Publications by authors named "Muhammad S Hussain"

64 Publications

Engineering of a critical membrane-anchored enzyme for high solubility and catalytic activity.

Arch Biochem Biophys 2021 Apr 5;703:108870. Epub 2021 Apr 5.

Department of Chemistry & Biochemistry, University of Toledo, Toledo, OH, 43606, USA. Electronic address:

Membrane-associated proteins carry out a wide range of essential cellular functions but the structural characterization needed to understand these functions is dramatically underrepresented in the Protein Data Bank. Producing a soluble, stable and active form of a membrane-associated protein presents formidable challenges, as evidenced by the variety of approaches that have been attempted with a multitude of different membrane proteins to achieve this goal. Aspartate N-acetyltransferase (ANAT) is a membrane-anchored enzyme that performs a critical function, the synthesis of N-acetyl-l-aspartate (NAA), the second most abundant amino acid in the brain. This amino acid is a precursor for a neurotransmitter, and alterations in brain NAA levels have been implicated as a causative effect in Canavan disease and has been suggested to be involved in other neurological disorders. Numerous prior attempts have failed to produce a soluble form of ANAT that is amenable for functional and structural investigations. Through the application of a range of different approaches, including fusion partner constructs, linker modifications, membrane-anchor modifications, and domain truncations, a highly soluble, stable and fully active form of ANAT has now been obtained. Producing this modified enzyme form will accelerate studies aimed at structural characterization and structure-guided inhibitor development.
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http://dx.doi.org/10.1016/j.abb.2021.108870DOI Listing
April 2021

Mediating the Fate of Cancer Cell Uptake: Dual-Targeted Magnetic Nanovectors with Biotin and Folate Surface Ligands.

ACS Biomater Sci Eng 2020 11 22;6(11):6138-6147. Epub 2020 Oct 22.

Institute of Inorganic Chemistry, University of Cologne, Greinstraße 6, 50939 Cologne, Germany.

Recognition of folate and biotin surface receptors by dual-functionalized nanoparticles (NPs) is key for site-selective receptor-mediated transport of anticancer drugs to cancer cells. We present here dopamine-capped iron oxide nanoprobes (FeO, 10 ± 2 nm) containing two surface-grafted biologically relevant ligands, namely, folic acid (FA) and biotin (BT). The covalent attachment of both FA and BT on FeO nanoparticles was achieved by following carbodiimide coupling and click-chemistry protocols. The dual-function FeO probes were delivered into E-G7 and human HeLa cancer cell lines and tested toward their cellular uptake by immunofluorescence and flow cytometry analysis. Owing to receptor-mediated endocytosis, enhanced accumulation of nanoprobes in cancer cells was successfully monitored by confocal laser microscopy. When compared to dual-function probes, single-functionalized nanoparticles possessing either FA or BT ligands showed significantly reduced uptake in the tested cell lines, underlining the superior interaction potential of dual-purpose probes. A time-dependent receptor-mediated endocytosis of FA-FeO-BT nanovectors was demonstrated by flow cytometry analysis, whereas the unfunctionalized NPs did not show any specificity in terms of uptake. Besides their specific uptake, the surface-functionalized nanoparticles exhibited promising cytotoxicity profiles by demonstrating good viability of more than 95% with analogous cancer cell lines. Our results demonstrate that dual and/or multivariate conjugation of receptor-specific ligands on NPs is highly effective in molecular recognition of surface biomarkers that enhances their potential in anticancer treatment for pretargeting-radio strategies based on biotin/avidin interactions.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00771DOI Listing
November 2020

RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis.

Nat Commun 2020 11 16;11(1):5816. Epub 2020 Nov 16.

Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen, Denmark.

Primary microcephaly (MCPH) is characterized by reduced brain size and intellectual disability. The exact pathophysiological mechanism underlying MCPH remains to be elucidated, but dysfunction of neuronal progenitors in the developing neocortex plays a major role. We identified a homozygous missense mutation (p.W155C) in Ribosomal RNA Processing 7 Homolog A, RRP7A, segregating with MCPH in a consanguineous family with 10 affected individuals. RRP7A is highly expressed in neural stem cells in developing human forebrain, and targeted mutation of Rrp7a leads to defects in neurogenesis and proliferation in a mouse stem cell model. RRP7A localizes to centrosomes, cilia and nucleoli, and patient-derived fibroblasts display defects in ribosomal RNA processing, primary cilia resorption, and cell cycle progression. Analysis of zebrafish embryos supported that the patient mutation in RRP7A causes reduced brain size, impaired neurogenesis and cell proliferation, and defective ribosomal RNA processing. These findings provide novel insight into human brain development and MCPH.
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http://dx.doi.org/10.1038/s41467-020-19658-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670429PMC
November 2020

Discovery of Novel Inhibitors of a Critical Brain Enzyme Using a Homology Model and a Deep Convolutional Neural Network.

J Med Chem 2020 08 30;63(16):8867-8875. Epub 2020 Jul 30.

Department of Chemistry and Biochemistry, University of Toledo, Toledo, Ohio 43606, United States.

Rare neglected diseases may be neglected but are hardly rare, affecting hundreds of millions of people around the world. Here, we present a hit identification approach using AtomNet, the world's first deep convolutional neural network for structure-based drug discovery, to identify inhibitors targeting aspartate -acetyltransferase (ANAT), a promising target for the treatment of patients suffering from Canavan disease. Despite the lack of a protein structure or high sequence identity homologous templates, the approach successfully identified five low-micromolar inhibitors with drug-like properties.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00473DOI Listing
August 2020

Mutation in CEP135 causing primary microcephaly and subcortical heterotopia.

