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Medical and socioeconomic factors may impact decisions to change the goals of care for patients with intracerebral hemorrhage (ICH) to comfort measures only.We reviewed prospectively collected data on patients with ICH, including baseline patient demographics, Glasgow Coma Scale (GCS), National Institute of Health Stroke Scale (NIHSS), and ICH score. We conducted multivariable logistic regression analysis to identify predictors of change to comfort measures only status.Of 198 patients included in the analysis, 39 (19.7%) were made comfort measures only. Age, gender, insurance status, substance use, and medical comorbidities were similar between groups. Race was significantly different between the comfort measures only (black 15.4%, white 51.3%, other 33.3%) and noncomfort measures only groups (black 39.6%, white 45.9%, other 14.5%; P = .003). Patients changed to comfort measures only had higher mean income based on zip code ($59,264 versus $49,916; P = .021), higher median NIHSS (23 versus 16; P = .0001), higher ICH score (2.7 versus 1.5; P.0001), lower median GCS (7 versus 13; P.0001). Following multivariable analysis, factors associated with comfort measures only were GCS odds ratio (OR) 0.77, 95% confidence interval (CI) 0.68-0.86, P.0001), intraventricular hemorrhage (IVH) volume (OR 1.03, 95% CI 1.01-1.06, P = .002), and black race (OR 0.24, 95% CI 0.07-0.82, P = .022). Mortality, poor outcome, and hospital length of stay were not significantly different between black and white patients.Lower GCS score, higher IVH volume, and race were independent predictors of comfort measures only. Black patients were 76% less likely to withdraw life support than white patients. There were no significant differences in mortality between black and white patients. Providers should be aware of potential racial disparities.

Subarachnoid hemorrhage (SAH) results in severe neuronal dysfunction and degeneration. Since the nicotinic acetylcholine α(7) receptors (α(7)-AChR) are involved in neuronal function and survival, we investigated if stimulation of α(7)-AChR would promote neuronal survival and improve behavioral outcome following SAH in mice. Male mice subjected to SAH were treated with either galantamine (α(7)-AChR agonist) or vehicle. Neurobehavioral testing was performed 24 hours after SAH, and mice were euthanized for analysis of neuronal cell death or a cell survival (PI3K/Akt) signaling pathway. Neuron cell cultures were subjected to hemoglobin toxicity to assess the direct effects of α(7)-AChR agonism independent of other cells. Treatment with the α(7)-AChR agonist promoted neuronal survival and improved functional outcomes 24 hours post-SAH. The improved outcomes corresponded with increased PI3K/Akt activity. Antagonism of α(7)-AChR or PI3K effectively reversed galantamine’s beneficial effects. Tissue from α(7)-AChR knockout mice confirmed α(7)-AChR’s role in neuronal survival after SAH. Data from the neuronal cell culture experiment supported a direct effect of α(7)-AChR agonism in promoting cell survival. Our findings indicate that α(7)-AChR is a therapeutic target following SAH which can promote neuronal survival, thereby improving neurobehavioral outcome. Thus, the clinically relevant α(7)-AChR agonist, galantamine, might be a potential candidate for human use to improve outcome after SAH.

Corticosteroids (CSs) are used frequently in the neurocritical care unit mainly for their antiinflammatory and immunosuppressive effects. Despite their broad use, limited evidence exists for their efficacy in diseases confronted in the neurocritical care setting. There are considerable safety concerns associated with administering these drugs and should be limited to specific conditions in which their benefits outweigh the risks. The application of CSs in neurologic diseases, range from traumatic head and spinal cord injuries to central nervous system infections. Based on animal studies, it is speculated that the benefit of CSs therapy in brain and spinal cord, include neuroprotection from free radicals, specifically when given at a higher supraphysiologic doses. Regardless of these advantages and promising results in animal studies, clinical trials have failed to show a significant benefit of CSs administration on neurologic outcomes or mortality in patients with head and acute spinal injuries. This article reviews various chemical structures between natural and synthetic steroids, discuss its pharmacokinetic and pharmacodynamic profiles, and describe their use in clinical practice.

Background Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is an important determinant of clinical outcomes. However, a major hindrance to studies of EBI is the lack of radiographic surrogate marker. Objective To propose a scoring system based on early changes in clinically obtained computed tomography (CT), called the Subarachnoid hemorrhage Early Brain Edema Score (SEBES). Methods Patients with spontaneous aneurysmal SAH and a CT within 24 h of ictus were included. We defined SEBES as a scale of 0 to 4 points according to the (1) absence of visible sulci caused by effacement of sulci or (2) absence of visible sulci with disruption of the gray-white matter junction at 2 predetermined levels in each hemisphere. Prognostic value of the SEBES grade for the prediction of delayed cerebral ischemia (DCI) and unfavorable outcomes was assessed. A separate cohort of patients was used as a validation cohort. Results Of the 164 subjects in our study, high-grade SEBES (3 or 4 points) was identified in 48 patients (29.3%). CT interobserver reliability of SEBES grades was high with a Kappa value of 0.89. After adjusting for covariables, SEBES was identified as an independent predictor of DCI (OR = 2.24, 95% CI: 1.58-3.17) and unfavorable outcome (OR = 3.45, 95% CI: 1.95-6.07). In our validation cohort, 84 subjects showed similar predictive power of SEBES for a prediction of DCI and unfavorable long-term outcome. Conclusion SEBES may be a surrogate marker of EBI and predicts DCI and clinical outcomes after SAH.

Background Plasma-based resuscitation improves outcomes in trauma patients with hemorrhagic shock, while large-animal and limited clinical data suggest that it also improves outcomes and is neuroprotective in the setting of combined hemorrhage and traumatic brain injury. However, the choice of initial resuscitation fluid, including the role of plasma, is unclear for patients after isolated traumatic brain injury. Methods We reviewed adult trauma patients admitted from January 2011 to July 2015 with isolated traumatic brain injury. “Early plasma” was defined as transfusion of plasma within 4 hours. Purposeful multiple logistic regression modeling was performed to analyze the relationship of early plasma and inhospital survival. After testing for interaction, subgroup analysis was performed based on the pattern of brain injury on initial head computed tomography: epidural hematoma, intraparenchymal contusion, subarachnoid hemorrhage, subdural hematoma, or multifocal intracranial hemorrhage. Results Of the 633 isolated traumatic brain injury patients included, 178 (28%) who received early plasma were injured more severely coagulopathic, hypoperfused, and hypotensive on admission. Survival was similar in the early plasma versus no early plasma groups (78% vs 84%, P = .08). After adjustment for covariates, early plasma was not associated with improved survival (odds ratio 1.18, 95% confidence interval 0.71–1.96). On subgroup analysis, multifocal intracranial hemorrhage was the largest subgroup with 242 patients. Of these, 61 (25%) received plasma within 4 hours. Within-group logistic regression analysis with adjustment for covariates found that early plasma was associated with improved survival (odds ratio 3.34, 95% confidence interval 1.20–9.35). Conclusion Although early plasma transfusion was not associated with improved in-hospital survival for all isolated traumatic brain injury patients, early plasma was associated with increased in-hospital survival in those with multifocal intracranial hemorrhage.

