Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage

The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow.Mitochondria are directly affected by direct factors such as ischemia,hypoxia,excitotoxicity,and toxicity of free hemoglobin and its degradation products,which trigger mitochondrial dysfunction.Dysfunctional mitochondria release large amounts of reactive oxygen species,inflammatory mediators,and apoptotic proteins that activate apoptotic pathways,further damaging cells.In response to this array of damage,cells have adopted multiple mitochondrial quality control mechanisms through evolution,including mitochondrial protein quality control,mitochondrial dynamics,mitophagy,mitochondrial biogenesis,and intercellular mitochondrial transfer,to maintain mitochondrial homeostasis under pathological conditions.Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage.This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage,particularly mitochondrial quality control mechanisms.It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.

Simple procedure for assessing diffuse subarachnoid hemorrhage successfully created using filament perforation method in mice

The murine model of subarachnoid hemorrhage(SAH)is a valuable experimental tool for investigating molecular and cellular mechanisms,and the endovascular filament perforation technique can be used to simulate prominent pathophysiological features observed after human SAH;however,current validation methods for assessing an appropriate SAH model are limited.Here,we introduce a simple procedure for se-lecting a mouse model of diffuse SAH.SAH was induced in 24 mice using a standard filament perforation method.After confirming survival at 24 h,SAH was scored 0-1 based on T2*-weighted images on whole-brain magnetic resonance imaging(MRI)and visual surveillance of the cisterna magna(CM)through the dura mater.The CM-based SAH grading correlated well with a reference parameter defined by extracted brain(r^(2)=0.53,p<0.0001).The receiver operating characteristic curve revealed a sensi-tivity of 85%and a specificity of 91%for detecting diffuse SAH,with a similar area under the curve(0.89±0.06[standard error of the mean])as the MRI-based grading(0.72±0.10,p=0.12).Our data suggest that confirming an SAH clot in the CM is a valuable way to select a clinically relevant diffuse SAH model that can be used in future experimental studies.

Therapeutic potential of stem cells in subarachnoid hemorrhage

Aneurysm rupture can result in subarachnoid hemorrhage,a condition with potentially severe consequences,such as disability and death.In the acute stage,early brain injury manifests as intracranial pressure elevation,global cerebral ischemia,acute hydrocephalus,and direct blood–brain contact due to aneurysm rupture.This may subsequently cause delayed cerebral infarction,often with cerebral vasospasm,significantly affecting patient outcomes.Chronic complications such as brain volume loss and chronic hydrocephalus can further impact outcomes.Investigating the mechanisms of subarachnoid hemorrhage-induced brain injury is paramount for identifying effective treatments.Stem cell therapy,with its multipotent differentiation capacity and anti-inflammatory effects,has emerged as a promising approach for treating previously deemed incurable conditions.This review focuses on the potential application of stem cells in subarachnoid hemorrhage pathology and explores their role in neurogenesis and as a therapeutic intervention in preclinical and clinical subarachnoid hemorrhage studies.

Tumor necrosis factor-stimulated gene-6 ameliorates early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome-mediated astrocyte pyroptosis

Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have confirmed that tumor necrosis factor-stimulated gene-6(TSG-6)can exert a neuroprotective effect by suppressing oxidative stress and apoptosis.However,no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage.In this study,a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method.Our results indicated that TSG-6 expression was predominantly detected in astrocytes,along with NLRC4 and gasdermin-D(GSDMD).The expression of NLRC4,GSDMD and its N-terminal domain(GSDMD-N),and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment.To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage,recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles.Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits.Moreover,TSG-6 knockdown further increased the expression of NLRC4,which was accompanied by more severe astrocyte pyroptosis.In summary,our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.

Use of Color Doppler Ultrasound for the Diagnosis of Subarachnoid Hemorrhage in Asymptomatic Full-Term Neonate:A Case Report

Cerebral hemorrhages are fairly common in full-term neonates with no history of traumatic birth, mostly limited, and with benign evolution. We report a case of a full-term neonate from vaginal birth with caput succedaneum in the right parietal area. The neonate underwent cranial ultrasonography and color Doppler which showed extra-axial blood effusion. Color Doppler showed vessels crossing the collection area, which allowed the diagnosis of subarachnoid hematoma.

