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Molecular Neurobiology Jun 2024Neuroinflammation is a critical pathogenic event following hemorrhagic stroke. Endoplasmic reticulum (ER) stress-induced apoptosis and nucleotide-binding domain,...
Neuroinflammation is a critical pathogenic event following hemorrhagic stroke. Endoplasmic reticulum (ER) stress-induced apoptosis and nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3(NLRP3)-associated pyroptosis can contribute to the escalation of neuroinflammatory responses, leading to increased brain damage. G protein-coupled estrogen receptor 1(GPER1), as the most extensively characterized brain-derived estrogen, was reported to trigger neuroprotective effects. However, the anti-apoptotic and anti-pyroptotic effect of GPER1 activation and the underlying mechanism has not been fully elucidated. We established the experimental SAH model by intravascular perforation. The GPER1 selective agonist G1 was intravenously administered 1 h following SAH. For mechanistic exploration, the selective inhibitor of adenosine monophosphate-activated protein kinase (AMPK), dorsomorphin, was administered via intracerebroventricular injection 30 min prior to SAH induction. Post-SAH assessments included SAH grade, the short-term and long-term neurological outcomes, brain edema, cerebral blood flow, transmission electron microscopy (TEM), western blot (WB), ELISA, TUNEL staining, Fluoro-Jade C staining (FJC), and immunofluorescence staining. The expression of GPER1 was observed to elevate at 6 h and peaked at 24 h subsequent to SAH, predominantly co-localized with neurons. Post-treatment with G1 markedly ameliorated both the short-term and long-term neurological deficits of SAH mouse, as well as inhibiting the expression of neuronal ER stress-associated apoptotic proteins (i.e., CHOP, GRP78, Caspase-12, Cleaved Caspase-3, Bax, Bcl2) and pyroptosis-associated proteins (i.e., NLRP3, ASC, Cleaved Caspase-1). Additionally, our research revealed that inhibition of AMPK with dorsomorphin attenuated the neuroprotective effects of G1. This was accompanied by modifications in the molecular pathways associated with ER stress-induced apoptosis and pyroptosis. These data herein elucidated that GPER1 exerted neuroprotective effects by mitigating neuroinflammation in an AMPK-dependent manner, which modulates neuronal ER stress-associated apoptosis and pyroptosis. Boosting the anti-apoptotic and anti-pyroptotic effect by activating GPER1 may be an efficient treatment strategy for SAH patients.
PubMed: 38935231
DOI: 10.1007/s12035-024-04312-3 -
Annals of Pediatric Cardiology 2024Aortico right atrial tunnel (ARAT) is a rare extracardiac communication between the aorta and the right atrium with two anatomical types. A recent global review...
BACKGROUND
Aortico right atrial tunnel (ARAT) is a rare extracardiac communication between the aorta and the right atrium with two anatomical types. A recent global review identified 59 patients.
METHODS
Patients with ARAT from two centers were analyzed for their demographics, symptoms, morphology, management, and follow-up thromboprophylaxis.
RESULTS
Among 21 patients including 8 males with a median age of 3 years (18 days-72 years) diagnosed as ARAT, 12 (57%) had posterior tunnels and 9 had anterior tunnels. Four patients had multiple exits. Eighteen tunnels were closed after arteriovenous circuit formation. Six patients (29%) weighing <10 kg presented early with heart failure. Transcatheter closure normalized the hemodynamics including in one infant after failed surgery. Two elderly patients (10%) above 60 years presented with angina and atrial fibrillation. The rest were asymptomatic. Occluders were positioned in the narrow proximal aortic end of the tunnel in all except two patients, where the distal atrial end was closed. All procedures were successful without complications. There was one late death after 1 year from subarachnoid hemorrhage. At a median follow-up of 96 months, all survivors were asymptomatic. Thromboprophylaxis with dual antiplatelets for 1-2 years followed earlier was recently changed to aspirin with Coumadin. Complete remodeling occurred when the proximal aortic end was closed, but partial persistence of the track was noted after distal closure.
CONCLUSIONS
This largest cohort of ARAT showed the safety and efficacy of transcatheter closure even in neonates. The narrow proximal aortic end should be the target for closure rather than the distal atrial end to achieve complete remodeling.
PubMed: 38933058
DOI: 10.4103/apc.apc_1_24 -
International Journal of Molecular... Jun 2024We aimed to investigate the characteristics of serum metabolomics in aneurysmal subarachnoid hemorrhage patients (aSAH) with different 3-month outcomes (good = modified...
