UCL Throwing Injuries in Nonprofessional Baseball Players: A 14-Year Retrospective Study.

BACKGROUND: This study evaluated treatment modality (surgical vs nonoperative) of medial ulnar collateral ligament (UCL) injuries in nonprofessional throwing baseball athletes by comparing type, severity, and location of UCL injury. HYPOTHESIS: Baseball players with closed medial epicondyle physes and concomitant throwing-related UCL injury will be more likely to undergo surgical intervention than players with open medial epicondyle physes. STUDY DESIGN: Retrospective. LEVEL OF EVIDENCE: Level 5. METHODS: A total of 119 baseball players with a mean age of 16.9 ± 2.5 years (range, 11-25 years) were included in the study. Datapoints included sex, age at time of injury, severity, and location of UCL injury, growth plate status, operative versus conservative management, and concomitant flexor forearm injury. RESULTS: A total of 75 players were treated conservatively; 43 underwent UCL reconstruction (UCL-R), and 1 had an unknown treatment outcome. No significant difference was found for age related to treatment type, UCL-R (17.2 ± 2.2) versus conservative treatment (16.8 ± 2.6). Athletes with closed medial epicondylar growth plates were more likely to undergo UCL-R than athletes with open medial epicondylar growth plates (P = 0.02). There were no significant differences between UCL injury location (42 distal, 37 proximal, 18 combined tear locations, 11 complete tears, and 11 intact UCLs with inflammation) by treatment type (P = 0.09). There was a significant difference for UCL severity (11 complete tears, 96 partial tears) by treatment type (P = 0.03). CONCLUSION: Nonprofessional athletes with closed medial epicondylar growth plates and throwing-related UCL injuries were more likely to be treated surgically. Baseball athletes with partial tears, if skeletally immature, require further long-term evaluation. CLINICAL RELEVANCE: Continued knowledge gains in this area of throwing medicine will further improve our treatment algorithms in nonprofessional baseball players.

Neutrophils: Novel Contributors to Estrogen-Dependent Intracranial Aneurysm Rupture Via Neutrophil Extracellular Traps.

Background Intracranial aneurysms (IAs) are more prevalent in women than men, and aneurysmal subarachnoid hemorrhage disproportionately affects postmenopausal women. These sex differences suggest estrogen protects against IA progression that can lead to rupture, but the underlying mechanisms are not fully understood. Although studies have demonstrated estrogen regulates inflammatory processes that contribute to IA pathogenesis, the role of neutrophils remains to be characterized. Using a murine model, we tested our hypothesis that neutrophils contribute to IA pathophysiology in an estrogen-dependent manner. Methods and Results We compared neutrophil infiltration in C57BL/6 female mice that develop IAs to those with a normal circle of Willis. Next, we investigated the estrogen-dependent role of neutrophils in IA formation, rupture, and symptom-free survival using a neutrophil depletion antibody. Finally, we studied the role of neutrophil extracellular trap formation (NETosis) as an underlying mechanism of aneurysm progression. Mice that developed aneurysms had increased neutrophil infiltration compared with those with a normal circle of Willis. In estrogen-deficient female mice, both neutrophil depletion and NETosis inhibition decreased aneurysm rupture. In estrogen-deficient female mice treated with estrogen rescue and estrogen-intact female mice, neither neutrophil depletion nor NETosis inhibition affected IA formation, rupture, or symptom-free survival. Conclusions Neutrophils contribute to aneurysm rupture in an estrogen-dependent manner. NETosis appears to be an underlying mechanism for neutrophil-mediated IA rupture in estrogen deficiency. Targeting NETosis may lead to the development of novel therapeutics to protect against IA rupture in the setting of estrogen deficiency.

Theory for High-Throughput Genetic Interaction Screening.

Systematic, genome-scale genetic screens have been instrumental for elucidating genotype-phenotype relationships, but approaches for probing genetic interactions have been limited to at most ∼100 pre-selected gene combinations in mammalian cells. Here, we introduce a theory for high-throughput genetic interaction screens. The theory extends our recently developed Multiplexing using Spectral Imaging and Combinatorics (MuSIC) approach to propose ∼105 spectrally unique, genetically encoded MuSIC barcodes from 18 currently available fluorescent proteins. Simulation studies based on constraints imposed by spectral flow cytometry equipment suggest that genetic interaction screens at the human genome-scale may be possible if MuSIC barcodes can be paired to guide RNAs. While experimental testing of this theory awaits, it offers transformative potential for genetic perturbation technology and knowledge of genetic function. More broadly, the availability of a genome-scale spectral barcode library for non-destructive identification of single cells could find more widespread applications such as traditional genetic screening and high-dimensional lineage tracing.