The value of three-dimensional computed tomographic angiography in the early diagnosis and treatment of spontaneous subarachnoid hemorrhage (616 cases report)

Objective To evaluate the clinical value of three dimensional computerized tomography angiography in the diagnosis and treatment of spontaneous subarachnoid hemorrhage. Methods 616 cases were diagnosed as suspected intracranial aneurysms in 3D CTA system. Computed tomographic scans and CTA studies were

The mechanism and relevant mediators associated with neuronal apoptosis and potential therapeutic targets in subarachnoid hemorrhage

Subarachnoid hemorrhage(SAH)is a dominant cause of death and disability wo rldwide.A sharp increase in intracranial pressure after SAH leads to a reduction in cerebral perfusion and insufficient blood supply for neuro ns,which subsequently promotes a series of pathophysiological responses leading to neuronal death.Many previous experimental studies have reported that excitotoxicity,mitochondrial death pathways,the release of free radicals,protein misfolding,apoptosis,nec rosis,autophagy,and inflammation are involved solely or in combination in this disorder.Among them,irreversible neuronal apoptosis plays a key role in both short-and long-term prognoses after SAH.Neuronal apoptosis occurs through multiple pathways including extrinsic,mitochondrial,endoplasmic reticulum,p53 and oxidative stress.Meanwhile,a large number of blood contents enter the subarachnoid space after SAH,and the secondary metabolites,including oxygenated hemoglo bin and heme,further aggravate the destruction of the blood-brain barrier and vasogenic and cytotoxic brain edema,causing early brain injury and delayed cerebral ischemia,and ultimately increasing neuronal apoptosis.Even there is no clear and effective therapeutic strategy for SAH thus far,but by understanding apoptosis,we might excavate new ideas and approaches,as targeting the upstream and downstream molecules of apoptosis-related pathways shows promise in the treatment of SAH.In this review,we summarize the existing evidence on molecules and related drugs or molecules involved in the apoptotic pathway after SAH,which provides a possible target or new strategy for the treatment of SAH.

Velamentous Cord Insertion: Interest of Antenatal Diagnosis and Review of the Literature

Velamentous insertion of the umbilical cord corresponds to the insertion of the cord directly on amniotic membranes. It is a rare situation whose frequency varies from 0.5% to 1.69% of single pregnancies. It must be diagnosed during the morphological ultrasound of the 2nd trimester, actively looking for the association with a vasa previa, due to the risk of fetal haemorrhagic threat. We report an antenatal diagnosis of velamentous cord insertion and its management with literature review.

A prospective cohort study on serum A20 as a prognostic biomarker of aneurysmal subarachnoid hemorrhage

BACKGROUND:A20 may be a neuroprotective factor.Herein,we aimed to investigate whether serum A20 levels were associated with disease severity,delayed cerebral ischemia(DCI),and outcome after aneurysmal subarachnoid hemorrhage(aSAH).METHODS:In this prospective cohort study containing 112 aSAH patients and 112 controls,serum A20 levels were quantified.At 90 d poststroke,Modified Rankin Scale(MRS) scores≥3 were defined as a poor outcome.All correlations and associations were assessed using multivariate analysis.RESULTS:Compared with controls,there was a significant elevation of serum A20 levels in patients(median 123.7 pg/mL vs.25.8 pg/mL;P<0.001).Serum A20 levels were independently correlated with Hunt-Hess scores(β 9.854;95% confidence interval [95% CI] 2.481-17.227,P=0.009) and modified Fisher scores(β 10.349,95% CI 1.273-19.424,P=0.026).Independent associations were found between serum A20 levels and poor outcome(odds ratio [OR] 1.015,95%CI 1.000-1.031,P=0.047) and DCI(OR 1.018,95% CI 1.001-1.035,P=0.042).Areas under the curve for predicting poor outcome and DCI were 0.771(95% CI 0.682-0.845) and 0.777(95% CI 0.688-0.850),respectively.Serum A20 levels ≥128.15 pg/mL predicted poor outcome,with a sensitivity of 73.9% and specificity of 74.2%,and A20 levels ≥160.55 pg/mL distinguished the risk of DCI with65.5% sensitivity and 89.2% specificity.Its ability to predict poor outcome and DCI was similar to those of Hunt-Hess scores and modified Fisher scores(both P>0.05).CONCLUSION:Enhanced serum A20 levels are significantly associated with stroke severity and poor clinical outcome after aSAH,implying that serum A20 may be a potential prognostic biomarker for aSAH.

