnant fibrillar collagen in adventitia. CONCLUSIONS: Progressive and non-progressive BBAs may not be distinct pathological lesions but represent different stages during the BBA development. Early intervention, regardless of treatment methods, is recommended for salvageable patients with progressive BBAs, but microsurgery should be performed with caution for non-progressive BBAs due to increased surgical risk.

Presence of vasa vasorum in human intracranial aneurysms.

OBJECTIVES: Vasa vasorum is associated with the pathogenesis of various cerebrovascular diseases, but its presence in intracranial aneurysms (IA) and its ability to act as a predicting factor of IA rupture remain unrevealed. METHODS: Histological investigation was performed for 3 middle meningeal arteries and 25 human IAs that were sequentially collected from 2017 to 2019. Relevant medical information was collected from the hospital information and imaging system. Fisher's exact tests and Student's t tests were performed to identify the histological and clinical differences between aneurysms with and without vasa vasorum. RESULTS: Vasa vasorum were present in 14/25 (56%) aneurysm samples. They were detected at a similar frequency in male patients (4/9, 44.4%) and (10/16, 62.5%) female patients. Patients with vasa vasorum present aneurysms (47.07 ± 3.668 years, n = 14) or vasa vasorum absent aneurysms (50.27 ± 2.289 years, n = 11) did not differ in age (p = 0.49). True aneurysms and pseudoaneurysms also shared a similar rate of vasa vasorum presence (10/16, 62.5% in true aneurysms vs 4/9, 44.4% in pseudoaneurysms). The average size of aneurysms with vasa vasorum varied from 21.70 to 3.00 mm, and no statistical difference in size was detected when comparing aneurysms with and without vasa vasorum (p = 0.71). The vasa vasorum in almost all IAs had uniform vascular trajectory with occasional exceptions. The presence of vasa vasorum appears to be tightly associated with important histopathological changes of myointimal hyperplasia and increased immune cell infiltration in IAs (both p value < 0.05), though it does not appear to be indicative of IA rupture or other rupture-related histological degenerations (all p values > 0.05). CONCLUSIONS: The presence of vasa vasorum is common in IAs. While it is associated with aneurysm wall remodeling and robust inflammatory cell infiltration, our results indicate that it is not a single specific marker of rupture-prone aneurysms.

Giant mid-esophageal diverticula successfully treated by per-oral endoscopic myotomy.

BACKGROUND: Surgery is currently the preferred treatment choice for mid-esophageal diverticula, while endoscopic therapy is rapidly establishing itself. METHOD: We report the first two cases of giant mid-esophageal diverticula presented with dysphagia successfully treated with per-oral endoscopic myotomy (POEM). RESULT: There were no complications during the procedure and the patients' conditions improved remarkably within short time of recovery. CONCLUSION: POEM could provide a safe, effective and less invasive treatment of mid-esophageal diverticula if appropriately used. Further studies on long-term efficacy with larger number of cases are necessary.

Anticoagulation therapy in non-valvular atrial fibrillation after intracerebral hemorrhage: A propensity score-matched study.

BACKGROUND: The effect of antithrombotic therapy on patients with atrial fibrillation who sustained previous intracerebral hemorrhage (ICH) remains uncertain. Data regarding antithrombotic therapy use in these patients are limited. This study aims to compare the clinical and overall outcomes of antithrombotic therapy and usual care in patients with atrial fibrillation who sustained ICH. METHODS: We assembled consecutive patients with atrial fibrillation sustaining an ICH from our institution. Multivariable regression analysis and propensity-matched analysis were applied to assess associations of different antithrombotic therapies and outcomes. The primary outcome was mortality within the longest follow-up. Kaplan-Meier curves and log-rank tests of the time-to-event data were used to assess differences in survival. RESULTS: In total, 296 consecutive patients with atrial fibrillation who survived an ICH were included in this study. Our analysis demonstrated that antithrombotic therapy was associated with reduced mortality up to a 4-year duration of follow-up (OR, 0.49, 95 % CI 0.30-0.81). Similar results were obtained from the propensity-matched analysis (OR, 0.58, 95 % CI 0.34-0.98). Subgroup analysis showed that compared with usual care, direct oral anticoagulant (DOAC) with or without antiplatelet was associated with a lower risk of long-term mortality (OR, 0.34, 95 % CI 0.17-0.69). In addition, our analysis observed a significant interaction between cardiac insufficiency and treatment effect (P = 0.04). CONCLUSIONS: In patients with atrial fibrillation who have a history of ICH, administration of antithrombotic therapy, especially DOAC, was associated with lower mortality. Future randomized trials are warranted to test the positive net clinical benefit of DOAC therapy.

Single-Cell Transcriptomics Revealed White Matter Repair Following Subarachnoid Hemorrhage.

Existing research indicates the potential for white matter injury repair during the subacute phase following subarachnoid hemorrhage (SAH). However, elucidating the role of brain cell subpopulations in the acute and subacute phases of SAH pathogenesis remains challenging due to the cellular heterogeneity of the central nervous system. In this study, single-cell RNA sequencing was conducted on SAH model mice to delineate distinct cell populations. Gene Set Enrichment Analysis was performed to identify involved pathways, and cellular interactions were explored using the CellChat package in R software. Validation of the findings involved a comprehensive approach, including magnetic resonance imaging, immunofluorescence double staining, and Western blot analyses. This study identified ten major brain clusters with cell type-specific gene expression patterns. Notably, we observed infiltration and clonal expansion of reparative microglia in white matter-enriched regions during the subacute stage after SAH. Additionally, microglia-associated pleiotrophin (PTN) was identified as having a role in mediating the regulation of oligodendrocyte precursor cells (OPCs) in SAH model mice, implicating the activation of the mTOR signaling pathway. These findings emphasize the vital role of microglia-OPC interactions might occur via the PTN pathway, potentially contributing to white matter repair during the subacute phase after SAH. Our analysis revealed precise transcriptional changes in the acute and subacute phases after SAH, offering insights into the mechanism of SAH and for the development of drugs that target-specific cell subtypes.

Comprehensive analysis of immune cell infiltration and role of MSR1 expression in aneurysmal subarachnoid haemorrhage.

Aneurysmal subarachnoid haemorrhage (aSAH), resulting from the rupture of intracranial aneurysms, can yield high mortality and disability. This study aimed to explore the immune infiltration of aneurysmal tissues and investigate a novel mechanism underlying aSAH. We downloaded datasets containing expression profiles of aneurysmal and normal arterial tissues from the online database. Then a comprehensive bioinformatic strategy was conducted to select the biomarkers of aneurysmal tissues. Two calculation algorithms were performed to identify the unique immune characteristics between aneurysmal tissues and normal arteries. Double immunofluorescence staining was used to investigate the role of pathway-related proteins in the inflammatory process after aSAH. Six microarray datasets were integrated, and another RNA-sequencing dataset was used as the validation dataset. Functional enrichment analysis of the differentially expressed genes indicated that immune-related processes were closely related to the progression of aSAH. We then performed immune microenvironment infiltration analysis, and the results suggested macrophages were abnormally enriched in aneurysmal tissues. Core gene MSR1 was filtered through a comprehensive bioinformatic strategy. Our analysis suggested that MSR1 might be associated with macrophage activation and migration. Our study elucidated the impact of macrophage and MSR1 on aSAH progression. These findings were helpful in gaining insight into the immune heterogeneity of aneurysmal tissues and normal arteries, and in identifying patients who might benefit from immunotherapy.