Explore the vast range of titles available.

Background Cerebral vasospasm (CV) can contribute to significant morbidity in subarachnoid hemorrhage (SAH) patients. A key unknown is how CV induction is triggered following SAH. Methods Human aneurysmal blood and cerebral spinal fluid were collected for evaluation. To confirm mechanism, c57/bl6 wild type and c57/bl6 IL-6 female knockout (KO) mice were utilized with groups: saline injected, SAH, SAH + IL-6 blockade, SAH IL-6 KO, SAH IL-6 KO + IL-6 administration, SAH + p-STAT3 inhibition. Dual-labeled microglia/myeloid mice were used to show myeloid diapedesis. For SAH, 50 μm blood was collected from tail puncture and administered into basal cisterns. IL-6 blockade was given at various time points. Various markers of neuroinflammation were measured with western blot and immunohistochemistry. Cerebral blood flow was also measured. Vasospasm was measured via cardiac injection of India ink/gelatin. Turning test and Garcia’s modified SAH score were utilized. P  < 0.05 was considered significant. Results IL-6 expression peaked 3 days following SAH ( p  < 0.05). Human IL-6 was increased in aneurysmal blood ( p  < 0.05) and in cerebral spinal fluid ( p  < 0.01). Receptor upregulation was periventricular and perivascular. Microglia activation following SAH resulted in increased caveolin 3 and myeloid diapedesis. A significant increase in BBB markers endothelin 1 and occludin was noted following SAH, but reduced with IL-6 blockade ( p  < 0.01). CV occurred 5 days post-SAH, but was absent in IL-6 KO mice and mitigated with IL-6 blockade ( p  < 0.05). IL-6 blockade, and IL-6 KO mitigated effects of SAH on cerebral blood flow ( p  < 0.05). SAH mice had impaired performance on turn test and poor modified Garcia scores compared to saline and IL-6 blockade. A distinct microglia phenotype was noted day 5 in the SAH group (overlap coefficients r  = 0.96 and r  = 0.94) for Arg1 and iNOS, which was altered by IL-6 blockade. Day 7, a significant increase in toll-like receptor 4 and Stat3 was noted. This was mitigated by IL-6 blockade and IL-6 KO, which also reduced Caspase 3 ( p  < 0.05). To confirm the mechanism, we developed a p-STAT3 inhibitor that targets the IL-6 pathway and this reduced NFΚB, TLR4, and nitrotyrosine ( p  < 0.001). Ventricular dilation and increased Tunel positivity was noted day 9, but resolved by IL-6 blockade ( p  < 0.05). Conclusion Correlation between IL-6 and CV has been well documented. We show that a mechanistic connection exists via the p-STAT3 pathway, and IL-6 blockade provides benefit in reducing CV and its consequences mediated by myeloid cell origin diapedesis. Graphical abstract

Abstract BACKGROUND Estrogen deficiency is associated with cerebral aneurysm rupture, but the precise mechanism is unknown. OBJECTIVE To test the hypothesis that IL-6 is required for the increase in aneurysm rupture rate observed in estrogen-deficient mice. METHODS We analyzed IL-6 expression in human cerebral aneurysms. We induced cerebral aneurysms in estrogen-deficient female C57BL/6 mice that had undergone 4-vinylcyclohexene diepoxide (VCD) treatment or bilateral ovariectomy (OVE). Mice were blindly randomized to selective IL-6 inhibition (IL-6 receptor [IL-6R] neutralizing antibody, n = 25) or control (isotype-matched IgG, n = 28). Murine cerebral arteries at the circle of Willis were assessed for aneurysm rupture and macrophage infiltration. RESULTS IL-6 is expressed in human cerebral aneurysms, but not in control arteries. Serum IL-6 is elevated in ovariectomized female mice compared to sham control (14.3 ± 1.7 pg/mL vs 7.4 ± 1.5 pg/mL, P = .008). Selective IL-6R inhibition suppressed cerebral aneurysm rupture in estrogen-deficient mice compared with control (VCD: 31.6% vs 70.0%, P = .026; OVE: 28.6% vs 65.2%, P = .019). IL-6R inhibition had no effect on formation or rupture rate in wild-type mice. IL-6R neutralizing antibody significantly reduced macrophage infiltration at the circle of Willis (1.9 ± 0.2 vs 5.7 ± 0.6 cells/2500 μm2; n = 8 vs n = 15; P < .001). CONCLUSION IL-6 is increased in the serum of estrogen-deficient mice and appears to play a role in promoting murine estrogen deficiency-associated cerebral aneurysm rupture via enhanced macrophage infiltration at the circle of Willis. Inhibition of IL-6 signaling via IL-6 receptor neutralizing antibody inhibits aneurysm rupture in estrogen-deficient mice. IL-6 receptor inhibition had no effect on aneurysm formation or rupture in wild-type animals.