Whole-brain CT Perfusion at Admission and During Delayed Time-window Detects the Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage

Objective To evaluate the utility of computed tomography perfusion(CTP)both at admission and during delayed cerebral ischemia time-window(DCITW)in the detection of delayed cerebral ischemia(DCI)and the change in CTP parameters from admission to DCITW following aneurysmal subarachnoid hemorrhage.Methods Eighty patients underwent CTP at admission and during DCITW.The mean and extreme values of all CTP parameters at admission and during DCITW were compared between the DCI group and non-DCI group,and comparisons were also made between admission and DCITW within each group.The qualitative color-coded perfusion maps were recorded.Finally,the relationship between CTP parameters and DCI was assessed by receiver operating characteristic(ROC)analyses.Results With the exception of cerebral blood volume(P=0.295,admission;P=0.682,DCITW),there were significant differences in the mean quantitative CTP parameters between DCI and non-DCI patients both at admission and during DCITW.In the DCI group,the extreme parameters were significantly different between admission and DCITW.The DCI group also showed a deteriorative trend in the qualitative color-coded perfusion maps.For the detection of DCI,mean transit time to the center of the impulse response function(Tmax)at admission and mean time to start(TTS)during DCITW had the largest area under curve(AUC),0.698 and 0.789,respectively.Conclusion Whole-brain CTP can predict the occurrence of DCI at admission and diagnose DCI during DCITW.The extreme quantitative parameters and qualitative color-coded perfusion maps can better reflect the perfusion changes of patients with DCI from admission to DCITW.

Current guidelines for diagnosis and management of hepatic involvement in hereditary hemorrhagic teleangiectasia

Hereditary hemorrhagic teleangiectasia(HHT),also known as Rendu-Osler-Weber syndrome,is the most common cause of hepatic vascular malformations in adults.Different vascular shunts(arteriovenous,arterioportal or portovenous)lead to different clinical manifestations.Even though no hepatic-related symptoms are reported in the majority of cases,the severity of liver disease could lead to refractory medical conditions,in some cases requiring liver transplantation.The aim of this manuscript is to provide an updated overview of the current evidence regarding the diagnosis and treatment of HHT liver involvement and liver-related complications.

BMSCs transplantation inhibits neuronal apoptosis after subarachnoid hemorrhage in rats through activation of AMPK/mTOR signaling pathway-mediated autophagy

Objective:To explore the impacts of bone marrow mesenchymal stem cells(BMSCs)intervention on the neuronal withering and autophagy in rats after subarachnoid hemorrhage(SAH)in rats and its process.Methods:forty-eight SD rats(males),were randomly assigned to the followings:sham surgery(Sham)group,modeling(SAH)group,modeling group+bone marrow mesenchymal stem cells(BMSCs)group,the modeling group+BMSCs+AMPK inhibitor(Compound C)group,twelve rats in each group.Except Sham group,other groups formed SAH samples with intravascular points.Separate groups Compound C and BMSCs,respectively Compound C and 10μL of normal saline were injected into the left lateral ventricle of rats using a stereoscope brain machine 30 minutes before modeling,and 2μL concentration is 1×10^(8)/mL cell suspension was injected into the ventricles of the brain 1 hour after the model was established.Observe whether the rats have severe brain swelling.Garcia were used to test the neural function of rats.TUNEL staining was used to monitor neuronal apoptosis in the rat hippocampal gyrus.Immunohistochemical fluorescence reflected the expression of two proteins,LC3-II and Beclin-1,in rat hippocampal gyrus.Western blotting is applied to measure the expressions of autophagy-associated proteins in the AMPK pathway.Results:Compared with the group undergoing sham-surgery,brain edema worsened in the model group,neuronal apoptosis rate was increased,neural function was weakened,Protein granules decreased(P<0.05)and expression levels of p-AMPK and other proteins decreased(P<0.05);brain swelling and neuronal apoptosis were reduced in the BMSCs group by comparison with the modeling group’s,with substantial elevation in the expression of proteins comprising LC3-Ⅱ,Beclin-1,and p-AMPK.And the standard of p-mTOR protein expression was considerably lessened(P<0.05);rats belonging to group compound C showed increased brain swelling which is relative to that of BMSCs group,increased neuronal apoptosis,decreased neuronal function(P<0.05),increased p-AMPK protein expression,and decreased LC3-Ⅱ,Beclin-1,and p-mTOR protein expression(P<0.05).Conclusion:BMSCs transplantation can reduce neuronal apoptosis after SAH;its principle may be to activate AMPK/mTOR pathway,strengthen autophagy of neurons,and thus inhibit their transformation to apoptosis.