Clopidogrel Is Associated with Reduced Likelihood of Aneurysmal Subarachnoid Hemorrhage: a Multi-Center Matched Retrospective Analysis.

Maladaptive inflammation underlies the formation and rupture of human intracranial aneurysms. There is a growing body of evidence that anti-inflammatory pharmaceuticals may beneficially modulate this process. Clopidogrel (Plavix) is a commonly used irreversible P2Y12 receptor antagonist with anti-inflammatory activity. In this paper, we investigate whether clopidogrel is associated with the likelihood of aneurysm rupture in a multi-institutional propensity-matched cohort analysis. Patients presenting for endovascular treatment of their unruptured intracranial aneurysms and those presenting with aneurysm rupture between 2015 and 2019 were prospectively identified at two quaternary referral centers. Patient demographics, comorbidities, and medication usage at the time of presentation were collected. Patients taking clopidogrel or not taking clopidogrel were matched in a 1:1 fashion with respect to location, age, smoking status, aneurysm size, aspirin usage, and hypertension. A total of 1048 patients with electively treated aneurysms or subarachnoid hemorrhages were prospectively identified. Nine hundred twenty-one patients were confirmed to harbor aneurysms during catheter-based diagnostic angiography. A total of 172/921 (19%) patients were actively taking clopidogrel at the time of presentation. Three hundred thirty-two patients were matched in a 1:1 fashion. A smaller proportion of patients taking clopidogrel at presentation had ruptured aneurysms than those who were not taking clopidogrel (6.6% vs 23.5%, p < .0001). Estimated treatment effect analysis demonstrated that clopidogrel usage decreased aneurysm rupture risk by 15%. We present, to the best of our knowledge, the first large-scale multi-institutional analysis suggesting clopidogrel use is protective against intracranial aneurysm rupture. It is our hope that these data will guide future investigation, revealing the pathophysiologic underpinning of this association.

Cost Comparison: Evaluating Transfemoral and Transradial Access for Diagnostic Cerebral Angiography.

BACKGROUND: Modern medicine necessitates the delivery of increasingly complex health care while minimizing cost. Transradial access (TRA) for neuroendovascular procedures is becoming more common as accumulating data demonstrate fewer complications, improved patient satisfaction, and high rates of treatment success compared with the transfemoral access (TFA) approach; however, disparities in cost between these approaches remain unclear. We compared supply and equipment costs between TRA and TFA for diagnostic cerebral angiography and evaluate the specific items that account for these differences. METHODS: We reviewed all adult patients who underwent diagnostic cerebral angiography from July 1, 2019 to December 31, 2019. Data related to patient demographics, vascular access site, catheters used, cost of catheters, arterial access sheath use, cost of sheaths, closure devices used, and cost of closure devices were collected. RESULTS: The transradial approach resulted in higher price of radial access sheath; however, the overall cost of closure devices was much lower in TRA group than in the TFA cohort. There was no significant difference in the cost of catheters. Overall, the total supply costs for TRA cerebral angiography were significantly lower than those of TFA cerebral angiography. The relative materials cost difference of using TRA was 20.9%. CONCLUSION: This study is the first itemized materials cost analysis of TRA versus TFA cerebral angiography. TRA necessitates the use of a more expensive access sheath device; however, this cost is offset by the increased cost of devices used for femoral arteriotomy closure. Overall, the supply and equipment costs were significantly lower for TRA than TFA.

Decrease in cortical vein opacification predicts outcome after aneurysmal subarachnoid hemorrhage.