Stroke is the fifth leading cause of death in the United States. Subarachnoid hemorrhage (SAH) is a type of stroke often caused by the spontaneous rupture of a cerebral aneurysm. About 30% of the SAH patients develop delayed cerebral ischemia (DCI) a serious secondary complication with devastating impact. Cerebral vasospasm is one of the major precursors of DCI. Predicting the risk of vasospasm would enable better treatment and improved outcomes. Our overarching goal is to find a brain vasculature representation that can be used to find predictive image-based biomarkers. We propose a new methodology that leverages sparse dictionary learning and covariance-based features in order to encode the whole vessel structure in a vector of fixed size. Using 3D brain angiograms, we use this vasculature representation to train a logistic regression model to predict the occurrence of cerebral vasospasm with an area under the ROC curve of 0.93.

INTRODUCTION: traumatic brain injury (TBI) is associated with secondary injury to the central nervous system (CNS) via inflammatory mechanisms. The combination of polytrauma and TBI (TBI) further exacerbates the inflammatory response to injury, however combined injury phenomena has not been thoroughly studied. In this study, we examined the inflammatory differences between patients with TBI versus patients with polytrauma but no TBI (polytrauma). We hypothesize that patients with TBI have a heightened early inflammatory response compared to polytrauma. METHODS: We conducted a single center retrospective study of a cohort of patients with polytrauma who were enrolled in the PROPPR study. These patients had blood samples prospectively collected at eight time points in the first 3 days of admission. Using radiological data to determine TBI, our polytrauma cohort was dichotomized into TBI (n=30) or polytrauma (n=54). Inflammatory biomarkers were measured using ELISA. Data across time were compared for TBI vs. polytrauma groups using Wilcoxon rank sum test. Network analysis techniques were used to systematically characterize the inflammatory responses at admission. RESULTS: Patients with TBI (51.6%) had a higher 30-day mortality compared to polytrauma (16.9%) (p-value

Background Inflammatory mechanism has been implicated in delayed cerebral ischemia (DCI) and poor functional outcomes after subarachnoid hemorrhage (SAH). Identification of cytokine patterns associated with inflammation in acute SAH will provide insights into underlying biological processes of DCI and poor outcomes that may be amenable to interventions. Methods Serum samples were collected from a prospective cohort of 60 patients with acute non-traumatic SAH at four time periods ( Results Of the 60 patients enrolled in the study, 14 (23.3%) developed DCI and 16 (26.7%) had poor functional outcomes at 3 months. DCI was associated with increased levels of PDGF-ABBB and CCL5 and decreased levels of IP-10 and MIP-1α. Poor functional outcome was associated with increased levels of IL-6 and MCP-1α. Network analysis identified distinct cytokine clusters associated with DCI and functional outcomes. Conclusions Serum cytokine patterns in early SAH are associated with poor functional outcomes and DCI. The significant cytokines primarily modulate the inflammatory response. This supports earlier SAH studies linking inflammation and poor outcomes. In particular, this study identifies novel cytokine patterns over time that may indicate impending DCI.

Inhibitors targeting KRAS(G12C), a mutant form of the guanosine triphosphatase (GTPase) KRAS, are a promising new class of oncogene-specific therapeutics for the treatment of tumors driven by the mutant protein. These inhibitors react with the mutant cysteine residue by binding covalently to the switch-II pocket (S-IIP) that is present only in the inactive guanosine diphosphate (GDP)–bound form of KRAS(G12C), sparing the wild-type protein. We used a genome-scale CRISPR interference (CRISPRi) functional genomics platform to systematically identify genetic interactions with a KRAS(G12C) inhibitor in cellular models of KRAS(G12C) mutant lung and pancreatic cancer. Our data revealed genes that were selectively essential in this oncogenic driver–limited cell state, meaning that their loss enhanced cellular susceptibility to direct KRAS(G12C) inhibition. We termed such genes “collateral dependencies” (CDs) and identified two classes of combination therapies targeting these CDs that increased KRAS(G12C) target engagement or blocked residual survival pathways in cells and in vivo. From our findings, we propose a framework for assessing genetic dependencies induced by oncogene inhibition.

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.

Preventing secondary brain injury after neurological insults is one of the primary goals of the neurocritical care unit. Our understanding of the roles of intracranial pressure (ICP) and cerebral edema in managing patients in the neurocritical care units is still evolving. Recent clinical trials examining the monitoring and treatment of elevated ICP have influenced the way we think about intracranial hypertension. Additionally, new methods of monitoring ICP, new physiologic surrogates derived from ICP measurements, and evolving technology to measure cerebral edema are currently being studied and tested for clinical efficacy. In this article, we will discuss both traditional and novel methods of monitoring ICP and cerebral edema.

Background and Purpose Hemicraniectomy is a decompressive surgery used to remove a large bone flap to allow edematous brain tissue to bulge extracranially. However, early indicators of the decompressive effects of hemicraniectomy are unclear. We investigated whether reduction of midline shift following hemicraniectomy is associated with improved consciousness and survival in patients with malignant middle cerebral artery infarctions. Methods We studied 70 patients with malignant middle cerebral artery infarctions (MMI) who underwent hemicraniectomies. Midline shift was measured preoperatively and postoperatively using computed tomography (CT). Consciousness level was evaluated using the Glasgow Coma Scale on postoperative day 1. Patient survival was assessed six months after stroke onset. Results The median time interval between preoperative and postoperative CT was 8.3 hours (interquartile range, 6.1–10.2 hours). Reduction in midline shift was associated with higher postoperative Glasgow Coma Scale scores (P

Introduction A left ventricular assist device (LVAD) is used in certain heart failure cases, but LVADs can have significant neurological complications including intracranial hemorrhages (ICH). Prediction and management of ICHs is challenging due to medical comorbidities and blood thinners. Methods A retrospective review of LVAD patients with ICHs from 2015 to 2019 was performed. The data included demographics, premorbid conditions, hemorrhage type, treatments, and outcomes. Results Twenty-two patients were included with a median age of 53 and a median time of 16 months from LVAD insertion to ICH. All patients were on blood thinners prior to ICH. The hemorrhage type included subarachnoid hemorrhage (41 %), intracerebral hemorrhage (32 %), and subdural hematomas (23 %). The blood-thinning agent was reversed in 64 % of patients with a median of 3.5 days prior to resumption of these medications. Ten re-hemorrhages occurred with 4 of these hemorrhages within two weeks of anticoagulation resumption. Open cranial surgery was performed in 32 % of all patients, and the mortality was 41 %. Conclusions Management of these patients is challenging with a relatively high rate of re-hemorrhage and need for surgical intervention. Despite maximal management, the mortality remains high.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Advanced HCC has proven particularly difficult to treat because of a scarcity of clear genetic drivers of cancer progression; thus, there are currently no predictive markers that guide HCC therapy. HCC arises in the context of co-morbid hepatitis due to hepatitis B virus (HBV), hepatitis C (HCV) or fatty liver disease. We hypothesize that protein-protein interactions (PPIs) between viral proteins and HCC genes may contribute to tumor initiation and maintenance. In order to characterize these PPIs, we performed affinity purification - mass spectrometry (APMS), defining 145 HBV/host PPIs including known and novel interacting partners. We next used a network propagation algorithm to identify host genes and protein complexes that were preferentially mutated in the absence of HBV infection. HBV is a small DNA virus, with 4 genes of which only one has enzymatic activity, raising a question as to how HBV interaction modifies host behavior. Using AP-MS of host proteins, we found that the HBV X protein (HBx) remodels multiple host protein complexes through direct interaction. These physical effects on complex components result in distinct biochemical behavior from the CRL4 E3 ubiquitin ligase complex as well as the phosphatase PP2A, as determined through global phosphoproteomics and ubiquitin analysis. We show that this remodeling driven by HBx substantially changes cellular protein turnover and downstream signaling dynamics. We followed this up with assessments of cellular viability and proliferation in response to pharmacological inhibition or CRISPRi-based knockdown of HBx effectors. Our data support a model where HBV proteins alter the components and behavior of key regulatory protein complexes in the cell, altering tumor behavior and raising the possibility of precision therapeutics for HCC. Citation Format: John D. Gordan, Adriana Pitea, Manon Eckhardt, Gwendolyn Jang, Rigney E. Turnham, Alex L M. Choi, John Von Dollen, Huat C. Lim, Elizabeth F. Thayer, R. Katie Kelley, Danielle L. Swaney, Wei Zhang, Fabian J. Theis, Trey Ideker, Nevan J. Krogan. Hepatitis B virus remodels host protein interaction networks to generate distinct cellular dependencies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4891.