Computed tomographic angiography for diagnosis of post-pancreatoduodenectomy hemorrhage

To the Editor:Even in high volume specialist hepato-pancreato-biliary surgery centres,hemorrhage after pancreatoduodenectomy remains a feared and potentially lethal complication[1]and an important cause of postoperative morbidity and mortality[2].Whilst early hemorrhage after pancreatoduodenectomy is typically managed by re-operation,detection and treatment of bleeding later in the postoperative course can be problematic.Patients who are hemodynamically unstable with evidence of brisk bleeding are usually treated by urgent re-operation.However,not all bleeding episodes present in such a dramatic fashion.The“sentinel bleed”–a harbinger of major hemorrhage–represents a clinical opportunity for detection and treatment[3].Traditionally,patients who presented with luminal bleeding episodes with hematemesis or melena underwent fibre optic endoscopy as first-line investigation whereas patients presenting with a bleed into surgical drains would have undergone selective mesenteric angiography[4].

Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities.Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure,followed by global cerebral ischemia.Post-subarachnoid hemorrhage ischemia,tissue injuries as well as extravasated blood components and the breakdown products activate microglia,astrocytes and Toll-like receptor 4,and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades.Once blood-brain barrier is disrupted,brain tissues are directly exposed to harmful blood contents and immune cells,which aggravate brain injuries furthermore.Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins.Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage,but the exact mechanisms remain unclear.Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage.This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage.

Optic radiation injury in patients with aneurismal subarachnoid hemorrhage: a preliminary diffusion tensor imaging report

Visual field defect is one of the various clinical manifestations in patients with subarachnoid hemorrhage（SAH）. Little is known about the pathogenic mechanism of visual field defect in SAH. In the current study,we investigated the diffusion tensor imaging （DTI） finding of the optic radiation in patients with SAH followingrupture of a cerebral artery aneurysm. We recruited 21 patients with aneurismal SAH （12 males, 9 females, mean age, 52.67 years; range, 41–68 years） who showed no definite lesion along the visual pathway.Twenty-one age-and sex-matched normal control subjects were also recruited. DTI data were acquired at an average of 5.9 weeks （range： 3–12 weeks） after onset and reconstruction of the optic radiation was performed using DTI-Studio software. The fractional anisotropy value, apparent diffusion coefficient value,and fiber number of the optic radiation were measured. The fractional anisotropy value of the optic radiation was significantly decreased, and the apparent diffusion coefficient value was significantly increased, in patients with aneurismal SAH than in normal control subjects. However, there was no significant difference in the fiber number of the optic radiation between patients with aneurismal SAH and normal control subjects. The decrement of fractional anisotropy value and increment of apparent diffusion coefficient value of the optic radiation in patients with aneurismal SAH suggest optic radiation injury. Therefore, we recommend a thorough evaluation for optic radiation injury in patient with aneurismal SAH.

Dynamic expression of nerve growth factor and its receptor Trk A after subarachnoid hemorrhage in rat brain

Delayed ischemic neurologic deficit after subarachnoid hemorrhage results from loss of neural cells.Nerve growth factor and its receptor Trk A may promote regeneration of neural cells,but their expression after subarachnoid hemorrhage remains unclear.In the present study,a rat model of subarachnoid hemorrhage was established using two injections of autologous blood into the cistern magna.Immunohistochemical staining suggested that the expression of nerve growth factor and Trk A in the cerebral cortex and brainstem increased at 6 hours,peaked at 12 hours and decreased 1 day after induction of subarachnoid hemorrhage,whereas the expression in the hippocampus increased at 6 hours,peaked on day 1,and decreased 3 days later.Compared with those for the rats in the sham and saline groups,neurobehavioral scores decreased significantly 12 hours and 3 days after subarachnoid hemorrhage（P 〈 0.05）.These results suggest that the expression of nerve growth factor and its receptor Trk A is dynamically changed in the rat brain and may thus participate in neuronal survival and nerve regeneration after subarachnoid hemorrhage.