Primary care use helps reduce utilization of more expensive modes of care, such as the emergency department (ED). Although most studies have investigated this association among patients with insurance, few have done so for patients without insurance. We used data from a free clinic network to assess the association between free clinic use and intent to use the ED. Data were collected from a free clinic network's electronic health records on adult patients from January 2015 to February 2020. Our outcome was whether patients reported themselves as ‘very likely’ to visit the ED if the free clinics were unavailable. The independent variable was frequency of free clinic use. Using a multivariable logistic regression model, we controlled for other factors, such as patient demographic factors, social determinants of health, health status, and year effect. Our sample included 5008 visits. When controlling for other factors, higher odds of expressing ED interest were observed for patients who are non-Hispanic Black, older, not married, lived with others, had lower education, were homeless, had personal transportation, lived in rural areas, and had a higher comorbidity burden. In sensitivity analyses, higher odds were observed for dental, gastrointestinal, genitourinary, musculoskeletal, or respiratory conditions. In the free clinic space, several patient demographic, social determinants of health and medical conditions were independently associated with greater odds of reporting intent on visiting the ED. Additional interventions that improve access and use of free clinics (e.g., dental) may keep patients without insurance from the ED.

Pediatric traumatic brain injury (TBI) and autism spectrum disorder (ASD) are two serious conditions that affect youth. Recent data, both preclinical and clinical, show that pediatric TBI and ASD share not only similar symptoms but also some of the same biologic mechanisms that cause these symptoms. Prominent symptoms for both disorders include gastrointestinal problems, learning difficulties, seizures, and sensory processing disruption. In this review, we highlight some of these shared mechanisms in order to discuss potential treatment options that might be applied for each condition. We discuss potential therapeutic and pharmacologic options as well as potential novel drug targets. Furthermore, we highlight advances in understanding of brain circuitry that is being propelled by improved imaging modalities. Going forward, advanced imaging will help in diagnosis and treatment planning strategies for pediatric patients. Lessons from each field can be applied to design better and more rigorous trials that can be used to improve guidelines for pediatric patients suffering from TBI or ASD.

In the article titled “Pediatric Traumatic Brain Injury and Autism: Elucidating Shared Mechanisms” [1], Dr. Rabia Qaiser was missing from the authors’ list. Dr. Qaiser supervised the project and reviewed the text and revised the reporting of the clinical management and tables. The corrected authors’ list is shown above.

Delayed cerebral ischemia (DCI) contributes to extensive morbidity and mortality for patients with aneurysmal subarachnoid hemorrhage (SAH). Recent contributions to the basic and translational investigation of DCI have shed light on emerging concepts that may aid in the development of novel therapeutics. A clear association between cerebral vasospasm (CV) and DCI exists, but it is also known that DCI can affect brain parenchyma remote from sites of vasospasm. In this review, we highlight the most recent contributions to the understanding of the underlying pathophysiology of DCI including the emerging role of the glymphatic system. Furthermore, we discuss treatments for DCI, including both pharmacologic therapies and endovascular treatment of vasospasm. There continues to be a disconnect between interventions and targeted treatment against pathophysiology. This review is intended to serve as a catalyst for further research and discovery that can aid in improved treatment options for DCI. •Vasospasm causes deleterious effects following subarachnoid hemorrhage.•Improving understanding of vasospasm mechanisms is critical.•The glymphatic system is emerging as a key regulator of the pathways.•Targeting vessel dilation with stent retrievers is good initial step.