Dissemination is an essential early step in metastasis but its molecular basis remains incompletely understood. To define the essential targetable effectors of this process, we developed a 3D mammary epithelial culture model, in which dissemination is induced by overexpression of the transcription factor Twist1. Transcriptomic analysis and ChIP-PCR together demonstrated that protein kinase D1 (Prkd1) is a direct transcriptional target of Twist1 and is not expressed in the normal mammary epithelium. Pharmacologic and genetic inhibition of Prkd1 in the Twist1-induced dissemination model demonstrated that Prkd1 was required for cells to initiate extracellular matrix (ECM)–directed protrusions, release from the epithelium, and migrate through the ECM. Antibody-based protein profiling revealed that Prkd1 induced broad phosphorylation changes, including an inactivating phosphorylation of β-catenin and two microtubule depolymerizing phosphorylations of Tau, potentially explaining the release of cell–cell contacts and persistent activation of Prkd1. In patients with breast cancer, TWIST1 and PRKD1 expression correlated with metastatic recurrence, particularly in basal breast cancer. Prkd1 knockdown was sufficient to block dissemination of both murine and human mammary tumor organoids. Finally, Prkd1 knockdown in vivo blocked primary tumor invasion and distant metastasis in a mouse model of basal breast cancer. Collectively, these data identify Prkd1 as a novel and targetable signaling node downstream of Twist1 that is required for epithelial invasion and dissemination. Significance: Twist1 is a known regulator of metastatic cell behaviors but not directly targetable. This study provides a molecular explanation for how Twist1-induced dissemination works and demonstrates that it can be targeted.

Survivors of cerebral aneurysm rupture are at risk for significant morbidity and neurological deficits. Much of this is related to the effects of blood in the subarachnoid space which induces an inflammatory cascade with numerous downstream consequences. Recent clinical trials have not been able to reduce the toxic effects of free hemoglobin or improve clinical outcome. One reason for this may be the inability to identify patients at high risk for neurologic decline. Recently, haptoglobin genotype has been identified as a pertinent factor in diabetes, sickle cell, and cardiovascular disease, with the Hp 2-2 genotype contributing to increased complications. Haptoglobin is a protein synthesized by the liver that binds free hemoglobin following red blood cell lysis, and in doing so, prevents hemoglobin induced toxicity and facilitates clearance. Clinical studies in patients with subarachnoid hemorrhage indicate that Hp 2-2 patients may be a high-risk group for hemorrhage related complications and poor outcome. We review the relevance of haptoglobin in subarachnoid hemorrhage and discuss the effects of genotype and expression levels on the known mechanisms of early brain injury (EBI) and cerebral ischemia after aneurysm rupture. A better understanding of haptoglobin and its role in preventing hemoglobin related toxicity should lead to novel therapeutic avenues.

Background: Infection with HIV predisposes patients to a myriad of neurologic disorders, including cerebrovascular disease. The pathophysiology is likely multifactorial, with proposed mechanisms including infectious vasculitis, HIV-induced endothelial dysfunction and adverse effects of combination antiretroviral therapy (cART). Epidemiologic data on clinically evident cerebral vasculopathy in HIV-infected adults is scarce, even though stroke hospitalizations are rising in this patient population. Methods: A total of 6,298 HIV-infected adults (San Francisco General Hospital, 2000-2013) were screened to generate a cohort of patients with dedicated neuroimaging of the intra- and extracranial cerebral vasculature. We extracted information regarding the extent of HIV disease (including serial viral load and CD4 counts), cardiovascular disease risk factors and exposure to cART (cross-referenced with pharmacy records) and performed multivariate logistic regression analysis to identify predictors of vasculopathy. Results: Of 144 patients, 55 patients (38.2%) had radiographic evidence of cerebral vasculopathy. Twenty (13.9%) had a vasculopathy characterized by vessel dolichoectasia and intracranial aneurysm formation. Thirty-five patients (24.3%) had intra- and or extracranial stenosis/occlusion. cART use (OR 2.27, 95% CI 1.03-5) and tobacco abuse (OR 2.35, 95% CI 1.04-5.25) were independently associated with the development of any vasculopathy, whereas cART use was also an independent risk factor for the stenosis/occlusion subtype specifically (OR 2.87, 95% CI 1.11-7.45). Conclusions: There was a high frequency of cerebral arterial disease in this neuroimaging cohort of HIV/AIDS patients. A history of cART use and a history of tobacco abuse were independent risk factors for vasculopathy, though these findings should be confirmed with large-scale prospective studies.

Background and Purpose— Neurological deterioration (ND) is a devastating complication after intracerebral hemorrhage but little is known about time course and predictors. Methods— We performed a retrospective cohort study of placebo patients in intracerebral hemorrhage trials. We performed computed tomographic scans within 3 hours of symptoms and at 24 and 72 hours; and clinical evaluations at baseline, 1-hour, and days 1, 2, 3, and 15. Timing of ND was predefined as follows: hyperacute (within 1 hour), acute (1–24 hours), subacute (1–3 days), and delayed (3–15 days). Results— We enrolled 376 patients and 176 (47%) had ND within 15 days. In multivariate analyses of ND by category, hyperacute ND was associated with hematoma expansion (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.7–7.6) and baseline intracerebral hemorrhage volume (OR, 1.04 per mL; 95% CI 1.02–1.06); acute ND with hematoma expansion (OR, 7.59; 95% CI, 3.91–14.74), baseline intracerebral hemorrhage volume (OR, 1.02 per mL; 95% CI, 1.01–1.04), admission Glasgow Coma Scale (OR, 0.77 per point; 95% CI, 0.65–0.91), and interventricular hemorrhage (OR, 2.14; 95% CI, 1.05–4.35); subacute ND with 72-hour edema (OR, 1.03 per mL; 95% CI, 1.02–1.05) and fever (OR, 2.49; 95% CI, 1.01–6.14); and delayed ND with age (OR, 1.11 per year; 95% CI, 1.04–1.18), troponin (OR, 4.30 per point; 95% CI, 1.71–10.77), and infections (OR, 3.69; 95% CI, 1.11–12.23). Patients with ND had worse 90-day modified Rankin scores (5 versus 3; P Conclusions— ND occurs frequently and predicts poor outcomes. Our results implicate hematoma expansion and interventricular hemorrhage in early ND, and cerebral edema, fever, and medical complications in later ND.