We aimed to investigate the characteristics of serum metabolomics in aneurysmal subarachnoid hemorrhage patients (aSAH) with different 3-month outcomes (good = modified Rankin score: 0-3 vs. poor = mRS 4-6). We collected serum samples from 46 aSAH patients at 24 (D1) and 168 (D7) hours after injury for analysis by liquid chromatography-mass spectrometry. Ninety-six different metabolites were identified. Groups were compared using multivariate (orthogonal partial least squares discriminant analysis), univariate, and receiving operator characteristic (ROC) methods. We observed a marked decrease in serum homocysteine levels at the late phase (D7) compared to the early phase (D1). At both D1 and D7, mannose and sorbose levels were notably higher, alongside elevated levels of kynurenine (D1) and increased 2-hydroxybutyrate, methyl-galactoside, creatine, xanthosine, p-hydroxyphenylacetate, N-acetylalanine, and N-acetylmethionine (all D7) in the poor outcome group. Conversely, levels of guanidinoacetate (D7) and several amino acids (both D1 and D7) were significantly lower in patients with poor outcomes. Our results indicate significant changes in energy metabolism, shifting towards ketosis and alternative energy sources, both in the early and late phases, even with adequate enteral nutrition, particularly in patients with poor outcomes. The early activation of the kynurenine pathway may also play a role in this process.
Topics: Humans; Subarachnoid Hemorrhage; Male; Female; Middle Aged; Metabolomics; Metabolome; Aged; Adult; Homocysteine; Kynurenine; Biomarkers; Prognosis; Hydroxybutyrates
PubMed: 38928303
DOI: 10.3390/ijms25126597 -
Scientific Reports Jun 2024The incidence and clinical distribution of intracranial haemorrhage (ICH) in neonates at risk of cerebral hypoxia-ischaemia have not been reported in specific studies....
The incidence and clinical distribution of intracranial haemorrhage (ICH) in neonates at risk of cerebral hypoxia-ischaemia have not been reported in specific studies. Based on conventional magnetic resonance imaging (MRI) versus susceptibility weighted imaging (SWI), this study aimed to analyse the occurrence of asymptomatic ICH in newborns with or without risk of cerebral hypoxia-ischaemia and to accumulate objective data for clinical evaluations of high-risk neonates and corresponding response strategies. 317 newborns were included. MRI revealed that the overall incidence of ICH was 59.31%. The most common subtype was intracranial extracerebral haemorrhage (ICECH) which included subarachnoid haemorrhage (SAH) and subdural haemorrhage (SDH). ICECH accounted for 92.02% of ICH. The positive detection rate of ICECH by SWI was significantly higher than that by T1WI. The incidence of total ICH, ICECH and SAH was greater among children who were delivered vaginally than among those who underwent caesarean delivery. Asymptomatic neonatal ICH may be a common complication of the neonatal birth process, and SWI may improve the detection rate. Transvaginal delivery and a weight greater than 2500 g were associated with a high incidence of ICECH in neonates. The impact of neonatal cerebral hypoxia-ischaemia risk factors on the occurrence of asymptomatic ICH may be negligible.
Topics: Humans; Infant, Newborn; Female; Magnetic Resonance Imaging; Incidence; Male; Intracranial Hemorrhages; Hypoxia-Ischemia, Brain; Risk Factors
PubMed: 38926428
DOI: 10.1038/s41598-024-62473-6 -
Clinical Neurology and Neurosurgery Jun 2024Giant ruptured distal anterior cerebral artery aneurysms are rare, challenging pathologies that may require a combination of microsurgical and endovascular techniques...
Giant ruptured distal anterior cerebral artery aneurysms are rare, challenging pathologies that may require a combination of microsurgical and endovascular techniques for optimal treatment [1-9]. We describe the case of a female in her 40 s who presented with a Hunt-Hess 4, Fisher 4 subarachnoid hemorrhage from a multiply ruptured, giant distal anterior cerebral artery aneurysm. The patient underwent coil and n-BCA glue embolization of the aneurysm and its feeding A2 anterior cerebral artery. She subsequently underwent decompressive craniectomy, intracerebral hematoma evacuation, and microsurgical trapping and resection of the aneurysm. Postoperative imaging demonstrated no further aneurysm filling, complete hematoma evacuation, and good decompression. The technical considerations and literature for the combined treatment of large and giant ruptured aneurysms are reviewed. The case presentation, operative nuances, and postoperative course with imaging are reviewed with detailed anatomical diagrams to orient the viewer. The patient consented to the procedure and to the publication of her imaging.
