Endovascular therapy versus medical management for ischemic stroke presenting beyond 24 hours: Systematic review and meta-analysis.

OBJECTIVE: The ideal management for ischemic stroke presenting in the very late time window, or beyond 24 hours from onset, is poorly understood. It is unknown if endovascular therapy (EVT) or best medical management (MM) is associated with superior clinical outcomes. METHODS: A systematic literature and comparative meta-analysis was completed to evaluate the safety and efficacy of EVT vs. MM for stroke presenting beyond 24 hours. Outcome measures included: 90 day functional independence (mRS 0-2), 90 day mortality, and symptomatic intracranial hemorrhage (sICH) occurrence. A random effects model was used for quantitative synthesis. RESULTS: From the five included studies, a total of 704 patients were included with 461 treated with EVT and 243 treated with MM alone. The proportion of patients achieving functional independence was significantly higher in patients treated with EVT (34.6 %) compared to MM alone (15.9 %) (OR: 4.24; CI: 2.61-6.88, P < 0.00001; I2 =0 %). While sICH occurred more in EVT patients (6.8 %) compared to MM (2.8 %), this was not significant (OR: 1.96; CI: 0.61-6.27, P=0.26; I2 = 67 %). Lastly, 90 day morality occurred significantly less in the EVT group (24.5 %) compared to patients treated with MM (33.1 %), and with significantly lower odds (OR: 0.51; CI: 0.35-0.73, P=0.0003; I2=0 %). CONCLUSIONS: In certain patients presenting beyond 24 hours with ischemic stroke, EVT is associated with a significantly higher odds of achieving functional independence and lower odds of mortality compared with MM. While these results do not function as proof, they do encourage further research into extending the window beyond 24 hours for EVT. Randomized clinical trials are warranted to validate these findings.

Histone content, and thus DNA content, is associated with differential in vitro lysis of acute ischemic stroke clots.

BACKGROUND: Fibrin, von Willebrand factor, and extracellular DNA from neutrophil extracellular traps all contribute to acute ischemic stroke thrombus integrity. OBJECTIVES: In this study, we explored how the proteomic composition of retrieved thromboemboli relates to susceptibility to lysis with distinct thrombolytics. METHODS: Twenty-six retrieved stroke thromboemboli were portioned into 4 segments, with each subjected to 1 hour of in vitro lysis at 37 °C in 1 of 4 solutions: tissue plasminogen activator (tPA), tPA + von Willebrand factor-cleaving ADAMTS-13, tPA + DNA-cleaving deoxyribonuclease (DNase) I, and all 3 enzymes. Lysis, characterized by the percent change in prelysis and postlysis weight, was compared across the solutions and related to the corresponding abundance of proteins identified on mass spectrometry for each of the thromboemboli used in lysis. RESULTS: Solutions containing DNase resulted in approximately 3-fold greater thrombolysis than that with the standard-of-care tPA solution (post hoc Tukey, P < .01 for all). DNA content was directly related to lysis in solutions containing DNase (Spearman's ρ > 0.39 and P < .05 for all significant histones) and inversely related to lysis in solutions without DNase (Spearman's ρ < -0.40 and P < .05 for all significant histones). Functional analysis suggests distinct pathways associated with susceptibility to thrombolysis with tPA (platelet-mediated) or DNase (innate immune system-mediated). CONCLUSION: This study demonstrates synergy of DNase and tPA in thrombolysis of stroke emboli and points to DNase as a potential adjunct to our currently limited selection of thrombolytics in treating acute ischemic stroke.

Symptomatic carotid artery intraluminal thrombus: risk of medical management failure and distal embolization.