The mechanism of early neurological deterioration (END) in patients with stroke remains unclear. We assessed the relationship between nocturnal oxygen desaturation (NOD) in the stroke unit (SU) and END, especially occurring at nighttime, following acute stroke.A retrospective analysis was performed on a total of 276 patients with ischemic stroke who were admitted to the SU between July 2013 and June 2015. The oxygen desaturation index was calculated from pulse oximetry data sampled every 1 minute during 9 hours on the first night (10:00 PM to 7:00 AM) after admission, and NOD was defined as oxygen desaturation index ≥ 5 events/h. END was defined as an increase of ≥ 2 points from the baseline National Institutes of Health Stroke Scale during 7 days after onset. We compared clinical characteristics and NOD between patients with and without END.Among the included patients (mean age 69.2; male 55.4%), 42 patients (15.2%) experienced END. The proportion of NOD was significantly greater in the END group (45.2% versus 12.8%,NOD in the SU was associated with END, especially during nighttime, after ischemic stroke. This suggests that treatment of sleep-disordered breathing could be a modifiable factor to possibly reduce the risk of neurological worsening among acute stroke patients.

Early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) is defined as brain injury occurring within 72 h of aneurysmal rupture. Although EBI is the most significant predictor of outcomes after aSAH, its underlying pathophysiology is not well understood. We hypothesize that EBI after aSAH is associated with an increase in peripheral inflammation measured by cytokine expression levels and changes in associations between cytokines. aSAH patients were enrolled into a prospective observational study and were assessed for markers of EBI: global cerebral edema (GCE), subarachnoid hemorrhage early brain edema score (SEBES), and Hunt–Hess grade. Serum samples collected at ≤ 48 h of admission were analyzed using multiplex bead-based assays to determine levels of 13 pro- and anti-inflammatory cytokines. Pairwise correlation coefficients between cytokines were represented as networks. Cytokine levels and differences in correlation networks were compared between EBI groups. Of the 71 patients enrolled in the study, 17 (24%) subjects had GCE, 31 (44%) subjects had SEBES ≥ 3, and 21 (29%) had HH ≥ 4. IL-6 was elevated in groups with GCE, SEBES ≥ 3, and HH ≥ 4. MIP1β was independently associated with high-grade SEBES. Correlation network analysis suggests higher systematic inflammation in subjects with SEBES ≥ 3. EBI after SAH is associated with increased levels of specific cytokines. Peripheral levels of IL-10, IL-6, and MIP1β may be important markers of EBI. Investigating systematic correlations in addition to expression levels of individual cytokines may offer deeper insight into the underlying mechanisms related to EBI.

SUMMARYAlthough macrophages are armed with potent anti-bacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage-intrinsic bacterial control, and the Mtb strategies to overcome them are poorly understood. To further study these processes, we used a systematic affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two new factors involved in Mtb pathogenesis - the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL. We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl-/- macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between anti-bacterial and anti-viral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map as a resource for developing a deeper understanding of the intricate interactions between Mtb and its host.

Background: Thrombelastography (TEG) provides a global, dynamic measure of coagulation. We examined the effect of antiplatelet (AP) medications on coagulation in patients with acute stroke as measured by TEG. Methods: We reviewed prospectively collected data on patients presenting with acute ischemic stroke (AIS) and spontaneous intracerebral hemorrhage (ICH) between 2009 and 2014. Patient demographics and baseline TEG values were compared among 4 different drug use groups: aspirin only, clopidogrel only, both aspirin and clopidogrel, and no AP. Multivariable regression models were conducted to compare the differences in TEG components. Results: A total of 202 patients were included, 139 with AIS and 63 with ICH. Forty-eight (24%) patients were taking aspirin alone, 12 (6%) were taking clopidogrel, 16 (8%) dual AP, and 126 (62%) no AP. Dual AP use was associated with prolonged mean R (time to initiate clotting) of 5.5 minutes as compared to no AP use (4.6 minutes, P = .04). Additionally, mean maximal amplitude (MA; final clot strength) and angle (rate of clot formation) were decreased in the dual AP group (MA = 59.3 mm, angle = 57.8°) as compared to the no AP group (MA = 64.5 mm, angle = 64.5°; P = .04 and P = .01, respectively). Patients on single AP therapy (either aspirin or clopidogrel) did not differ from those on no AP therapy in any TEG parameters measured. Conclusion: Dual AP therapy is associated with a detectable coagulopathy which may have implications in the management of patients with AIS and hemorrhagic stroke. The effects of single AP therapy may not be demonstrated by TEG.

Although macrophages are armed with potent antibacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage intrinsic bacterial control, and the Mtb strategies to overcome them, are poorly understood. To further study these processes, we used an affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two factors involved in Mtb pathogenesis - the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL. We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl(−/−) macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between antibacterial and antiviral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map for developing a deeper understanding of the intricate interactions between Mtb and its host.

Background. The gut is a major reservoir for human immunodeficiency virus (HIV) in patients receiving antiretroviral therapy (ART). We hypothesized that distinct immune environments within the gut may support varying levels of HIV.Methods. In 8 HIV-1-positive adults who were receiving ART and had CD4 + T cell counts of >200 cells/µL and plasma viral loads of

Objective:To investigate inflammatory processes after aneurysmal subarachnoid hemorrhage (aSAH) with network models.Methods:This is a retrospective observational study of serum samples from 45 participants with aSAH analyzed at multiple predetermined time points: Results:Network models revealed that systematic inflammatory activity peaks at 24 to 48 hours after the bleed. Individual cytokine levels changed significantly over time, exhibiting increasing, decreasing, and peaking trends. Platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, soluble CD40 ligand, and tumor necrosis factor-α (TNF-α) increased over time. Colony-stimulating factor (CSF) 3, interleukin (IL)-13, and FMS-like tyrosine kinase 3 ligand decreased over time. IL-6, IL-5, and IL-15 peaked and decreased. Some cytokines with insignificant trends show high correlations with other cytokines and vice versa. Many correlated cytokine clusters, including a platelet-derived factor cluster and an endothelial growth factor cluster, were observed at all times. Participants with higher clinical severity at admission had elevated levels of several proinflammatory and anti-inflammatory cytokines, including IL-6, CCL2, CCL11, CSF3, IL-8, IL-10, CX3CL1, and TNF-α, compared to those with lower clinical severity.Conclusions:Combining reductionist and systematic techniques may lead to a better understanding of the underlying complexities of the inflammatory reaction after aSAH.