An early neuroprotective effect of atorvastatin against subarachnoid hemorrhage

Atorvastatin has been shown to reduce early brain edema and neuronal death after subarachnoid hemorrhage,but its mechanism is not clear.In this study,rat models of subarachnoid hemorrhage were established by autologous blood injection in the cisterna magna.Rat models were intragastrically administered 20 mg/kg atorvastatin 24 hours before subarachnoid hemorrhage,12 and 36 hours after subarachnoid hemorrhage.Compared with the controls,atorvastatin treatment demonstrated that at 72 hours after subarachnoid hemorrhage,neurological function had clearly improved;brain edema was remarkably relieved;cell apoptosis was markedly reduced in the cerebral cortex of rats;the number of autophagy-related protein Beclin-1-positive cells and the expression levels of Beclin-1 and LC3 were increased compared with subarachnoid hemorrhage only.The ultrastructural damage of neurons in the temporal lobe was also noticeably alleviated.The similarities between the effects of atorvastatin and rapamycin were seen in all the measured outcomes of subarachnoid hemorrhage.However,these were contrary to the results of 3-methyladenine injection,which inhibits the signaling pathway of autophagy.These findings indicate that atorvastatin plays an early neuroprotective role in subarachnoid hemorrhage by activating autophagy.The experimental protocol was approved by the Animal Ethics Committee of Anhui Medical University,China(904 Hospital of Joint Logistic Support Force of PLA;approval No.YXLL-2017-09)on February 22,2017.

The “Brain Stress Timing” phenomenon and other misinterpretations of randomized clinical trial on aneurysmal subarachnoid hemorrhage

Clipping and coiling are currently the two alternatives in treatment of ruptured cerebral aneurysms. In spite of some meritorious analysis, further discussion is helpful to understand the actual state of art. Retreatment and rebleeding rates clearly favors clipping, although short-term functional outcome seems to be beneficial for clipping, while this different is not such if we perform the comparison at a longer follow up. Longterm follow ups and cost analysis are mandatory to have a clear view of the current picture in treatment of subarachnoid hemorrhage. Treatment strategy should be made by a multi-disciplinary team in accredited centers with proficient experience in both techniques.

Serum Gamma-glutamyl Transferase Levels Predict Functional Outcomes after Aneurysmal Subarachnoid Hemorrhage

Objective We aim to explore the potential association between serum gamma-glutamyl transferase levels and functional outcome after aneurysmal subarachnoid hemorrhage in a Chinese population. Methods A total of 386 aneurysmal subarachnoid hemorrhage patients were included in the study from September 2007 to February 2015. Baseline serum gamma-glutamyl transferase levels and 6-month follow-up functional outcomes were determined. A poor outcome was defined as a modified ranking scale score of ≥ 3. The multivariable logistic model was used to analyze the relationship between serum gamma-glutamyl transferase and clinical outcomes after aneurysmal subarachnoid hemorrhage. Results The adjusted poor outcome rates of patients with gamma-glutamyl transferase levels of 〈 30 U/L, 30-50 U/L and ≥ 50 U/L were 16.7%, 19.6%, and 34.4%, respectively （P 〈 0.01）. The age-sex and multivariable adjusted odds ratios （95% confidence intervals） of poor prognosis comparing the top group （≥ 50 U/L） with the lowest group （〈 30 U/L） were 5.76 （2.74-12.13）, 6.64 （2.05-21.52）, and 6.36 （1.92-21.02）. A significant linear trend existed between gamma-glutamyl transferase level and aneurysmal subarachnoid hemorrhage prognosis. This association was also observed among nondrinkers. Conclusion Patients with higher gamma-glutamyl transferase levels were more likely to have a poor prognosis. Serum gamma-glutamyl transferase can be considered to be an independent predictor of functional outcomes after aneurysmal subarachnoid hemorrhage.

Serial lumbar puncture reduces cerebrospinal fluid (CSF) infection during removal of hemorrhagic CSF in aneurysmal subarachnoid hemorrhage after endovascular coiling

The present study aimed to compare the complications and clinical outcomes of serial lumbar puncture（LP） and lumbar cerebrospinal fluid（CSF） drainage（LD） of patients with aneurysmal subarachnoid hemorrhage and provide more evidence to guide clinical management.In this retrospective study,41 and 39 aneurysmal subarachnoid hemorrhage patients were enrolled in the LP and LD group,respectively.Clinical outcomes,including CSF infection,intracerebral hemorrhage,vasospasm,hydrocephalus,death,length of stay,duration of drainage and the Glasgow Outcome Scale score were compared between the two groups.By comparing with the LP group,the LD group showed a significantly higher rate of CSF infection（P= 0.029） and shorter duration of drainage（P〈 0.001）.Both groups displayed similar rates of vasospasm,hydrocephalus,intracerebral hemorrhage,the Glasgow Outcome Scale score one month after endovascular coiling and length of stay（P〉 0.05,respectively）.In conclusion,both LD and serial LP are effective methods in the treatment of aneurysmal subarachnoid hemorrhage; besides,serial LP can reduce the incidence of CSF infection in draining hemorrhagic CSF in aneurysmal subarachnoid hemorrhage after endovascular coiling.