BACKGROUND: Carotid artery intraluminal thrombus (ILT), or free-floating thrombus, is an uncommon cerebrovascular entity with considerable equipoise regarding its clinical management. Likewise, in patients treated with medical management (MM), distal embolization and/or intracranial hemorrhage (ICH) may still occur. METHODS: All patients with symptomatic ILT from 2016 to 2023 were identified from our tertiary care institution. Patients with MM failure (recurrent cerebral ischemia and/or symptomatic ICH) were compared with patients with MM non-failure. Differences in ILT volume and length were calculated. Receiver operator characteristic (ROC) curve analysis was used to identify the cut-off volume and length for risk of MM failure. RESULTS: In total, 45 patients with ILT were identified with 41 treated with frontline MM. Of these 41 patients treated with MM, seven (17%) had MM failure with six (14.6%) having new embolic stroke and one (2.3%) with symptomatic ICH. Patients with MM failure had a significantly higher mean thrombus volume than MM non-failure patients (257 mm3 vs 59.6 mm3, P=0.0006). Likewise, patients with MM failure had significantly longer thrombus on average (21 mm vs 6.6 mm, P=0.0009). ROC curve analysis showed that an ILT volume of 90 mm3 resulted in a sensitivity of 71.4% and specificity of 85.3% for MM failure (AUC 0.775; CI 0.55 to 1.0, P=0.023). CONCLUSIONS: Carotid ILTs that fail MM are significantly larger and longer. These findings suggest that a thrombus volume of 90 mm3 may serve as a guide for intervention with good sensitivity and specificity for risk of MM failure.

Ischemic Stroke Thrombus Perviousness Is Associated with Distinguishable Proteomic Features and Susceptibility to ADAMTS13-Augmented Thrombolysis.

BACKGROUND AND PURPOSE: Perviousness is the differential attenuation on CT of an intracranial arterial occlusive thrombus before and after IV contrast administration. While perviousness/permeability has been shown to be related to various clinical outcomes and reflects histopathologic composition, it remains unclear whether perviousness is also associated with differences in proteomic composition. MATERIALS AND METHODS: Retrieved clots from 59 patients were evaluated with quantitative mass spectrometry. Proteomic differences between high-perviousness (≥11 HU) and low-perviousness (<11 HU) clots were investigated. Perviousness as a continuous variable was also correlated with protein abundance. Last, an ex vivo lysis assay was performed to investigate the differential susceptibility to tPA, deoxyribonuclease, and ADAMTS13 thrombolysis as a function of perviousness. RESULTS: In total, 2790 distinct proteins were identified. Thrombus perviousness was associated with distinct proteomic features, including depletion of the macrophage marker CD14 (P = .039, z = 1.176) and hemoglobin subunit ζ (P = .046, z = 1.68) in pervious clots. Additionally, proteins involved in platelet cytoskeleton remodeling (tropomyosin α-3-chain) and granule secretion/aggregation (synaptotagmin-like protein 4/FC region receptor II-a) were associated with increasing perviousness (P < .006), among numerous other proteins. Monocyte/macrophage-associated proteins (apoptosis-associated specklike protein containing a CARD/SAMHD1) were also depleted in pervious emboli (P < .002). Ex vivo lysis indicated that pervious clots were more susceptible to ADAMTS13-augmented tPA thrombolysis compared with impervious clots (P < .05), though without differences in deoxyribonuclease digestion. CONCLUSIONS: Thrombus perviousness is associated with complex proteomic features, including differential abundance of platelet-related proteins in highly permeable clots with monocyte/macrophage depletion. This association may help to explain why highly pervious thrombi were also found more susceptible to ADAMTS13-augmented thrombolysis.

Prevalence of SLEC-negative spontaneous intracranial hypotension in patients with spinal nerve root sleeve diverticula on MRI.