PubMed: 38924843
DOI: 10.1016/j.clineuro.2024.108383 -
Journal of Clinical Neuroscience :... Jun 2024Aneurysmal subarachnoid hemorrhage (aSAH) is a severe event often complicated by cerebral vasospasm (CV). This study aimed to assess the efficacy and safety of... (Review)
Review
BACKGROUND
Aneurysmal subarachnoid hemorrhage (aSAH) is a severe event often complicated by cerebral vasospasm (CV). This study aimed to assess the efficacy and safety of clazosentan, an endothelin receptor antagonist, in reducing CV, delayed cerebral ischemia (DCI), and the need for rescue therapy in aSAH patients, while evaluating its impact on functional outcomes and mortality.
METHODS
We conducted a literature search across multiple databases to identify relevant studies evaluating the effects of clazosentan in aSAH patients. Both cohort studies and randomized controlled trials (RCTs) were included. The primary outcomes were vasospasm incidence, moderate to severe vasospasm, DCI, and the need for rescue therapy. Secondary outcomes included functional outcomes, mortality, and adverse events. The data were pooled as Risk ratios (R/R) with 95 % confidence intervals (CI) using RevMan 5.4 software.
RESULTS
A total of 11 studies, including 10 published and one unpublished, comprising 8,469 patients were included in the meta-analysis. Clazosentan significantly reduced the incidence of vasospasm (R/R = 0.49: 0.34-0.70), moderate to severe vasospasm (R/R = 0.53: 0.46-0.61), DCI (R/R = 0.70: 0.59-0.82), and the need for rescue therapy (R/R = 0.65: 0.52-0.83) compared to placebo. However, no significant improvement in functional outcomes or mortality rates was observed. Clazosentan was associated with increased rates of pulmonary adverse events (R/R = 1.89: 1.64-2.18), hypotension (R/R = 2.47: 1.79-3.42), and anemia (R/R = 1.49: 1.23-1.79) but no increased risk of hepatobiliary adverse events or cerebral hemorrhage.
CONCLUSIONS
Clazosentan demonstrates efficacy in reducing vasospasm, moderate to severe vasospasm, DCI, and the need for rescue therapy in aSAH patients, but does not significantly improve functional outcomes or mortality rates. While associated with specific adverse events, clazosentan may be a valuable adjunctive therapy in the management of aSAH, particularly in a high-risk population for vasospasm.
PubMed: 38924824
DOI: 10.1016/j.jocn.2024.06.019 -
Journal of Clinical Pharmacology Jun 2024Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are...
Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH that contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain is an off-label intervention that has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize the population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 13 females) treated with IT nicardipine every 6 h (q6h, n = 8) or every 8 h (q8h, n = 8) for an average of 72 ± 21 doses. High-performance liquid chromatography was used to quantify CSF concentration from each sample. Our popPK analysis showed that the CSF pharmacokinetics of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time. Model parameter estimates were reliable (relative standard error <50%). Intracranial pressure influenced both the total clearance and the central volume of nicardipine (i.e., negative correlation, P <-.001). Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.
PubMed: 38923537
DOI: 10.1002/jcph.2488 -
Stroke Jun 2024Periventricular white matter hyperintensities (PVWMHs) in cerebral amyloid angiopathy (CAA) have been reported posterior predominant using semiautomated segmentation...
BACKGROUND
Periventricular white matter hyperintensities (PVWMHs) in cerebral amyloid angiopathy (CAA) have been reported posterior predominant using semiautomated segmentation method and logarithmic transformation. We aimed to compare PVWMH extent and posterior/anterior distribution between patients with CAA and patients with hypertensive arteriopathy with radiological tools available in daily practice.
METHODS
We retrospectively analyzed confluent PVWMH directly adjacent to lateral ventricles on axial FLAIR (fluid-attenuated inversion recovery) from 108 patients with CAA and 99 patients with hypertensive arteriopathy presenting with hemorrhage-related symptoms consecutively recruited in our stroke database (Nîmes University Hospital, France) between January 2015 and March 2022. For each of the left (L), right (R), anterior (A), and posterior (P) horns of lateral ventricles, the maximal distance between the outer PVWMH border and ventricle border was measured. The sum of anterior left PVWMH and anterior right PVWMH, and posterior left PVWMH and posterior right PVWMH resulted in anterior and posterior extent, respectively.
RESULTS
Compared with hypertensive arteriopathy, patients with CAA were older (median, 77 versus 71; =0.0010) and less frequently male (46% versus 64%; =0.012) and had less frequent hypertension (45% versus 63%; =0.013) and more chronic hemorrhages (<0.0001). CAA showed slightly more extensive anterior right PVWMH (median, 6.50 versus 5.90 mm; =0.034), far more extensive (all <0.0001) posterior left PVWMH (median, 13.95 versus 6.95 mm), posterior right PVWMH (median, 14.15 versus 5.45 mm), posterior (median, 27.95 versus 13.00 mm), and total (median, 39.60 versus 24.65 mm) PVWMH, and higher posterior/anterior ratios (median, 1.82 versus 1.01). Age-/sex-adjusted model predicting CAA incorporating total PVWMH extent and posterior/anterior ratios for the given score (-4.3683+0.0268×PVWMH-T+0.3749×posterior/anterior PVWMH ratio+0.0394×age+0.3046 when female) showed highest area under the curve (0.76 [0.70-0.83]), with a 72% [62.50-80.99] sensitivity and 76% [67.18-84.12] specificity. Values above the optimal threshold of 0.22 for the score showed a crude relative risk of 2.75 (2.26-2.37; <0.0001).
CONCLUSIONS
Severe posterior PVWMH and high posterior/anterior PVWMH ratio assessed by radiological tools used in daily practice are associated with probable CAA versus hypertensive arteriopathy.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT05486897.
PubMed: 38920025
DOI: 10.1161/STROKEAHA.123.046379 -
Neurocritical Care Jun 2024Acute muscle wasting is common in critically ill patients, and this can lead to unfavorable clinical outcomes. The aim of this study was to identify factors associated...
BACKGROUND
Acute muscle wasting is common in critically ill patients, and this can lead to unfavorable clinical outcomes. The aim of this study was to identify factors associated with muscle wasting and to investigate the association between skeletal muscle wasting and prolonged hospital stay in critically ill patients with acute brain injury.
METHODS
This single-center prospective observational study was conducted in critically ill patients with acute brain injury who stayed in the intensive care unit for at least 1 week. The rectus femoris cross-sectional area was measured via ultrasound at baseline and a week after the first assessment. Univariate and multivariate logistic regression analyses were performed to identify factors that predicted prolonged hospital stay.
RESULTS
A total of 86 patients were included in the study. Their mean age was 49.4 ± 16.9 years, 57% were male, and 46.5% had an admission diagnosis of subarachnoid hemorrhage. The percentage change in the rectus femoris cross-sectional area was 15.8% (95% confidence interval [CI] - 19.8% to - 12.0%; p < 0.001), and 57% of all patients had acute muscle wasting. According to the univariate analysis, there was a significant association between prolonged hospital stay and acute muscle wasting (odds ratio [OR] 3.677; 95% CI 1.487-9.043; p = 0.005), mechanical ventilation status (OR 3.600; 95% CI 1.455-8.904; p = 0.006), and Glasgow Coma Scale score (OR 0.888; 95% CI 0.808-0.976; p = 0.014) at intensive care unit admission. The multivariate analysis demonstrated that acute muscle wasting (OR 3.449; 95% CI 1.344-8.853; p = 0.010) was an independent risk factor for prolonged hospital stay.
CONCLUSIONS
There was considerable muscle wasting in critically ill patients with brain injuries over a 1-week period. Acute muscle wasting was associated with prolonged hospital stay in critically ill patients with acute brain injury.
PubMed: 38918337
DOI: 10.1007/s12028-024-02017-y -
Seminars in Neurology Jun 2024Cannabinoid use, particularly for recreational purposes, is increasing exponentially across all age groups, especially in younger populations, due to its perceived low...
Cannabinoid use, particularly for recreational purposes, is increasing exponentially across all age groups, especially in younger populations, due to its perceived low risk and legalization. While cannabinoids may be largely considered as safe, there is mounting evidence of increased risk of systemic and neurological complications through their interaction with the poorly understood endocannabinoid receptor network within the central nervous system and other organ systems. Acute cannabinoid exposure can cause neuropsychiatric symptoms in addition to altering cerebral blood flow, leading to cerebrovascular complications such as ischemic stroke, subarachnoid hemorrhage, and reversible cerebral vasoconstriction syndrome (RCVS). Chronic use, particularly among adolescents, may be associated with increased risk of long-term cognitive deficits, schizophrenia, and other neuropsychiatric effects. Synthetic cannabinoids have increased potency, with reports of causing profound neurological complications including coma, seizures, posterior reversible encephalopathy syndrome, and RCVS. Despite increasing evidence, the quality of literature describing neurologic complications with cannabinoids remains limited to case series and retrospective cohort studies, with significant confounding factors such as concomitant use of other illicit drugs, limiting interpretation. In this review, we summarize the effect of cannabinoids on the neurologic system and associated neurological complications.
PubMed: 38914126
DOI: 10.1055/s-0044-1787570