Faculty Bibliography

Objective: To describe the ischemic stroke subtypes related to coronavirus disease 2019 (COVID-19) in a cohort of New York City hospitals and explore their etiopathogenesis. Background: Most neurological manifestations are non-focal, but few have reported the characteristics of ischemic strokes or investigated its pathophysiology. Methods: Data were collected prospectively April 1-April 15, 2020 from two centers in New York City to review possible ischemic stroke types seen in COVID-19-positive patients. Patient presentation, demographics, related vascular risk factors, associated laboratory markers, as well as imaging and outcomes were collected. Results: The age of patients ranged between 27 and 82 years. Approximately 81% of patients had known vascular risk factors, the commonest being hypertension (75%) followed by diabetes (50%) coronary disease or atrial fibrillation. Eight patients presented with large vessel occlusion (LVO) with median age 55 years (27-82) and all were male. Eight patients presented with non-LVO syndromes, with median age 65.5 years (59-82) and most were female (62.5%). Both groups were 50% African Americans and 37.5% South Asian. Both groups had similar D-dimer levels although other acute phase reactants/disease severity markers (Ferritin, CRP, procalcitonin) were higher in the LVO group. The LVO group also had a significantly higher mortality compared to the non-LVO group. The most common etiology was cryptogenic (6 patients) followed by small vessel occlusion (3 patients) and undetermined-unclassified (3 patients). For the remaining 4 patients, 2 were identified as cardioembolic and 2 with large artery atherosclerosis. Conclusion: COVID-19-related ischemic events can present as small vessel occlusions, branch emboli or large vessel occlusions. The most common etiology is cryptogenic. Patients with LVO syndromes tend to be younger, male and may have elevated acute inflammatory markers.

To identify the factors mediating the progression of diabetic nephropathy (DN), we performed RNA sequencing of kidney biopsy samples from patients with early DN, advanced DN, and normal kidney tissue from nephrectomy samples. A set of genes that were upregulated at early but downregulated in late DN were shown to be largely renoprotective, which included genes in the retinoic acid pathway and glucagon-like peptide 1 receptor. Another group of genes that were downregulated at early but highly upregulated in advanced DN consisted mostly of genes associated with kidney disease pathogenesis, such as those related to immune response and fibrosis. Correlation with estimated glomerular filtration rate (eGFR) identified genes in the pathways of iron transport and cell differentiation to be positively associated with eGFR, while those in the immune response and fibrosis pathways were negatively associated. Correlation with various histopathological features also identified the association with the distinct gene ontological pathways. Deconvolution analysis of the RNA sequencing data set indicated a significant increase in monocytes, fibroblasts, and myofibroblasts in advanced DN kidneys. Our study thus provides potential molecular mechanisms for DN progression and association of differential gene expression with the functional and structural changes observed in patients with early and advanced DN.

PURPOSE OF REVIEW/OBJECTIVE:A major goal in neurocritical care is to monitor for and prevent secondary brain injuries. However, injuries occurring at the cellular and molecular levels evade detection by conventional hemodynamic monitoring and the neurological exam. Cerebral microdialysis (CMD) is an invasive means of providing nearly continuous measurements of cerebral metabolism and is a promising tool that can detect signs of cellular distress before systemic manifestations of intracranial catastrophe. RECENT FINDINGS/RESULTS:In this review, we describe the technique of CMD and the common biomarkers used to monitor cerebral energy metabolism. We examine the published evidence on how CMD data reflect secondary injuries and improve understanding of the pathophysiology of traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage. We also discuss some of the caveats of the technique, including how CMD probe position affect the sensitivity of capturing energy failures, and how abnormal levels of cerebral glucose and lactate can reflect different states of cerebral energy metabolism. In order to best incorporate cerebral metabolic monitoring into the management of neurocritical care patients, neurointensivists must be familiar with the nuances in the limitations as well as the interpretations of data obtained from cerebral microdialysis.