BACKGROUND: The pathophysiology of brain injury after aneurysmal subarachnoid hemorrhage (aSAH) remains incompletely understood. Cerebral venous flow patterns may be a marker of hemodynamic disruptions after aneurysm rupture. We hypothesized that a decrease in venous filling after aSAH would predict cerebral ischemia and poor outcome. OBJECTIVE: To examine the hypotheses that venous filling as measured by the cortical venous opacification score (COVES) would (1) decrease after aSAH and (2) that decreased COVES would be associated with higher rates of hydrocephalus, vasospasm, delayed cerebral iscemia (DCI), and poor functional evaluation at outcome. METHODS: In this retrospective observational cohort study of consecutive patients with aSAH admitted to our tertiary care center between 2016 and 2018, we measured the COVES at admission and at subsequent CT angiography (CTA). We collected clinical variables and compared hydrocephalus, vasospasm, DCI, and outcome at discharge in patients with decrease in COVES with patients with stable COVES. RESULTS: A total of 22 patients were included in the analysis. COVES decreased from first CTA to second CTA in 11 (50%) patients, by an average of 1.1 points (P=0.01). Patients whose COVES decreased between admission and follow-up imaging were more likely to develop DCI (58% vs 0%, P=0.03) and have a poor outcome at discharge (100% vs 55%, P=0.03) than patients who had no change in COVES. aSAH severity was not associated with initial COVES, and there was no association between change in COVES and development of hydrocephalus or vasospasm. CONCLUSIONS: Development of decreased venous filling on CTA is associated with poor outcome after aSAH. This association suggests that venous hemodynamics may be reflective of, or contribute to, the pathophysiological mechanisms of brain injury after aSAH. Larger prospective studies are necessary to substantiate our findings.

Combination release of chemokines from coated coils to target aneurysm healing.

BACKGROUND: Monocyte 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. OBJECTIVE: To create coils coated with both MCP-1 and OPN to target aneurysm healing. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: This 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.

Traumatic Brain Injury and Secondary Neurodegenerative Disease.

Traumatic brain injury (TBI) is a devastating event with severe long-term complications. TBI and its sequelae are one of the leading causes of death and disability in those under 50 years old. The full extent of secondary brain injury is still being intensely investigated; however, it is now clear that neurotrauma can incite chronic neurodegenerative processes. Chronic traumatic encephalopathy, Parkinson's disease, and many other neurodegenerative syndromes have all been associated with a history of traumatic brain injury. The complex nature of these pathologies can make clinical assessment, diagnosis, and treatment challenging. The goal of this review is to provide a concise appraisal of the literature with focus on emerging strategies to improve clinical outcomes. First, we review the pathways involved in the pathogenesis of neurotrauma-related neurodegeneration and discuss the clinical implications of this rapidly evolving field. Next, because clinical evaluation and neuroimaging are essential to the diagnosis and management of neurodegenerative diseases, we analyze the clinical investigations that are transforming these areas of research. Finally, we briefly review some of the preclinical therapies that have shown the most promise in improving outcomes after neurotrauma.

Headache persisting after aneurysmal subarachnoid hemorrhage: A narrative review of pathophysiology and therapeutic strategies.

OBJECTIVE: This narrative review of the literature concerns persistent headache attributed to past non-traumatic subarachnoid hemorrhage (SAH), based off demographic and clinical features, what are pathophysiologic mechanisms by which these headaches occur, which medical and interventional treatments have the most evidence for pain alleviation, and what pre-clinical evidence is there for emerging treatments for these patients. BACKGROUND: Following initial stabilization and treatment of spontaneous SAH, most commonly due to aneurysmal rupture, headache in the immediate inpatient setting and persisting after discharge are an important cause of morbidity. These headaches often receive heterogenous treatment of uncertain efficacy, and the risk factors and pathophysiology of their development has received little study. METHODS: A narrative review of current literature discussing post-SAH headache was conducted using a literature search in PubMed with search term combinations including "post subarachnoid hemorrhage pain", "subarachnoid hemorrhage headache", and "post subarachnoid hemorrhage headache". Clinical studies mentioning headache after SAH and/or treatment in the abstract/title were included through March, 2022. RESULTS AND CONCLUSION: Post-SAH headaches are shown to decrease quality of life, have a multi-modal pathophysiology in their occurrence, and only a select few medications (reviewed herein) have been demonstrated to have efficacy in alleviation of these headaches, while also harboring possible risks including vasospasm and re-bleeding. An effective treatment paradigm of these headaches will include trials of evidence-based therapeutics, rapid reduction of opioid medications if not effective, and consideration of multi-modal pain control strategies including nerve blocks.

Investigation and modulation of interleukin-6 following subarachnoid hemorrhage: targeting inflammatory activation for cerebral vasospasm.

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.