It is common for patients who die from subarachnoid hemorrhage to have a focus on comfort measures at the end of life. The potential role of ethnicity in end-of-life decisions after brain injury has not been extensively studied. Patients with subarachnoid hemorrhage were prospectively followed in an observational database. Demographic information including ethnicity was collected from medical records and self-reported by patients or their family. Significant in-hospital events including do-not-resuscitate orders, comfort measures only orders (CMO; care withheld or withdrawn), and mortality were recorded prospectively. 1255 patients were included in our analysis: 650 (52 %) were White, 387 (31 %) Hispanic, and 218 (17 %) Black. Mortality was similar between the groups. CMO was more commonly observed in Whites (14 %) compared to either Blacks (10 %) or Hispanics (9 %) (p = 0.04). In a multivariate analysis controlling for age and Hunt-Hess grade, Hispanics were less likely to have CMO than Whites (OR, 0.6; 95 %CI, 0.4–0.9; p = 0.02). Of the 229 patients who died, 77 % of Whites had CMO compared to 54 % of Blacks and 49 % of Hispanics (p

Malignant cerebral edema following ischemic stroke is life threatening, as it can cause inadequate blood flow and perfusion leading to irreversible tissue hypoxia and metabolic crisis. Increased intracranial pressure and brain shift can cause herniation syndrome and finally brain death. Multiple randomized clinical trials have shown that preemptive decompressive hemicraniectomy effectively reduces mortality and morbidity in patients with malignant middle cerebral artery infarction. Another life-saving decompressive surgery is suboccipital craniectomy for patients with brainstem compression by edematous cerebellar infarction. In addition to decompressive surgery, cerebrospinal fluid drainage by ventriculostomy should be considered for patients with acute hydrocephalus following stroke. Medical treatment begins with sedation, analgesia, and general measures including ventilatory support, head elevation, maintaining a neutral neck position, and avoiding conditions associated with intracranial hypertension. Optimization of cerebral perfusion pressure and reduction of intracranial pressure should always be pursued simultaneously. Osmotherapy with mannitol is the standard treatment for intracranial hypertension, but hypertonic saline is also an effective alternative. Therapeutic hypothermia may also be considered for treatment of brain edema and intracranial hypertension, but its neuroprotective effects have not been demonstrated in stroke. Barbiturate coma therapy has been used to reduce metabolic demand, but has become less popular because of its systemic adverse effects. Furthermore, general medical care is critical because of the complex interactions between the brain and other organ systems. Some challenging aspects of critical care, including ventilator support, sedation and analgesia, and performing neurological examinations in the setting of a minimal stimulation protocol, are addressed in this review.

To determine the association between exposure to hyperoxia and the risk of delayed cerebral ischaemia (DCI) after subarachnoid haemorrhage (SAH).We analysed data from a single centre, prospective, observational cohort database. Patient inclusion criteria were age ≥18 years, aneurysmal SAH, endotracheal intubation with mechanical ventilation, and arterial partial pressure of oxygen (PaO2) measurements. Hyperoxia was defined as the highest quartile of an area under the curve of PaO2, until the development of DCI (PaO2≥173 mm Hg). Poor outcome was defined as modified Rankin Scale 4-6 at 3 months after SAH.Of 252 patients, there were no differences in baseline characteristics between the hyperoxia and control group. Ninety-seven (38.5%) patients developed DCI. The hyperoxia group had a higher incidence of DCI (p0.001) and poor outcome (p=0.087). After adjusting for modified Fisher scale, rebleeding, global cerebral oedema, intracranial pressure crisis, pneumonia and sepsis, hyperoxia was independently associated with DCI (OR, 3.16; 95% CI 1.69 to 5.92; p0.001). After adjusting for age, Hunt-Hess grade, aneurysm size, Acute Physiology and Chronic Health Evaluation II score, rebleeding, pneumonia and sepsis, hyperoxia was independently associated with poor outcome (OR, 2.30; 95% CI 1.03 to 5.12; p=0.042).In SAH patients, exposure to hyperoxia was associated with DCI. Our findings suggest that exposure to excess oxygen after SAH may represent a modifiable factor for morbidity and mortality in this population.

Background Cerebral microbleeds (CMBs) are commonly found after stroke but have not previously been studied in patients with subarachnoid hemorrhage (SAH). Objective To study the prevalence, radiographic patterns, predictors, and impact on outcome of CMBs in patients with SAH. Methods We analyzed retrospectively 39 consecutive patients who underwent T2*-weighted gradient-echo imaging within 7 days after onset of spontaneous SAH. We report the frequency and location of CMBs and show their association with demographics, vascular risk factors, the Hunt-Hess grade, the modified Fisher Scale, the Acute Physiological and Chronic Health Evaluation II, magnetic resonance imaging findings including diffusion-weighted imaging lesions, and laboratory data, as well as data on rebleeding, global cerebral edema, delayed cerebral ischemia, seizures, the Telephone Interview for Cognitive Status, and the modified Rankin Scale. Results Eighteen patients (46%) had CMBs. Of these patients, 9 had multiple CMBs, and overall a total of 50 CMBs were identified. The most common locations of CMBs were lobar (n = 23), followed by deep (n = 15) and infratentorial (n = 12). After adjustment for age and history of hypertension, CMBs were related to the presence of diffusion-weighted imaging lesions (odds ratio, 5.24; 95% confidence interval, 1.14-24.00; P = .03). Three months after SAH, patients with CMBs had nonsignificantly higher modified Rankin Scale scores (odds ratio, 2.50; 95% confidence interval, 0.67-9.39; P = .18). Conclusion This study suggests that CMBs are commonly observed and associated with diffusion-weighted imaging lesions in patients with SAH. Our findings may represent a new mechanism of tissue injury in SAH. Further studies are needed to investigate the clinical implications of CMBs.

Multilevel functional data is collected in many biomedical studies. For example, in a study of the effect of Nimodipine on patients with subarachnoid hemorrhage (SAH), patients underwent multiple 4-hour treatment cycles. Within each treatment cycle, subjects' vital signs were reported every 10 minutes. This data has a natural multilevel structure with treatment cycles nested within subjects and measurements nested within cycles. Most literature on nonparametric analysis of such multilevel functional data focus on conditional approaches using functional mixed effects models. However, parameters obtained from the conditional models do not have direct interpretations as population average effects. When population effects are of interest, we may employ marginal regression models. In this work, we propose marginal approaches to fit multilevel functional data through penalized spline generalized estimating equation (penalized spline GEE). The procedure is effective for modeling multilevel correlated generalized outcomes as well as continuous outcomes without suffering from numerical difficulties. We provide a variance estimator robust to misspecification of correlation structure. We investigate the large sample properties of the penalized spline GEE estimator with multilevel continuous data and show that the asymptotics falls into two categories. In the small knots scenario, the estimated mean function is asymptotically efficient when the true correlation function is used and the asymptotic bias does not depend on the working correlation matrix. In the large knots scenario, both the asymptotic bias and variance depend on the working correlation. We propose a new method to select the smoothing parameter for penalized spline GEE based on an estimate of the asymptotic mean squared error (MSE). We conduct extensive simulation studies to examine property of the proposed estimator under different correlation structures and sensitivity of the variance estimation to the choice of smoothing parameter. Finally, we apply the methods to the SAH study to evaluate a recent debate on discontinuing the use of Nimodipine in the clinical community.

The objective of this study was to quantify coagulopathy using thrombelastography (TEG) in patients with renal dysfunction and intracerebral hemorrhage (ICH).We reviewed patients admitted with spontaneous ICH between November 2009 and May 2015. TEG was performed at the time of admission. Creatinine clearance (CCr) was calculated using the Cockroft-Gault equation. Patients were divided into 2 groups based on normal (CCr ≥ 90) or reduced renal function (CCr 90). Multivariable regression models were conducted to compare the differences of TEG components.A total of 120 patients were included in the analysis. The normal CCr group was younger (56.1 versus 62.3 years, P .01), was more often male (73.6% versus 53.7%, P = .03), and had higher mean admission hemoglobin (14.2 versus 13.2 mEq/L, P .01) than the reduced renal function group. The 2 groups were similar with respect to antiplatelet or anticoagulant use, coagulation studies, and baseline ICH volume. Following multivariate analysis, the reduced renal function group was found to have shorter K (1.5 versus 2.2 min, P = 004), increased angle (66 versus 62.2 degrees, P = .04), increased MA (67.3 versus 62.3, P = .02), and increased G (11.3 versus 9.9 dynes/cmPatients with ICH and reduced CCr display faster clotting rate and increased clot strength, suggesting that patients with renal dysfunction present with a relatively hypercoagulable state based on TEG parameters thought to reflect platelet activity.

Methionine is an essential proteinogenic amino acid that is obtained from the diet. In addition to its requirement for protein biosynthesis, methionine is metabolized to generate metabolites that play key roles in a number of cellular functions. Metabolism of methionine via the transmethylation pathway generates S-adenosylmethionine (SAM) that serves as the principal methyl (-CH3) donor for DNA and histone methyltransferases to regulate epigenetic changes in gene expression. SAM is also required for methylation of other cellular proteins that serve various functions and phosphatidylcholine synthesis that participate in cellular signaling.. Under conditions of oxidative stress, homocysteine (which is derived from SAM) enters the transsulfuration pathway to generate glutathione, an important cytoprotective molecule against oxidative damage. As both experimental and clinical studies have shown that traumatic brain injury (TBI) alters DNA and histone methylation and causes oxidative stress, we examined if TBI alters the plasma levels of methionine and its metabolites in human patients. Blood samples were collected from healthy volunteers (n = 20) and patients with mild TBI (GCS > 12; n = 20) or severe TBI (GCS < 8; n = 20) within the first 24 hours of injury. The levels of methionine and its metabolites in the plasma samples were analyzed by either liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry (LC-MS or GC-MS). Severe TBI decreased the levels of methionine, SAM, betaine and 2-methylglycine as compared to healthy volunteers, indicating a decrease in metabolism through the transmethylation cycle. In addition, precursors for the generation of glutathione, cysteine and glycine were also found to be decreased as were intermediate metabolites of the gamma-glutamyl cycle (gamma-glutamyl amino acids and 5-oxoproline). Mild TBI also decreased the levels of methionine, α-ketobutyrate, 2 hydroxybutyrate and glycine, albeit to lesser degrees than detected in the severe TBI group. Taken together, these results suggest that decreased levels of methionine and its metabolic products are likely to alter cellular function in the injured brain and other body systems.

Hypothermia is widely accepted as the gold-standard method by which the body can protect the brain. Therapeutic cooling--or targeted temperature management (TTM)--is increasingly being used to prevent secondary brain injury in patients admitted to the emergency department and intensive care unit. Rapid cooling to 33 °C for 24 h is considered the standard of care for minimizing neurological injury after cardiac arrest, mild-to-moderate hypothermia (33-35 °C) can be used as an effective component of multimodal therapy for patients with elevated intracranial pressure, and advanced cooling technology can control fever in patients who have experienced trauma, haemorrhagic stroke, or other forms of severe brain injury. However, the practical application of therapeutic hypothermia is not trivial, and the treatment carries risks. Development of clinical management protocols that focus on detection and control of shivering and minimize the risk of other potential complications of TTM will be essential to maximize the benefits of this emerging therapeutic modality. This Review provides an overview of the potential neuroprotective mechanisms of hypothermia, practical considerations for the application of TTM, and disease-specific evidence for the use of this therapy in patients with acute brain injuries.

Nimodipine is the only medication shown to improve outcomes after aneurysmal subarachnoid hemorrhage (SAH). Preliminary theories regarding the mechanism by which it prevents vasospasm have been challenged. The acute physiologic and metabolic effects of oral Nimodipine have not been examined in patients with poor-grade SAH.This is an observational study performed in 16 poor-grade SAH patients undergoing multimodality monitoring who received oral Nimodipine as part of routine clinical care. A total of 663 doses of Nimodipine were observed. Changes in physiologic measurements including MAP, CPP, ICP, P(bt)O(2), and CBF were examined.Administration of oral Nimodipine was associated with a 1.33 mmHg decrease in MAP (P0.001) and a 1.22 mmHg decrease in CPP (P0.001). When administration of Nimodipine was associated with MAP decreases, P(bt)O(2) (1.03 mmHg; P0.001) and CBF (0.39 ml/100 g/min; P = 0.002) also decreased.Despite CPP targeted therapy with vasopressor medication, oral Nimodipine was associated with a decrease in MAP and CPP. When Nimodipine administration was associated with a decrease in MAP, there were concomitant drops in P(bt)O(2) and CBF. These findings suggest that MAP support after oral Nimodipine may be important to maintain adequate CBF in patients with poor-grade subarachnoid hemorrhage.

Background and Purpose— Limited data exist to recommend specific cerebral perfusion pressure (CPP) targets in patients with intracerebral hemorrhage. We sought to determine the feasibility of brain multimodality monitoring for optimizing CPP and potentially reducing secondary brain injury after intracerebral hemorrhage. Methods— We retrospectively analyzed brain multimodality monitoring data targeted at perihematomal brain tissue in 18 comatose intracerebral hemorrhage patients (median monitoring, 164 hours). Physiological measures were averaged over 1-hour intervals corresponding to each microdialysis sample. Metabolic crisis was defined as a lactate/pyruvate ratio >40 with a brain glucose concentration bt O 2 Results— Median age was 59 years, median Glasgow Coma Scale score was 6, and median intracerebral hemorrhage volume was 37.5 mL. The risk of BTH, and to a lesser extent metabolic crisis, increased with lower CPP values. Multivariable analyses showed that CPP P =0.01) compared to CPP >100 mm Hg as a reference range. Six patients died (33%). Survivors had significantly higher CPP and P bt O 2 and lower ICP values starting on postbleed day 4, whereas lactate/pyruvate ratio and pressure reactivity index values were persistently lower, indicating preservation of aerobic metabolism and pressure autoregulation. Conclusions— P bt O 2 monitoring can be used to identify CPP targets for optimal brain tissue oxygenation. In patients who do not undergo multimodality monitoring, maintaining CPP >80 mm Hg may reduce the risk of BTH.

The biosynthesis of monolignols, the main components of lignin, involves many intermediates and enzymes. The cinnamoyl-CoA reductase (CCR) enzyme catalyzes the conversion of cinnamoyl-CoAs to cinnamaldehydes, i.e. the first specific step in lignin synthesis. The CCR and CCR-like gene family was studied partially in several plant species. This is a comprehensive study of the CCR and CCR-like gene family including genome organization, gene structure, phylogeny across land plant species, and, expression profiling in Populus. Analysis of amino acid motifs enabled the identification of sequence variations in the CCR catalytic site and annotates CCR and CCR-like genes. CCR and CCR-like genes were distributed in three major phylogenetic classes of which one includes the bona fide CCR genes. The other two classes include CCR and CCR-like, of which several genes present a high similarity to cinnamyl alcohol dehydrogenase, or dihydroflavonol reductase (DFR) genes. All CCR, CCR-like, and DFR classes were deeply rooted in the phylogeny of land plants suggesting that their evolution preceded the evolution of lycophytes. Over two thirds of CCR and CCR-like Populus genes were physically distributed on duplicated regions. This suggests that these duplication/retention processes contributed significantly to the size of the CCR and CCR-like gene family. The Populus CCR and CCR-like genes showed six expression patterns in the tissues studied with a preferential expression of PoptrCCR12 in xylem. The other genes present divergent expression profiles with some preferentially expressed in leaves, bark, or both. Several CCR and CCR-like genes were induced or repressed under various abiotic stresses suggesting that their duplication was followed by the evolution of divergent expression profiles and divergence of functions.