Am J Med Genet A 2020 10 9;182(10):2450-2453. Epub 2020 Jul 9.

Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

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http://dx.doi.org/10.1002/ajmg.a.61762DOI Listing
October 2020

Cost-Consequence Analysis of Mobile Stroke Units vs. Standard Prehospital Care and Transport.

Front Neurol 2019 12;10:1422. Epub 2020 Feb 12.

Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States.

Mobile stroke units (MSUs) are the latest approach to improving time-sensitive stroke care delivery. Currently, there are no published studies looking at the expanded value of the MSU to diagnose and transport patients to the closest most appropriate facility. The purpose of this paper is to perform a cost consequence analysis of standard transport (ST) vs. MSU. A cost consequence analysis was undertaken within a decision framework to compare the incremental cost of care for patients with confirmed stroke that were served by the MSU vs. their simulated care had they been served by standard emergency medical services between July 2014 and October 2015. At baseline values, the incremental cost between MSU and ST was $70,613 ($856,482 vs. $785,869) for 355 patient transports. The MSU avoided 76 secondary interhospital transfers and 76 emergency department (ED) encounters. Sensitivity analysis identified six variables that had measurable impact on the model's variability and a threshold value at which MSU becomes the optimal strategy: number of stroke patients (>391), probability of requiring transfer to a comprehensive stroke center (CSC, >0.52), annual cost of MSU operations (<$696,053), cost of air transfer (>$8,841), probability initial receiving hospital is a CSC (<0.32), and probability of ischemic stroke with ST (<0.76). MSUs can avert significant costs in the administration of stroke care once optimal thresholds are achieved. A comprehensive cost-effectiveness analysis is required to determine not just the operational value of an MSU but also its clinical value to patients and the society.
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http://dx.doi.org/10.3389/fneur.2019.01422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028763PMC
February 2020

A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: the MET-REMODEL trial.

Eur Heart J 2019 11;40(41):3409-3417

Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.

Aim: We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes.

Methods And Results: We randomly assigned 68 patients (mean age 65 ± 8 years) without diabetes who have CAD with IR and/or pre-diabetes to receive either metformin XL (2000 mg daily dose) or placebo for 12 months. Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging. In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference -1.37 (95% confidence interval: -2.63 to -0.12, P = 0.033). Metformin also significantly reduced other secondary study endpoints such as: LVM (P = 0.032), body weight (P = 0.001), subcutaneous adipose tissue (P = 0.024), office systolic blood pressure (BP, P = 0.022) and concentration of thiobarbituric acid reactive substances, a biomarker for oxidative stress (P = 0.04). The glycated haemoglobin A1C concentration and fasting IR index did not differ between study groups at the end of the study.

Conclusion: Metformin treatment significantly reduced LVMI, LVM, office systolic BP, body weight, and oxidative stress. Although LVH is a good surrogate marker of cardiovascular (CV) outcome, conclusive evidence for the cardio-protective role of metformin is required from large CV outcomes trials.
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http://dx.doi.org/10.1093/eurheartj/ehz203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823615PMC
November 2019

Cerebrospinal fluid drainage and blood pressure elevation to treat acute spinal cord infarct.

Surg Neurol Int 2018 21;9:195. Epub 2018 Sep 21.

Cerebrovascular Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Background: Current management of acute spinal cord infarction (SCI) is limited. Lumbar cerebrospinal fluid drainage (CSFD) with blood pressure augmentation is utilized in the thoracic/thoracoabdominal aortic repair and thoracic endovascular aortic repair (TEVAR) populations to increase spinal perfusion pressure.

Case Description: We identified 3 patients who sustained acute SCI and underwent CSFD and maintenance of elevated mean arterial pressure (MAP) within 24 hours of injury. The first patient exhibited delayed-onset ischemia after a TEVAR. The second patient presented with an acute type B aortic intramural hematoma. The third patient developed spinal cord ischemia following bronchial artery embolization. There was significant improvement in the motor examination (e.g., ASIA impairment scale grade B or C) to grade D utilizing both blood pressure augmentation and CSFD.

Conclusions: Lumbar CSFD with MAP elevation benefited 3 patients with acute SCI of varying etiologies.
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http://dx.doi.org/10.4103/sni.sni_2_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169349PMC
September 2018

ELVO: an operational definition.

J Neurointerv Surg 2018 Jun 8;10(6):507-509. Epub 2018 Feb 8.

Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1136/neurintsurg-2018-013792DOI Listing
June 2018

Interhospital Transfer Before Thrombectomy Is Associated With Delayed Treatment and Worse Outcome in the STRATIS Registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke).

Circulation 2017 Dec 24;136(24):2311-2321. Epub 2017 Sep 24.

Advanced Neuroscience Network/Tenet South Florida, Delray Beach (R.K., N.H.M.-K.).

Background: Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation.

Methods: STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0-2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass.

Results: A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients (<0.001). Clinical outcomes were better in the direct group, with 60.0% (299/498) achieving functional independence compared with 52.2% (213/408) in the transfer group (odds ratio, 1.38; 95% confidence interval, 1.06-1.79; =0.02). