Hemorrhagic transformation in patients with large-artery atherosclerotic stroke is associated with the gut microbiota and lipopolysaccharide

Hemorrhagic transformation is a major complication of large-artery atheroscle rotic stroke(a major ischemic stro ke subtype)that wo rsens outcomes and increases mortality.Disruption of the gut microbiota is an important feature of stroke,and some specific bacteria and bacterial metabolites may contribute to hemorrhagic transformation pathogenesis.We aimed to investigate the relationship between the gut microbiota and hemorrhagic transformation in largearte ry atheroscle rotic stro ke.An observational retrospective study was conducted.From May 2020 to September 2021,blood and fecal samples were obtained upon admission from 32 patients with first-ever acute ischemic stroke and not undergoing intravenous thrombolysis or endovascular thrombectomy,as well as 16 healthy controls.Patients with stro ke who developed hemorrhagic transfo rmation(n=15)were compared to those who did not develop hemorrhagic transformation(n=17)and with healthy controls.The gut microbiota was assessed through 16S ribosomal ribonucleic acid sequencing.We also examined key components of the lipopolysaccharide pathway:lipopolysaccharide,lipopolysaccharide-binding protein,and soluble CD14.We observed that bacterial diversity was decreased in both the hemorrhagic transformation and non-hemorrhagic transfo rmation group compared with the healthy controls.The patients with ischemic stro ke who developed hemorrhagic transfo rmation exhibited altered gut micro biota composition,in particular an increase in the relative abundance and dive rsity of members belonging to the Enterobacteriaceae family.Plasma lipopolysaccharide and lipopolysaccharide-binding protein levels were higher in the hemorrhagic transformation group compared with the non-hemorrhagic transfo rmation group.lipopolysaccharide,lipopolysaccharide-binding protein,and soluble CD14 concentrations were associated with increased abundance of Enterobacte riaceae.Next,the role of the gut microbiota in hemorrhagic transformation was evaluated using an experimental stroke rat model.In this model,transplantation of the gut microbiota from hemorrhagic transformation rats into the recipient rats triggered higher plasma levels of lipopolysaccharide,lipopolysaccharide-binding protein,and soluble CD14.Ta ken togethe r,our findings demonstrate a noticeable change in the gut microbiota and lipopolysaccharide-related inflammatory response in stroke patients with hemorrhagic transformation.This suggests that maintaining a balanced gut microbiota may be an important factor in preventing hemorrhagic transfo rmation after stro ke.

Advances in the Mechanisms of Hemorrhagic Transformation and Therapeutic Agents after Intravenous Thrombolysis in Ischemic Stroke

Ischemic stroke is an important disease leading to death and disability for all human beings, and the key to its treatment lies in the early opening of obstructed vessels and restoration of perfusion to the local infarcted area. Intravenous thrombolysis with tissue plasminogen activator (tPA) is one of the effective therapies to achieve revascularization, but it faces strict indications with a narrow therapeutic time window, and significantly increases the incidence of hemorrhagic transformation, HT, after reperfusion of the infarcted foci, which greatly reduces the incidence of patients with ischemic stroke. which significantly increases the incidence of hemorrhagic transformation (HT) after reperfusion of the infarcted focus, greatly reducing patient utilization and clinical benefit. Since the mechanism of HT has not been fully elucidated, and the related molecular mechanisms are complex and interactive, there is no specific and effective therapy to avoid the occurrence of HT. In this article, we focus on the research progress on the mechanism of HT after tPA intravenous thrombolysis in ischemic stroke patients from the aspects of vascular integrity disruption, oxidative stress, and neuroinflammatory response and the corresponding therapeutic strategies, in order to improve the safety and prognosis of tPA intravenous thrombolysis in the clinic.

Subdural effusion associated with COVID-19 encephalopathy: A case report

BACKGROUND The precise mechanism by which severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)impacts the central nervous system remains unclear,with manifestations spanning from mild symptoms(e.g.,olfactory and gustatory deficits,hallucinations,and headache)to severe complications(e.g.,stroke,seizures,encephalitis,and neurally demyelinating lesions).The occurrence of single-pass subdural effusion,as described below,is extremely rare.CASE SUMMARY A 56-year-old male patient presented with left-sided limb weakness and slurred speech as predominant clinical symptoms.Through comprehensive imaging and diagnostic assessments,he was diagnosed with cerebral infarction complicated by hemorrhagic transformation affecting the right frontal,temporal,and parietal regions.In addition,an intracranial infection with SARS-CoV-2 was identified during the rehabilitation process;consequently,an idiopathic subdural effusion developed.Remarkably,the subdural effusion underwent absorption within 6 d,with no recurrence observed during the 3-month follow-up.CONCLUSION Subdural effusion is a potentially rare intracranial complication associated with SARS-CoV-2 infection.

Exacerbated VEGF up-regulation accompanies diabetes-aggravated hemorrhage in mice after experimental cerebral ischemia and delayed reperfusion

Reperfusion therapy is the preferred treatment for ischemic stroke,but is hindered by its short treatment window,especially in patients with diabetes whose reperfusion after prolonged ischemia is often accompanied by exacerbated hemorrhage.The mechanisms underlying exacerbated hemorrhage are not fully understood.This study aimed to identify this mechanism by inducing prolonged 2-hour transient intraluminal middle cerebral artery occlusion in diabetic Ins2Akita/+mice to mimic patients with diabetes undergoing delayed mechanical thrombectomy.The results showed that at as early as 2 hours after reperfusion,Ins2Akita/+mice exhibited rapid development of neurological deficits,increased infarct and hemorrhagic transformation,together with exacerbated down-regulation of tight-junction protein ZO-1 and upregulation of blood-brain barrier-disrupting matrix metallopeptidase 2 and matrix metallopeptidase 9 when compared with normoglycemic Ins2+/+mice.This indicated that diabetes led to the rapid compromise of vessel integrity immediately after reperfusion,and consequently earlier death and further aggravation of hemorrhagic transformation 22 hours after reperfusion.This observation was associated with earlier and stronger up-regulation of pro-angiogenic vascular endothelial growth factor(VEGF)and its downstream phospho-Erk1/2 at 2 hours after reperfusion,which was suggestive of premature angiogenesis induced by early VEGF up-regulation,resulting in rapid vessel disintegration in diabetic stroke.Endoplasmic reticulum stress-related pro-apoptotic C/EBP homologous protein was overexpressed in challenged Ins2Akita/+mice,which suggests that the exacerbated VEGF up-regulation may be caused by overwhelming endoplasmic reticulum stress under diabetic conditions.In conclusion,the results mimicked complications in patients with diabetes undergoing delayed mechanical thrombectomy,and diabetes-induced accelerated VEGF up-regulation is likely to underlie exacerbated hemorrhagic transformation.Thus,suppression of the VEGF pathway could be a potential approach to allow reperfusion therapy in patients with diabetic stroke beyond the current treatment window.Experiments were approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong[CULATR 3834-15(approval date January 5,2016);3977-16(approval date April 13,2016);and 4666-18(approval date March 29,2018)].

Hemorrhagic transformation of ischemic cerebral proliferative angiopathy: A case report

BACKGROUND Cerebral proliferative angiopathy(CPA)is a rare vascular disease characterized by the presence of diffuse vascular proliferation,progressive vascular hyperflow and vasodilation of multiple vessels in the normal brain parenchyma.Unlike cerebral arteriovenous malformations,CPA has a mixed appearance between that of lesions with cell proliferation and endothelial proliferation.To date,the pathogenesis of CPA is unclear,in which changes induced by cortical ischemia in the elastic layer of the blood supply artery and smooth muscle cells may be involved.CASE SUMMARY In this article,we retrospectively analyzed a case of hemorrhagic transformation of ischemic CPA diagnosed by digital subtraction angiography and reviewed the related literature for further exploration of its pathogenesis,diagnosis and treatment.CONCLUSION The information in the present case report may facilitate further clinical research on this cerebrovascular disease.

Hemorrhagic transformation after acute ischemic stroke caused by polycythemia vera:Report of two case

BACKGROUNDPolycythemia vera (PV) is a chronic myeloproliferative disorder characterized byan increase in red blood cells in the peripheral blood. Previous work has reportedthe occurrence of thrombosis or hemorrhage arising in the cerebral vasculaturesecondary to PV. However, hemorrhagic transformation after PV-associated acuteischemic stroke has not been previously described.CASE SUMMARYWe herein present two cases of PV where hemorrhagic transformation occurredafter an acute ischemic stroke. Case 1 was a 57-year-old woman with a history ofhypertension who was admitted for left-sided weakness. Case 2 was a 68-year-oldman who was admitted for a 10-d sudden left arm weakness. Imaging examinationsfor the two patients revealed hemorrhagic transformation after acuteischemic stroke. Both patients had JAK-2-V617F mutation and receivedantiplatelet therapy. Both of them had a good prognosis during the follow-up.CONCLUSIONThis report suggested that hemorrhagic transformation may occur in acuteischemic stroke caused by PV. Antiplatelet drugs do not seem to influence thelong-term outcomes in such patients. Future research should focus on establishinga standard antiplatelet treatment strategy for this condition.

Villous Capillary Malformation and Intermediate Trophoblast Invasiveness:Histopathologic Findings From Fetomaternal Hemorrhage with Gestational Choriocarcinoma

To editor:Fetomaternal hemorrhage(FMH)refers to the fetal blood transfection into the maternal circulation,usually involving a bleeding volume exceeding 30 ml.This phenomenon can promptly trigger a sinusoidal fetal heart rate pattern,posing a significant risk of life-threatening fetal anemia and even mortality1,2 Upon suspicion of FMH,immediate intervention is essential to prevent neonatal death,often leading to the insufficient recognition of placental examination in many published reports.However,an increasing number of FMH case reports have underscored the potential subsequent risk of choriocarcinoma.

Validation of hyperintense middle cerebral artery sign in acute ischemic stroke Comparison between magnetic resonance imaging and angiography

We performed a retrospective analysis of non-contrast computed tomography （CT） scans, immediately subsequent magnetic resonance imaging （MRI）, and cerebral angiography data from 30 consecutive patients with acute ischemic stroke within 6 hours after symptom onset. Results showed that eleven patients developed subsequent hemorrhagic transformation at follow-up. A hyperintense middle cerebral artery sign on MRI was found in six hemorrhagic patients, all of who had acute thrombosis formation on magnetic resonance angiography and digital subtraction angiography. No patients in the non-hemorrhagic group had hyperintense middle cerebral artery sign on MRI. The sensitivity, specificity, and positive predictive values of the hyperintense middle cerebral artery sign on MRI T1-weighted image for subsequent hemorrhagic transformation were 54.5%, 100%, and 100% respectively. Hyperdense middle cerebral artery sign on non-contrast CT was observed in nine patients, five of who developed hemorrhagic transformation. These data suggest that hyperintense middle cerebral artery sign on MRI T1-weighted image is a highly specific and moderately sensitive indicator of subsequent hemorrhagic transformation in patients after acute ischemic stroke, and its specificity is superior to CT.

Increased globulin and its association with hemorrhagic transformation in patients receiving intra-arterial thrombolysis therapy

Previous studies have identified a diverse set of predisposing factors for the occurrence of hemorrhagic transformation （HT）, but the independent clinical predictors of HT after intra- arterial thrombolysis have not been determined. In this retrospective study, we investigated the characteristics of patients with or without HT who had received intra-arterial thrombolysis therapy, using biochemical analysis, renal function test, routine blood test, blood lipid test, coagulation blood test, liver function test, random blood glucose test, time- window for intra-arterial thrombolysis, recanalization, National Institutes of Health Stroke Scale （NIHSS） score and systolic blood pressure before intra-artedal thrombolysis. The mortality rates were similar in the HT and non-HT groups （P = 0.944）. In the single- factor analysis, patients with a higher globulin level （P 〈0.002）, prothrombin time activity percentage （PTA; P = 0.026）, and NIHSS score （P = 0.002）, had a significantly increased risk of developing HT. In the multifactor logistic regression model involving globulin level, PTA, white blood cell count, and NIHSS score, the globulin level （P 〈0.001; OR, 1.185; 95% confidence interval [CI], 1.090-1.288）, PTA （P = 0.018; OR, 1.016; 95% CI, 1.003-1.029）, white blood cell count （P = 0.025; OR, 1.097; 95% CI, 1.012-1.190） and NIHSS score （P = 0.003; OR, 1.097; 95% CI, 1.031-1.166） were significantly increased in the HT group. The increase in globulin level is an independent risk factor for HT in patients receiving intra-arterial thrombolysis. The possible mechanisms may involve inflammatory cytokines, matrix metalloproteinase 9, and positive acute-phase reactants synthesized by the liver.

Glomerular Filtration Rate is Associated with Hemorrhagic Transformation in Acute Ischemic Stroke Patients without Thrombolytic Therapy

Background： Whether there is a relationship between glomerular filtration rate IGFR） and hcnlorrhagic transformation （HT） after acute ischemic stroke （A1S） is still under debate. The aim of our study was to determine whether the GFR level is a predictor of HT in AIS patients without thrombolytic therapy （TT）. Methods： Consecutive A IS patients without TT were included in this prospective study fiom January 2014 to December 2016 in the First Affiliated Hospital of Chongqiug Medical University. We divided them into two groups （HT and non-HT group） and meticulously collected baseline characteristics and laboratory and imaging data of interested individuals. Multivariate regression analysis was performed to assess the correlation between GFR and HT in stroke patients without TT. Results： Among 426 consecutive patients, 74 （17.3%） presented HT （mean age： 65 ± 12 years, number of male patients： 47） on the follow-up scans. In multivariate regression analysis, HT was significantly associated with low GFR （odds ratio [OR] = 3.708, confidence interval [CI] = 1.326-10.693, P = 0.013）, atrial fibrillation （AF; OR = 2.444, CI= 1.087-5.356, P = 0.027）, large cerebral inthrction （OR = 2.583, CI= 1.236-5.262, P= 0.010）, and hypoalbuminemia （HA OR = 4.814, CI= 1.054 22.153, P = 0.037） for AIS patients without TT. Conclusions： The present study strongly showed that lower GFR is an independently predictor of HT： in addition, large inlhrct volume, AF, and HA are also important risks of HT for AIS patients without TT, which offered a practical information that risk factors should be paid attention or eliminated to prevent HT for stroke patients though the level of evidence seems to be unstable.