PURPOSE: While there is thought to be an association between spinal nerve root diverticula (NRD) and spontaneous intracranial hypotension (SIH) without a spinal longitudinal epidural collection (SLEC), it remains unclear what the overall prevalence of SLEC-negative SIH is in patients with NRD on MRI. METHODS: Spine MRI imaging reports from our single institution were electronically screened for instances of NRD over a 9-year period (2016-2023). From these cases, patients with brain MRIs consistent with SIH were also identified. Subsequently, the overall proportion of SLEC-negative SIH was determined as a function of total cases with NRD based on spinal level. RESULTS: In total, 83,843 patients with spinal MRIs were screened which identified 4174 (4.97%) with NRD. From these, there were 1203 cervical, 622 thoracic, and 2979 lumbosacral spine MRIs. In total, 16 patients (0.38%; Standard Error [SE]: 0.48%-0.28%) had a brain MRI compatible with SLEC-negative SIH and met ICHD-3 criteria. Patients with cervical NRD had SIH in 2 cases (0.16%; SE: 0.27%-0.05%). SLEC-negative SIH was present in 11 patients with lumbosacral NRD (0.34%; SE: 0.44%-0.24%). In patients with diverticula in the thoracic spine, 14 (2.3%; SE: 2.8%-1.8%) had SLEC-negative SIH. SLEC-negative SIH was significantly more prevalent in patients with thoracic diverticula compared to those with cervical (p<.0001) or lumbosacral NRD (p<.0001). CONCLUSION: In patients with spinal NRD, concurrent SLEC-negative SIH is present in approximately 0.38% of patients, suggesting that in the vast majority of cases, they are an incidental finding. However, SIH is present in approximately 2.3% of patients with thoracic NRD and may be more specific for leak localization.

A Soluble Platelet-Derived Growth Factor Receptor-ß Originates via Pre-mRNA Splicing in the Healthy Brain and Is Upregulated during Hypoxia and Aging.

The platelet-derived growth factor-BB (PDGF-BB) pathway provides critical regulation of cerebrovascular pericytes, orchestrating their investment and retention within the brain microcirculation. Dysregulated PDGF Receptor-beta (PDGFRß) signaling can lead to pericyte defects that compromise blood-brain barrier (BBB) integrity and cerebral perfusion, impairing neuronal activity and viability, which fuels cognitive and memory deficits. Receptor tyrosine kinases such as PDGF-BB and vascular endothelial growth factor-A (VEGF-A) are often modulated by soluble isoforms of cognate receptors that establish signaling activity within a physiological range. Soluble PDGFRß (sPDGFRß) isoforms have been reported to form by enzymatic cleavage from cerebrovascular mural cells, and pericytes in particular, largely under pathological conditions. However, pre-mRNA alternative splicing has not been widely explored as a possible mechanism for generating sPDGFRß variants, and specifically during tissue homeostasis. Here, we found sPDGFRß protein in the murine brain and other tissues under normal, physiological conditions. Utilizing brain samples for follow-on analysis, we identified mRNA sequences corresponding to sPDGFRß isoforms, which facilitated construction of predicted protein structures and related amino acid sequences. Human cell lines yielded comparable sequences and protein model predictions. Retention of ligand binding capacity was confirmed for sPDGFRß by co-immunoprecipitation. Visualizing fluorescently labeled sPDGFRß transcripts revealed a spatial distribution corresponding to murine brain pericytes alongside cerebrovascular endothelium. Soluble PDGFRß protein was detected throughout the brain parenchyma in distinct regions, such as along the lateral ventricles, with signals also found more broadly adjacent to cerebral microvessels consistent with pericyte labeling. To better understand how sPDGFRß variants might be regulated, we found elevated transcript and protein levels in the murine brain with age, and acute hypoxia increased sPDGFRß variant transcripts in a cell-based model of intact vessels. Our findings indicate that soluble isoforms of PDGFRß likely arise from pre-mRNA alternative splicing, in addition to enzymatic cleavage mechanisms, and these variants exist under normal physiological conditions. Follow-on studies will be needed to establish potential roles for sPDGFRß in regulating PDGF-BB signaling to maintain pericyte quiescence, BBB integrity, and cerebral perfusion-critical processes underlying neuronal health and function, and in turn, memory and cognition.

A Soluble Platelet-Derived Growth Factor Receptor-ß Originates via Pre-mRNA Splicing in the Healthy Brain and is Differentially Regulated during Hypoxia and Aging.

