Intracerebral hemorrhage (ICH) accounts for 10 to 15% of all strokes, but results in a disproportionately high morbidity and mortality. Although chronic hypertension accounts for the majority of ICH, other common causes include cerebral amyloid angiopathy, sympathomimetic drugs of abuse, and underlying cerebral vascular anomalies. Validated baseline predictors of clinical outcome after ICH include the Glasgow Coma Scale score, hematoma volume, presence and amount of intraventricular hemorrhage, infratentorial ICH location, and advanced age. Although no treatment of proven benefit currently exists for ICH, several recent large clinical trials have demonstrated the feasibility of surgical and medical treatments for ICH. Clinical research into ICH mechanisms of injury has demonstrated that hematoma expansion is common, even in patients without coagulopathy. Basic research has suggested that perihematoma injury is more likely related to toxicity of blood and iron in the brain ("neurohemoinflammation") rather than primary ischemic injury. Current guidelines for ICH treatment emphasize blood pressure management, urgent and rapid correction of coagulopathy, and surgery for cerebellar ICH. Ongoing clinical trials are investigating surgical evacuation of lobar hemorrhage, minimally invasive surgical hematoma evacuation, and aggressive blood pressure lowering.

Anoikis, a cell death mechanism triggered upon cell-matrix detachment, is regarded as a physiological suppressor of metastasis that can be regulated by a diverse array of signals. The protein encoded by GDF2 is BMP9 and is a member of the bone morphogenetic protein family and the transforming growth factor (TGF) β superfamily with emerging yet controversial roles in carcinogenesis. In an attempt to identify the function of growth and differentiation factor 2 (GDF2) in epithelial systems, we examined the signaling machinery that is involved and cell fate decisions in response to GDF2 in ovarian and breast epithelia. We find that GDF2 can robustly activate the SMAD1/5 signaling axis by increasing complex formation between the type I receptor serine threonine kinases activin receptor-like kinase (ALK) 3 and ALK6 and the type II receptor serine threonine kinase BMPRII. This activation is independent of cross talk with the SMAD2-transforming growth factor β pathway. By activating SMAD1/5, epithelial cells regulate anchorage-independent growth by increasing anoikis sensitivity that is dependent on GDF2’s ability to sustain the activation of SMAD1/5 via ALK3 and ALK6. Consistent with a role for GDF2 in promoting anoikis susceptibility, the analysis of cell lines and patient data suggests epigenetic silencing of GDF2 in cancer cell lines and increased promoter methylation in patients. These findings collectively indicate an antimetastatic role for GDF2 in ovarian and breast cancer. The work also implicates loss of GDF2 via promoter methylation-mediated downregulation in promotion of carcinogenesis with significant relevance for the use of epigenetic drugs currently in clinical trials.

BackgroundThe objective of this study was to determine who gets post-concussion syndrome (PCS) after mild traumatic brain injury or head injury.MethodsPatients presented within an hour of mild traumatic brain injury (mTBI). Written informed consent was obtained from all patients, who then provided detailed answers to surveys at the time of injury as well as at 1 week and 1 month follow-up. Statistical analyses were performed using JMP 11.0 for the Macintosh.ResultsThe most commonly reported symptoms of PCS at first follow-up were headache (27%), trouble falling asleep (18%), fatigue (17%), difficulty remembering (16%), and dizziness (16%). Furthermore, only 61% of the cohort was driving at 1 week follow-up, compared to 100% prior to the injury.Linear regression analysis revealed the consumption of alcohol prior to head injury, the mechanism of head injury being a result of motor vehicle collision (MVC) or fall, and the presence of a post-injury headache to be significantly associated with developing PCS at 1 week follow-up, while the occurrence of a seizure post-injury or having an alteration in consciousness post-injury was significantly associated with developing PCS at 1 month follow-up. On multivariate regression analysis, the presence of a headache post-injury was the most robust predictor, retaining statistical significance even after controlling for age, gender, and presence of loss of consciousness (LOC), alteration of consciousness (AOC), post-traumatic amnesia (PTA), seizure, or vomiting.ConclusionsThe results of this prospective study suggest that headache right after the head injury, an alteration of consciousness after the head injury, and alcohol consumption prior to the head injury are significant predictors of developing PCS, which occurs with equal frequency in men and women. Early identification of those who are at risk of developing PCS would diminish the burden of the injury and could potentially reduce the number of missed work and school days.

Objective. To study the impact of helmet use on outcomes after recreational vehicle accidents. Methods. This is an observational cohort of adult and pediatric patients who sustained a TBI while riding a recreational vehicle. Recreational vehicles included bicycles, motorcycles, and all-terrain vehicles (ATVs), as well as a category for other vehicles such as skateboards and scooters. Results. Lack of helmet use was significantly associated with having a more severe traumatic brain injury and being admitted to the hospital. Similarly, 25% of those who did wearing a helmet were admitted to the ICU versus 36% of those who did not (P = 0.0489). The hospital length of stay was significantly greater for patients who did not use helmets. Conclusion. Lack of helmet use is significantly correlated with abnormal neuroimaging and admission to the hospital and ICU; these data support a call for action to implement more widespread injury prevention and helmet safety education and advocacy.