Background and Purpose— Delayed cerebral ischemia (DCI) is an important complication after subarachnoid hemorrhage and appears to be associated with clot burden on CT. Quantification of hemorrhage on digitized images may be a more accurate method for predicting DCI than qualitative scales. Methods— Quantitative analysis of clot burden on CT was performed in 160 subarachnoid hemorrhage patients who were scanned within 24 hours from the symptom onset between June 25, 2005 and July 19, 2009. Cisternal plus intraventricular hemorrhage volumes (CIHV) were classified into quartiles to evaluate their association with DCI. DCI was defined as neurological deterioration or cerebral infarction, or both attributable to vasospasm. Results— DCI occurred in 25% of the patients included (age, 55.4±14.5; male, 36.3%). Compared to the lowest quartile of CIHV (P =0.01). Receiver-operating characteristic curve analysis showed that quantitative CIHV performed equivalently to the modified Fisher scale. Patients who had DCI develop in a specific vascular territory had higher amounts of blood volume in the corresponding cisterns. Patients in the highest quartile of CIHV also had a higher risk of death or severe disability at 3 months (71%) compared to other groups (23%, 19%, and 40% for first, second, and third quartiles, respectively). Conclusions— CIHV is a reasonable predictor for DCI and 3-month functional outcome in subarachnoid hemorrhage patients.

As the practice of aggressive temperature control has become more commonplace, new clinical problems are arising, of which shivering is the most common. Treatment for shivering while avoiding the negative consequences of many anti-shivering therapies is often difficult. We have developed a stepwise protocol that emphasizes use of the least sedating regimen to achieve adequate shiver control. All patients treated with temperature modulating devices in the neurological intensive care unit were prospectively entered into a database. Baseline demographic information, daily temperature goals, best daily GCS, and type and cumulative dose of anti-shivering agents were recorded. We collected 213 patients who underwent 1388 patient days of temperature modulation. Eighty-nine patients underwent hypothermia and 124 patients underwent induced normothermia. In 18% of patients and 33% of the total patient days only none-sedating baseline interventions were needed. The first agent used was most commonly dexmeditomidine at 50% of the time, followed by an opiate and increased doses of propofol. Younger patients, men, and decreased BSA were factors associated with increased number of anti-shivering interventions. A significant proportion of patients undergoing temperature modulation can be effectively treated for shivering without over-sedation and paralysis. Patients at higher risk for needing more interventions are younger men with decreased BSA.

We present a case of angiographically confirmed transection of the cisternal segment of the anterior choroidal artery (AChA) associated with a severe head trauma in a 15-year old boy. The initial brain computed tomography scan revealed a diffuse subarachnoid hemorrhage (SAH) and pneumocephalus with multiple skull fractures. Subsequent cerebral angiography clearly demonstrated a complete transection of the AChA at its origin with a massive extravasation of contrast medium as a jet trajectory creating a plume. We speculate that severe blunt traumatic force stretched and tore the left AChA between the internal carotid artery and the optic tract. In a simulation of the patient's brain using a fresh-frozen male cadaver, the AChA is shown to be vulnerable to stretching injury as the ipsilateral optic tract is retracted. We conclude that the arterial injury like an AChA rupture should be considered in the differential diagnosis of severe traumatic SAH.

Convulsive and nonconvulsive seizures frequently complicate acute brain injury particularly central nervous system hemorrhages and both have been associated with poor outcome. No randomized controlled trials have been conducted to guide decisions on seizure prophylaxis or treatment. The magnitude of additional injury from nonconvulsive seizures remains controversial and some argue that these epileptiform patterns primarily represent surrogate markers of severely injured brain. The deleterious effects of seizures on brain recovering from a recent injury have to be weighed against the deleterious effects of antiepileptic medications when making decisions on prophylaxis and treatment.Currently seizure prophylaxis is not generally recommended for patients with spontaneous intracerebral hemorrhage (ICH) or aneurysmal subarachnoid hemorrhage (aSAH). However, short-term prophylaxis (during the acute critical illness) is commonly instituted for patients in whom seizures would likely lead to additional injury such as herniation or rebleeding. ICH or aSAH patients with seizures at the onset of their hemorrhage, patients with ICH in close proximity to the cortical surface, and aSAH patients with a poor clinical grade (poor neurologic examination and/or thick cisternal blood) are at high risk of seizures, especially nonconvulsive, and are frequently kept on short-term prophylaxis. Convulsive seizures occur in 7% to 17% of patients with spontaneous ICH and in between 6% and 26% of those with aneurysmal aSAH. These should be treated as soon as possible regardless of the underlying causative factors. Nonconvulsive seizures are seen in about 20% of patients with ICH and in 8% to 18% of those with aSAH. It is controversial how aggressively to treat nonconvulsive seizures.Convulsive and nonconvulsive seizures are frequent after central nervous system hemorrhage and treatment is controversial, particularly for nonconvulsive seizures. Randomized controlled trials need to be conducted to better allow evidence-based guidelines for these common neurologic conditions.

Intraventricular nicardipine (IVTN) is a treatment option for severe vasospasm in patients with subarachnoid hemorrhage (SAH). However, its acute effects on cerebral hemodynamics have not been studied in detail.Between June 2008 and December 2010, IVTN was administered (mainly 4mg every 8h) to 11 SAH patients (54 doses) with multimodality monitoring for refractory vasospasm. Retrospective analyses on physiological parameters were made from baseline and up to 6h after IVTN injection. Statistical analysis was performed with a mixed-effects model.Mean intracranial pressure (ICP) increased slightly, reaching its peak at 20min after IVTN injection (2.5±0.9mmHg (mean±standard error), P0.01), and decreased gradually thereafter over the next hour. Mean cerebral perfusion pressure transiently decreased 20-30min after injection (3.7±1.8mmHg, P0.05). Mean arterial pressure, partial pressure of brain oxygen tension (PbtO2), cerebral blood flow (CBF), autoregulation indices did not change significantly. Lactate/pyruvate ratio and glucose remained stable. One patient underwent transcranial Doppler ultrasonography monitoring while on IVTN, which showed a transient increase in mean flow velocity with concomitant decrease in Pulsatility index, suggesting vasodilation in the distal resistance vessels.The vasodilatory effect of IVTN transiently increased ICP, but did not significantly affect PbtO2, CBF or oxidative glucose metabolism in the immediate phase after injection.