INTRODUCTION While coiling is often safer than clipping for prophylactic management of intracranial aneurysms, recurrence is a significant concern. Aneurysm healing after coiling is not fully understood, but inflammation appears to play a key role. CXCL1, an inflammatory cytokine, is highly expressed in human aneurysms but its role in aneurysm healing is unknown. METHODS Carotid artery aneurysms were created in female and male C57BL/6 mice. CXCL1 expression was compared between aneurysms and sham-operated carotid arteries. In a separate cohort, aneurysms were coiled with poly(lactic-co-glycolic acid)(PLGA)-coated coils. Mice received intraperitoneal injections of either CXCL1 neutralizing antibody or IgG control for 7, 14, or 21 days post-coiling. Coiled aneurysms were assessed for aneurysm healing, neutrophil infiltration, macrophage polarization, and total macrophage burden. RESULTS CXCL1 is highly expressed in murine carotid artery aneurysms. CXCL1 blockade significantly increased aneurysm healing compared to IgG when administered for 14 days (females: 66.4% vs. 51.2%, P = .03; males: 69.8% vs. 47.0%, P = .004) and 21 days (females: 71.9% vs. 45.6%, P = .02; males: 67.8% vs. 53.8%, P = .02), but not when given for only 7 days (females: 48.1% vs. 49.4%, P = .92; males: 52.3% vs. 50.4%, P = 1.00). 14 days of CXCL1 blockade decreased neutrophil infiltration (females: 0.33 vs. 8.58 cells/high power field(hpf), P = .05; males: 0.00 vs. 4.42 cells/hpf, P = .04) and increased reparative M2 macrophages (females: 2.25 vs. 0.79 cells/hpf, P = .03; males: 2.00 vs. 0.27 cells/hpf, P = .02). CONCLUSION CXCL1 blockade for 14 or 21 days improved aneurysm healing in female and male mice. 14 days of CXCL1 blockade decreased neutrophil infiltration and increased M2 macrophage polarization. A systemic drug such as CXCL1 blockade could be given to patients after coiling to improve aneurysm healing and, consequently, permanent occlusion rates.

BackgroundMonocyte chemoattractant protein 1 (MCP-1) and osteopontin (OPN) have been identified separately as key mediators of the aneurysm healing process following coil embolization in the rodent model. The ability of protein coated coils to accelerate this process is currently unknown.ObjectiveTo create coils coated with both MCP-1 and OPN to target aneurysm healing.MethodsWe used a polymer (poly(glycolide-co-caprolactone)) (Rao pharmaceuticals) (CG910) to test whether coils could be dual coated with active proteins with sequential reliable release. Coils were coated with poly-DL-lactic glycolic acid (PLGA), CG910, and subsequently dipped with protein OPN (inner layer for delayed release) and MCP-1 (outer layer for initial release). Release assays were used to measure protein elution from coils over time. To test in vivo feasibility, coated coils were implanted into carotid aneurysms to determine the effect on aneurysm healing.ResultsThe in vitro protein release assay demonstrated a significant amount of OPN and MCP-1 release within 2 days. Using a 200 µg/µL solution of MCP-1 in phosphate-buffered saline, we showed that CG910 coated coils provide effective release of MCP over time. In the carotid aneurysm model, MCP-1 and OPN coated coils significantly increased tissue ingrowth (74% and 80%) compared with PLGA and CG910 coated coils alone (58% and 53%). To determine synergistic impact of dual coating, we measured ingrowth for MCP-1/OPN coils (63%) as well as overlap coefficients for NOX4 and NFκB with CD31.ConclusionsThis study demonstrates that MCP-1 and OPN coated coils are viable and may promote early aneurysm healing. Dual coated coils may have synergistic benefit given different location of protein interaction measured in vivo. Further work is warranted.

The genetics of intracranial aneurysms is complex. Much work has been done looking at the extracellular matrix surrounding cerebral vasculature as well as the role of matrix metalloproteinases. This comprehensive review summarizes what is known to date about the important genetic components that predispose to aneurysm formation and critically discusses the published findings. We discuss promising pre-clinical models of aneurysm formation and subarachnoid hemorrhage, and highlight avenues for future discovery, while considering limitations in the research to date. This review will further serve as a comprehensive reference guide to understand the genetic underpinnings for aneurysm pathophysiology and act as a primer for further investigation. •Extracellular matrix dysfunction contributes to aneurysm formation.•Matrix metalloproteinases weaken vessel walls.•Genetic polymorphisms contribute to familial aneurysm diseases.•Understanding aneurysm genetics is necessary for treatment.