The platelet-derived growth factor-BB (PDGF-BB) pathway provides critical regulation of cerebrovascular pericytes, orchestrating their investment and retention within the brain microcirculation. Dysregulated PDGF Receptor-beta (PDGFRß) signaling can lead to pericyte defects that compromise blood-brain barrier (BBB) integrity and cerebral perfusion, impairing neuronal activity and viability, which fuels cognitive and memory deficits. Receptor tyrosine kinases (RTKs) like PDGF-BB and vascular endothelial growth factor-A (VEGF-A) are often modulated by soluble isoforms of cognate receptors that establish signaling activity within a physiological range. Soluble PDGFRß (sPDGFRß) isoforms have been reported to form by enzymatic cleavage from cerebrovascular mural cells, and pericytes in particular, largely under pathological conditions. However, pre-mRNA alternative splicing has not been widely explored as a possible mechanism for generating sPDGFRß variants, and specifically during tissue homeostasis. Here, we found sPDGFRß protein in the murine brain and other tissues under normal, physiological conditions. Utilizing brain samples for follow-on analysis, we identified mRNA sequences corresponding to sPDGFRß isoforms, which facilitated construction of predicted protein structures and related amino acid sequences. Human cell lines yielded comparable sequences and protein model predictions. Retention of ligand binding capacity was confirmed for sPDGFRß by co-immunoprecipitation. Visualizing fluorescently labeled sPDGFRß transcripts revealed a spatial distribution corresponding to murine brain pericytes alongside cerebrovascular endothelium. Soluble PDGFRß protein was detected throughout the brain parenchyma in distinct regions such as along the lateral ventricles, with signals also found more broadly adjacent to cerebral microvessels consistent with pericyte labeling. To better understand how sPDGFRß variants might be regulated, we found elevated transcript and protein levels in the murine brain with age, and acute hypoxia increased sPDGFRß variant transcripts in a cell-based model of intact vessels. Our findings indicate that soluble isoforms of PDGFRß likely arise from pre-mRNA alternative splicing, in addition to enzymatic cleavage mechanisms, and these variants exist under normal physiological conditions. Follow-on studies will be needed to establish potential roles for sPDGFRß in regulating PDGF-BB signaling to maintain pericyte quiescence, BBB integrity, and cerebral perfusion - critical processes underlying neuronal health and function, and in turn memory and cognition.

Meningitis due to intra-abdominal cerebrospinal fluid fistula following gunshot wound successfully treated with antibiotics and blood patch: A case report and literature review.

Background: Penetrating spinal cord injury (PSCI) represents an average of 5.5% of all SCIs among civilians in the United States. The formation of a cerebrospinal fluid (CSF) fistula following PSCI occurs in approximately 9% of cases. Intra-abdominal CSF fistulae are rarely reported. Case Description: We present the case of a 28-year-old Caucasian female who suffered a single gunshot wound to the abdomen with a missile fragment lodged within the left L2 pedicle and transverse process without obvious canal compromise. The patient developed bacterial meningitis 13 days after the initial injury, treated with IV antibiotics. CT myelogram demonstrated intra-abdominal ventral CSF fistula from the left L2-L3 neuroforamen. The patient was successfully treated with fluoroscopy-guided dorsal autologous blood patch graft. Conclusion: This case highlights a rare complication of PSCI successfully managed with the use of a blood patch graft.

The cerebral microvasculature: Basic and clinical perspectives on stroke and glioma.