Global cerebral edema (GCE) is a manifestation of early brain injury (EBI) after subarachnoid hemorrhage (SAH) and is an independent risk factor for poor outcome. The lack of a quantitative method to measure GCE limits the study of its pathophysiology. The goal of this study is to develop a quantitative surrogate marker that represents GCE after SAH. Patients with spontaneous SAH were enrolled into a prospective observational database. Initial CT scans were graded for GCE using established qualitative criteria. Selective sulcal volume (SSV) was defined as total mL of sulcal volumes on axial CT slices above the most cranial section of the lateral ventricles to the last visible section. Using a semiautomatic threshold approach, sulcal regions were traced out with manual adjustments when necessary. The volume of sulci in each slice was calculated and multiplied by the slice thickness and number of slices to calculate the SSV. All volumetric analysis was performed using Medical Image Processing, Analysis and Visualization Version 7.0.1 (MIPAV). A total of 109 subjects were included in our analysis. Mean selective sulcal volumes (SSV) differed between subjects with and without GCE 4.5 and 21.2 mL (P

ObjectiveInitial hemorrhage burden is an independent predictor for delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the association between clot clearance and DCI still remains to be elucidated.MethodsQuantitative analysis of hemorrhage volume and clot clearance was made in 116 consecutive patients who were scanned within 24 h from onset. Cisternal plus intraventricular hemorrhage volume (CIHV) was calculated as clot volume from the initial scans and scans performed up to 7 days after onset. Clot clearance was calculated as a percentage of residual clot volume compared with the clot volume on the initial scan. Initial clot volume and clot clearance were dichotomized to evaluate the association with DCI.ResultsIncluded patients were aged 55.5±15.2 years with a female preponderance (65.5%, (76/116)). The group with higher initial clot volume (≥17.2 mL) had higher odds for DCI (OR 4.3, 95% CI 1.3 to 14.0, p=0.015). However, the rate of DCI was not different between high and low clot clearance groups (26.7% vs 31.0%, p=0.66). Clot clearance rate was similar in patients with and without DCI up to day 7 after onset.ConclusionsThe quantitative clot clearance rate is not an independent predictor for DCI.

Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common single-gene disorder of cerebral small blood vessels caused by NOTCH3 mutations, little has been described about the variation in the clinical findings between its underlying types of mutations. In particular, the presence of cerebral microbleeds (CMBs) has been an increasingly recognized magnetic resonance imaging finding in CADASIL, but their clinical significance is not clear. The purpose of this study is to assess whether CMBs are associated with symptomatic stroke in the CADASIL patients with R544C mutation and to compare the cerebral distribution of CMBs between CADASIL patients with and without symptomatic stroke.This is a cohort study of patients who were diagnosed with genotype-confirmed R544C-mutation CADASIL. Primary neurologic symptoms were recorded. Symptomatic strokes were defined as transient ischemic attack, ischemic strokes and hemorrhagic strokes. CMBs were defined as focal areas of round signal loss on T2*-weighted gradient echo planar images with a diameter of less than 10 mm. The locations of CMBs were divided into lobar, basal ganglia, thalamus, brain stem and cerebellum. Multiple logistic regressions were performed to identify the epidemiologic or vascular risk factors associated with symptomatic stroke in patients with CADASIL.Among total of 51 subjects in this cohort, CMBs were present in 20 of 32 patients (64.5%) in the symptomatic stroke-group and in 8 of 19 patients (42.1%) in the non-stroke group (p = 0.16). CMBs were observed more frequently in the basal ganglia (p0.001) and the cerebellum (p0.018) in the symptomatic stoke group compared to the non-stroke group. The mean number of CMBs was significantly higher in the symptomatic stroke group (15.4±18.0 lesions per patients with CMBs) versus those without symptomatic stroke (3.3±3.0 lesions per patients with CMBs) (p = 0.003). Hypertension was an independent risk factor for symptomatic stroke in CADASIL (p = 0.014). It was independently associated with CMBs locations as basal ganglia (p = 0.016), thalamus (p = 0.010), brainstem (p = 0.044), and cerebellum (p = 0.049). However, It was not independently associated with CMBs on lobar lesion (p = 0.152).In this study hypertension was an independent predictor of CMBs presence in specific brain locations, as well as symptomatic stroke in the CADASIL patients. The distribution and burden of CMBs might be a clinically useful marker for the risk of symptomatic stroke. However, further prospective studies on the relationship between CMBs distribution and symptomatic stroke are required in order to support these preliminary findings.

Cleft lip and/or palate (CL/P) are common structural birth defects in humans. We used exome sequencing to study a patient with bilateral CL/P and identified a single nucleotide deletion in the patient and her similarly affected son—c.546_546delG, predicting p.Gln183Argfs*57 in the Distal-less 4 (DLX4) gene. The sequence variant was absent from databases, predicted to be deleterious and was verified by Sanger sequencing. In mammals, there are three Dlx homeobox clusters with closely located gene pairs (Dlx1/Dlx2, Dlx3/Dlx4, Dlx5/Dlx6). In situ hybridization showed that Dlx4 was expressed in the mesenchyme of the murine palatal shelves at E12.5, prior to palate closure. Wild-type human DLX4, but not mutant DLX4_c.546delG, could activate two murine Dlx conserved regulatory elements, implying that the mutation caused haploinsufficiency. We showed that reduced DLX4 expression after short interfering RNA treatment in a human cell line resulted in significant up-regulation of DLX3, DLX5 and DLX6, with reduced expression of DLX2 and significant up-regulation of BMP4, although the increased BMP4 expression was demonstrated only in HeLa cells. We used antisense morpholino oligonucleotides to target the orthologous Danio rerio gene, dlx4b, and found reduced cranial size and abnormal cartilaginous elements. We sequenced DLX4 in 155 patients with non-syndromic CL/P and CP, but observed no sequence variants. From the published literature, Dlx1/Dlx2 double homozygous null mice and Dlx5 homozygous null mice both have clefts of the secondary palate. This first finding of a DLX4 mutation in a family with CL/P establishes DLX4 as a potential cause of human clefts.

Background and Purpose Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common single-gene disorder of cerebral small blood vessels caused by NOTCH3 mutations, little has been described about the variation in the clinical findings between its underlying types of mutations. In particular, the presence of cerebral microbleeds (CMBs) has been an increasingly recognized magnetic resonance imaging finding in CADASIL, but their clinical significance is not clear. The purpose of this study is to assess whether CMBs are associated with symptomatic stroke in the CADASIL patients with R544C mutation and to compare the cerebral distribution of CMBs between CADASIL patients with and without symptomatic stroke. Methods This is a cohort study of patients who were diagnosed with genotype-confirmed R544C-mutation CADASIL. Primary neurologic symptoms were recorded. Symptomatic strokes were defined as transient ischemic attack, ischemic strokes and hemorrhagic strokes. CMBs were defined as focal areas of round signal loss on T2*-weighted gradient echo planar images with a diameter of less than 10 mm. The locations of CMBs were divided into lobar, basal ganglia, thalamus, brain stem and cerebellum. Multiple logistic regressions were performed to identify the epidemiologic or vascular risk factors associated with symptomatic stroke in patients with CADASIL. Results Among total of 51 subjects in this cohort, CMBs were present in 20 of 32 patients (64.5%) in the symptomatic stroke-group and in 8 of 19 patients (42.1%) in the non-stroke group (p = 0.16). CMBs were observed more frequently in the basal ganglia (p

Summary Cerebral microbleeds (CMBs) are commonly found in patients with stroke and cerebral amyloid angiopathy. However, there have been no reports of CMBs or their acute appearance in patients with status epilepticus. Herein we describe two patients with refractory status epilepticus of uncertain origin. Both patients were previously healthy, and their initial imaging showed no underlying CMBs. One patient's follow-up susceptibility-weighted imaging 29 days after initial imaging showed 63 new CMBs. The other patient's follow-up susceptibility-weighted imaging 41 days after initial imaging showed 14 new CMBs. Multimodal neuromonitoring revealed increase in lactate–pyruvate ratio, decrease in partial brain tissue oxygen tension, increase in pressure reactivity index, and fluctuations of blood pressure and cerebral perfusion pressure. This report demonstrates that multiple new CMBs may develop in patients with refractory status epilepticus (SE).