Mesowestern Blot: Simultaneous Analysis of Hundreds of Submicroliter Lysates.

Western blotting is a widely used technique for molecular-weight-resolved analysis of proteins and their posttranslational modifications, but high-throughput implementations of the standard slab gel arrangement are scarce. The previously developed Microwestern requires a piezoelectric pipetting instrument, which is not available for many labs. Here, we report the Mesowestern blot, which uses a 3D-printable gel casting mold to enable high-throughput Western blotting without piezoelectric pipetting and is compatible with the standard sample preparation and small (∼1 µL) sample sizes. The main tradeoffs are reduced molecular weight resolution and higher sample-to-sample CV, making it suitable for qualitative screening applications. The casted polyacrylamide gel contains 336, ∼0.5 µL micropipette-loadable sample wells arranged within a standard microplate footprint. Polyacrylamide % can be altered to change molecular weight resolution profiles. Proof-of-concept experiments using both infrared-fluorescent molecular weight protein ladder and cell lysate (RIPA buffer) demonstrate that the protein loaded in Mesowestern gels is amenable to the standard Western blotting steps. The main difference between Mesowestern and traditional Western is that semidry horizontal instead of immersed vertical gel electrophoresis is used. The linear range of detection is at least 32-fold, and at least ∼500 attomols of ß-actin can be detected (∼29 ng of total protein from mammalian cell lysates: ∼100-300 cells). Because the gel mold is 3D-printable, users with access to additive manufacturing cores have significant design freedom for custom layouts. We expect that the technique could be easily adopted by any typical cell and molecular biology laboratory already performing Western blots.

A scalable, open-source implementation of a large-scale mechanistic model for single cell proliferation and death signaling.

Mechanistic models of how single cells respond to different perturbations can help integrate disparate big data sets or predict response to varied drug combinations. However, the construction and simulation of such models have proved challenging. Here, we developed a python-based model creation and simulation pipeline that converts a few structured text files into an SBML standard and is high-performance- and cloud-computing ready. We applied this pipeline to our large-scale, mechanistic pan-cancer signaling model (named SPARCED) and demonstrate it by adding an IFNγ pathway submodel. We then investigated whether a putative crosstalk mechanism could be consistent with experimental observations from the LINCS MCF10A Data Cube that IFNγ acts as an anti-proliferative factor. The analyses suggested this observation can be explained by IFNγ-induced SOCS1 sequestering activated EGF receptors. This work forms a foundational recipe for increased mechanistic model-based data integration on a single-cell level, an important building block for clinically-predictive mechanistic models.

Sensorineural hearing loss due to delayed cerebral ischemia in bilateral auditory cortices following aneurysmal subarachnoid hemorrhage: illustrative case.

BACKGROUND: Recognizing rare signs of delayed cerebral ischemia (DCI) is crucial to caring for patients with subarachnoid hemorrhage. The authors presented a case of central hearing loss that occurred during the clinical course of a patient treated for aneurysmal subarachnoid hemorrhage. OBSERVATIONS: The patient had a ruptured right posterior communicating artery aneurysm successfully treated with coil embolization but later developed severe vasospasm and DCI. She developed bilateral hearing loss, and imaging revealed DCI to the left temporal lobe and the right auditory cortex. Computed tomography angiography and digital subtraction angiography demonstrated severe vasospasm of bilateral internal carotid arteries, bilateral middle cerebral arteries, and bilateral anterior cerebral arteries. One month after hospitalization, the patient had recovered fully neurologically intact except for persistent hearing loss. LESSONS: This case serves to teach important neuroanatomical features and discuss the unique pathophysiology of DCI affecting the auditory cortex.

Delayed cerebral ischemia: A look at the role of endothelial dysfunction, emerging endovascular management, and glymphatic clearance.

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.

Spinal cord injury and neurogenic lower urinary tract dysfunction: what do we know and where are we going?

One of the well reported but difficult to manage symptoms of spinal cord injury (SCI) is neurogenic lower urinary tract dysfunction (NLUTD). The type of NLUTD is variable based on location and extent of injury. SCI affects more males and NLUTD is especially debilitating for men with incomplete injury. This review summarizes the anatomical basis of NLUTD in SCI and discusses current diagnostic and management strategies that are being utilized clinically. The last two sections address new innovations and emerging discoveries with the goal of increasing scientific interest in improving treatment options for people with SCI. Areas warranting further investigation are pinpointed to address current gaps in knowledge and/or appropriate technology.