Introduction: Eptifibatide (Integrilin) has been demonstrated to improve clinical outcomes in both intracoronary and carotid artery stenting, when administered perioperatively. This evidence promotes the investigation of eptifibatide's role in neuroendovascular stenting. Methods: 38 patients between 2013-2017 underwent intracranial stenting with eptifibatide administration within 24 hours of procedure. Cumulative and average eptifibatide dosages were determined for all patients. Peri and post-procedural bleeding complications were defined as intercranial hemorrhage (ICH), symptomatic intercranial hemorrhage (sICH), and peripheral bleeding (retroperitoneal, access site bleeding, GI bleeding). Final Thrombolysis in Cerebral Infarction (TICI) scores as well as modified Rankin Scales (mRS) at discharge were also collected. Comparisons of these outcomes were made between patients with high-dose Integrilin and low-dose Integrilin, which we defined as above or equal to and below 0.75 mcg/kg/ min, respectively. A similar comparison was performed for patients who received above and below calculated dosage of median cumulative dose (0.71 mg/kg) Results: Of all 38 patients, 7 (21.8%) patients were found to have intracerebral hemorrhage, with 3 of these patients showing symptoms. Additionally, 6 patients (18.7%) experienced peripheral bleeding complications. Mean eptifibatide dosage was determined to be 0.77 mcg/kg/min. Analysis of the primary endpoint of all-cause bleeding complications yielded no significance between high-dose and low-dose Integrilin (p > 0.05). However, the incidence of sICH was significantly greater in patients receiving an average dosage at 0.75 mcg/kg/min or higher (p < 0.05). Furthermore, angiographic assessment revealed that more patients who receive a cumulative dosage of 0.71 mg/kg or greater achieved a TICI score of 2c-3 in comparison to those who achieved TICI 2b (p < 0.05). Conclusions: Usage of eptifibatide for patients undergoing neurovascular stenting at higher average dosages may result in a higher incidence of symptomatic ICH, however higher cumulative dosages may improve angiographic outcomes

Introduction: Eptifibitide is a commonly used antithrombotic shown to reduce ischemic complications related to percutaneous coronary intervention. Recent findings suggest that eptifibatide administration has the potential to improve post-procedural outcomes in the context of neuroendovascular therapy for acute ischemic stroke. Methods: 49 patients between 2014 and 2017 underwent thrombectomy for acute stroke and received eptifibitide. Cumulative and average eptifibatide dosages were determined for all patients. Peri- and and post-procedural bleeding complications were categorized into: intercranial hemorrhage (ICH), symptomatic intercranial hemorrhage (sICH), and peripheral bleeding (retroperitoneal, access site bleeding, and GI bleeding). Additionally, reperfusion Thrombolysis in Cerebral Infarction (TICI) scores as well as discharge modified Rankin Scales (mRS) were also collected. Patients were divided into those who received an average infusion rate of 0.75 mcg/kg/min or higher and those who received lower, with rates of functional and clinical outcomes analyzed. An identical analysis was done for patients above and below median cumulative dosage (0.32 mg/kg). Results: Of 49 total patients, 16 (32.7%) patients were found to have intracranial hemorrhage, with 5 showing resulting clinical symptoms. 14 patients (28.6%) experienced peripheral bleeding complications. The mean eptifibatide infusion for the selected patients was 0.75 mcg/kg/min with a median cumulative dosage of 0.32 mg/kg. On analysis, patients who received a higher average infusion of eptifibitide had higher incidence of all-cause bleeding complications (p < 0.05), however individual analysis of each bleeding complication showed no significant relationship (p > 0.05). Additionally, patients who received higher infusions of eptifibitide or higher cumulative doses of eptifibitide increased rate of achieving TICI scores of 2c-3 in comparison to patients who achieved a TICI score of 2b (p < 0.05). Conclusions: Usage of eptifibatide for patients undergoing neuroendovascular therapy for acute stroke at increased dosages may increase risk of overall bleeding complications. Higher dosage or infusion rate of eptifibatide may contribute to better post-procedural cerebral reperfusion

CREB-binding protein (CREBBP) is important for the cell-autonomous regulation of hematopoiesis, including the stem cell compartment. In the present study, we show that CREBBP plays an equally pivotal role in microenvironment-mediated regulation of hematopoiesis. We found that the BM microenvironment of Crebbp(+/-) mice was unable to properly maintain the immature stem cell and progenitor cell pools. Instead, it stimulates myeloid differentiation, which progresses into a myeloproliferation phenotype. Alterations in the BM microenvironment resulting from haploinsufficiency of Crebbp included a marked decrease in trabecular bone that was predominantly caused by increased osteoclastogenesis. Although CFU-fibroblast (CFU-F) and total osteoblast numbers were decreased, the bone formation rate was similar to that found in wild-type mice. At the molecular level, we found that the known hematopoietic modulators matrix metallopeptidase-9 (MMP9) and kit ligand (KITL) were decreased with heterozygous levels of Crebbp. Lastly, potentially important regulatory proteins, endothelial cell adhesion molecule 1 (ESAM1) and cadherin 5 (CDH5), were increased on Crebbp(+/-) endothelial cells. Our findings reveal that a full dose of Crebbp is essential in the BM microenvironment to maintain proper hematopoiesis and to prevent excessive myeloproliferation.