BackgroundTo characterize the patterns of presentation of adults with head injury to the Emergency Department.MethodsThis is a cohort study that sought to collect injury and outcome variables with the goal of characterizing the very early natural history of traumatic brain injury in adults. This IRB-approved project was conducted in collaboration with our Institution’s Center for Translational Science Institute. Data were entered in REDCap, a secure database. Statistical analyses were performed using JMP 10.0 pro for Windows.ResultsThe cohort consisted of 2,394 adults, with 40% being women and 79% Caucasian. The most common mechanism was fall (47%) followed by motor vehicle collision (MVC) (36%). Patients sustaining an MVC were significantly younger than those whose head injury was secondary to a fall (P < 0.0001). Ninety-one percent had CT imaging; hemorrhage was significantly more likely with worse severity as measured by the Glasgow Coma Score (chi-square, P < 0.0001). Forty-four percent were admitted to the hospital, with half requiring ICU admission. In-hospital death was observed in 5.4%, while neurosurgical intervention was required in 8%. For all outcomes, worse TBI severity per GCS was significantly associated with worse outcomes (logistic regression, P < 0.0001, adjusted for age).ConclusionThese cohort data highlight the burden of TBI in the Emergency Department and provide important demographic trends for further research.

IntroductionAlthough there are approximately 1.1 million case presentations of mild traumatic brain injury (mTBI) in the emergency department (ED) each year, little data is available to clinicians to identify patients who are at risk for poor outcomes, including 72-hour ED return after discharge. An understanding of patients at risk for ED return visits during the hyperacute phase following head injury would allow ED providers to develop clinical interventions that reduce its occurrence and improve outcomes.MethodsThis institutional review board-approved consecutive cohort study collected injury and outcome variables on adults with the purpose of identifying positive predictors for 72-hour ED return visits in mTBI patients.ResultsOf 2,787 mTBI patients, 145 (5%) returned unexpectedly to the ED within 72 hours of hospital discharge. Positive predictors for ED return visits included being male (p=0.0298), being black (p=0.0456), having a lower prehospital Glasgow Coma Score (p=0.0335), suffering the injury due to a motor vehicle collision (p=0.0065), or having a bleed on head computed tomography (CT) (p=0.0334). ED return visits were not significantly associated with age, fracture on head CT, or symptomology following head trauma. Patients with return visits most commonly reported post-concussion syndrome (43.1%), pain (18.7%), and recall for further clinical evaluation (14.6%) as the reason for return. Of the 124 patients who returned to the ED within 72 hours, one out of five were admitted to the hospital for further care, with five requiring intensive care unit stays and four undergoing neurosurgery.ConclusionApproximately 5% of adult patients who present to the ED for mTBI will return within 72 hours of discharge for further care. Clinicians should identify at-risk individuals during their initial visits and attempt to provide anticipatory guidance when possible.

Coronary computed tomographic angiography (CCTA) has emerged as a fast and robust tool with high sensitivity and excellent negative predictive value for the evaluation of coronary artery disease, but is unable to estimate the hemodynamic significance of a lesion. Advances in computed tomography (CT)-based diagnostic techniques, for example, CT-derived fractional flow reserve and CT perfusion, have helped transform CCTA primarily from an anatomic assessment tool to a technique that is able to provide both anatomic and functional information for a stenosis. With the results of the ISCHEMIA trial published in 2019, these advanced techniques can elevate CCTA into the role of a better gatekeeper for decision-making and can help guide referral for invasive management. In this article, we review the principles, limitations, diagnostic performance, and clinical utility of these 2 functional CT-based techniques in the evaluation of vessel-specific and lesion-specific ischemia.

Previous reports suggest that Alzheimer's disease is protected by cholinesterase inhibitors. We synthesized some isoalloxazine derivatives and evaluated them using in vitro cholinesterase inhibition assay. Two of the compounds (7m and 7q) were figured out as potent cholinesterase inhibitors. They further showed anti-Aβ aggregatory activity in the in vitro assay. The current study deals with the evaluation of neuroprotective potentials of the potent compounds (7m and 7q) using different in vitro and in vivo experiments. The compounds were first assessed for their tendency to cross blood-brain barrier using in vitro permeation assay. They were evaluated using scopolamine-induced amnesic mice model. Additionally, ROS scavenging and anti-apoptotic properties of 7m and 7q were established against Aβ1-42-induced toxicity in rat hippocampal neuronal cells. 7m and 7q were also evaluated using Aβ1-42-induced Alzheimer's rat model. Lastly, their involvement in Wnt/β-catenin pathway was also demonstrated. The results indicated good CNS penetration for 7m and 7q. The neuroprotective effects of 7m and 7q were evidenced by improved cognitive ability in both scopolamine and Aβ1-42-induced Alzheimer's-like condition in rodents. The in vivo results also confirmed their anti-cholinesterase and anti-oxidant potential. Immunoblot results showed that treatment with 7m and 7q decreased Aβ1-42, p-tau, cleaved caspase-3, and cleaved PARP levels in Aβ1-42-induced Alzheimer's rat brain. Additionally, immunoblot results demonstrated that 7m and 7q activated the Wnt/β-catenin pathway as evidenced by increased p-GSK-3, β-catenin, and neuroD1 levels in Aβ1-42-induced Alzheimer's rat brain. These findings have shown that isoalloxazine derivatives (7m and 7q) could be the potential leads for developing effective drugs for the treatment of AD.