Microvascular networks are vital components of the cardiovascular system, performing many key roles in maintaining the health and homeostasis of the tissues and organs in which they develop. As discussed in this review, the molecular and cellular components within the microcirculation orchestrate critical processes to establish functional capillary beds, including organization of endothelial cell (EC) polarity, guiding investment of vascular pericytes (PCs), and building the specialized extracellular matrix (ECM) that comprises the vascular basement membrane (vBM). Herein, we further discuss the unique features of the microvasculature in the central nervous system (CNS), focusing on the cells contributing to the neurovascular unit (NVU) that form and maintain the blood-brain barrier (BBB). With a focus on vascular PCs, we offer basic and clinical perspectives on neurovascular-related pathologies that involve defects within the cerebral microvasculature. Specifically, we present microvascular anomalies associated with glioblastoma multiforme (GBM) including defects in vascular-immune cell interactions and associated clinical therapies targeting microvessels (ie, vascular-disrupting/anti-angiogenic agents and focused ultrasound). We also discuss the involvement of the microcirculation in stroke responses and potential therapeutic approaches. Our goal was to compare the cellular and molecular changes that occur in the microvasculature and NVU, and to provide a commentary on factors driving disease progression in GBM and stroke. We conclude with a forward-looking perspective on the importance of microcirculation research in developing clinical treatments for these devastating conditions.

Pericytes in Vascular Development.

PURPOSE OF REVIEW: Pericytes are essential components of capillaries in many tissues and organs, contributing to vessel stability and integrity, with additional contributions to microvascular function still being discovered. We review current and foundational studies identifying pericyte differentiation mechanics and their roles in the earliest stages of vessel formation. RECENT FINDINGS: Recent advances in pericyte-focused tools and models have illuminated critical aspects of pericyte biology including their roles in vascular development.Pericytes likely collaborate with endothelial cells undergoing vasculogenesis, initiating direct interactions during sprouting and intussusceptive angiogenesis. Pericytes also provide important regulation of vascular growth including mechanisms underlying vessel pruning, rarefaction, and subsequent regrowth.

SINC, a type III secreted protein of Chlamydia psittaci, targets the inner nuclear membrane of infected cells and uninfected neighbors.

SINC, a new type III secreted protein of the avian and human pathogen Chlamydia psittaci, uniquely targets the nuclear envelope of C. psittaci-infected cells and uninfected neighboring cells. Digitonin-permeabilization studies of SINC-GFP-transfected HeLa cells indicate that SINC targets the inner nuclear membrane. SINC localization at the nuclear envelope was blocked by importazole, confirming SINC import into the nucleus. Candidate partners were identified by proximity to biotin ligase-fused SINC in HEK293 cells and mass spectrometry (BioID). This strategy identified 22 candidates with high confidence, including the nucleoporin ELYS, lamin B1, and four proteins (emerin, MAN1, LAP1, and LBR) of the inner nuclear membrane, suggesting that SINC interacts with host proteins that control nuclear structure, signaling, chromatin organization, and gene silencing. GFP-SINC association with the native LEM-domain protein emerin, a conserved component of nuclear "lamina" structure, or with a complex containing emerin was confirmed by GFP pull down. Our findings identify SINC as a novel bacterial protein that targets the nuclear envelope with the capability of globally altering nuclear envelope functions in the infected host cell and neighboring uninfected cells. These properties may contribute to the aggressive virulence of C. psittaci.

The molecular basis of emerin-emerin and emerin-BAF interactions.

Emerin is a conserved membrane component of nuclear lamina structure. Here, we report an advance in understanding the molecular basis of emerin function: intermolecular emerin-emerin association. There were two modes: one mediated by association of residues 170-220 in one emerin molecule to residues 170-220 in another, and the second involving residues 170-220 and 1-132. Deletion analysis showed residues 187-220 contain a positive element essential for intermolecular association in cells. By contrast, deletion of residues 168-186 inactivated a proposed negative element, required to limit or control association. Association of GFP-emerin with nuclear BAF in cells required the LEM domain (residues 1-47) and the positive element. Emerin peptide arrays revealed direct binding of residues 170-220 to residues 206-225 (the proposed positive element), residues 147-174 (particularly P(153)MYGRDSAYQSITHYRP(169)) and the LEM domain. Emerin residues 1-132 and 159-220 were each sufficient to bind lamin A or B1 tails in vitro, identifying two independent regions of molecular contact with lamins. These results, and predicted emerin intrinsic disorder, support the hypothesis that there are multiple 'backbone' and LEM-domain configurations in a proposed intermolecular emerin network at the nuclear envelope.