Behavioral Pediatrics: A Team-Based Interprofessional Approach.

An interprofessional approach to pediatric behavioral care is increasingly important in the care of pediatric patients, who present to healthcare settings with a wide variety of concerns ranging from potty training to depression. Previously, much of the care of these patients have focused on a narrow approach to the problem, based on the expertise of the professional providing care. Faculty from three disciplines: Social Work, Psychology, and Medicine collaborated to design a course for students from these three disciplines to collaborate in attaining three goals: (1) reinforce the importance of multidisciplinary collaboration, (2) share clinical techniques and skills in a simulated interprofessional setting, and (3) practice collaboration within interprofessional teams. We detail the course goals and design and topics covered and discuss implementation of this course. Suggested module content and pedagogical design are discussed, and case examples are detailed with the goal of encouraging the adoption of similar courses.

Gastrointestinal Microbiome and Neurologic Injury.

Communication between the enteric nervous system (ENS) of the gastrointestinal (GI) tract and the central nervous system (CNS) is vital for maintaining systemic homeostasis. Intrinsic and extrinsic neurological inputs of the gut regulate blood flow, peristalsis, hormone release, and immunological function. The health of the gut microbiome plays a vital role in regulating the overall function and well-being of the individual. Microbes release short-chain fatty acids (SCFAs) that regulate G-protein-coupled receptors to mediate hormone release, neurotransmitter release (i.e., serotonin, dopamine, noradrenaline, γ-aminobutyric acid (GABA), acetylcholine, and histamine), and regulate inflammation and mood. Further gaseous factors (i.e., nitric oxide) are important in regulating inflammation and have a response in injury. Neurologic injuries such as ischemic stroke, spinal cord injury, traumatic brain injury, and hemorrhagic cerebrovascular lesions can all lead to gut dysbiosis. Additionally, unfavorable alterations in the composition of the microbiota may be associated with increased risk for these neurologic injuries due to increased proinflammatory molecules and clotting factors. Interventions such as probiotics, fecal microbiota transplantation, and oral SCFAs have been shown to stabilize and improve the composition of the microbiome. However, the effect this has on neurologic injury prevention and recovery has not been studied extensively. The purpose of this review is to elaborate on the complex relationship between the nervous system and the microbiome and to report how neurologic injury modulates the status of the microbiome. Finally, we will propose various interventions that may be beneficial in the recovery from neurologic injury.

Ticagrelor resistance: a case series and algorithm for management of non-responders.

The placement of cervical and intracranial stents requires the administration of antiplatelet drugs to prevent thromboembolic complications. Ticagrelor has emerged as the most widely used alternative in clopidogrel non-responders owing to its potent antiplatelet effects. Because ticagrelor does not require hepatic activation, many neurointerventionalists choose to forgo laboratory testing of platelet inhibition. In rare instances, patients may not achieve adequate platelet inhibition following ticagrelor administration. In this paper we review the mechanism of action of ticagrelor and its use in cerebrovascular procedures. We present two cases of ticagrelor non-responsiveness from two high-volume cerebrovascular centers, discuss their management, and propose an algorithm for managing ticagrelor non-responsiveness.

Understanding the genetics of intracranial aneurysms: A primer.

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.

Interleukin-6: Important Mediator of Vasospasm Following Subarachnoid Hemorrhage.

The correlation of neuroinflammation with the development of cerebral vasospasm following subarachnoid hemorrhage has been well documented in the literature; both clinical and preclinical. The exact mechanisms by which this process occurs, however, are poorly elucidated. Recent evidence indicates that interleukin-6 is not only an important prognostic biomarker for subarachnoid hemorrhage and subsequent vasospasm development but also an integral component in the progression of injury following initial insult. In this review, we briefly highlight other pathways under investigation and focus heavily on what has been discovered regarding the role of interleukin 6 and cerebral vasospasm following subarachnoid hemorrhage. A proposed mechanistic pathway is highlighted in written and graphical format. A discussion regarding the human correlative findings and initial pre-clinical mechanistic studies is addressed. Finally, in the future investigation section, innovative developments and a clear description of areas warranting further scientific inquiry are emphasized. This review will catalyze continued discovery in this area of emerging significance and aid in the quest for effective vasospasm treatment where limited clinical therapeutics currently exist.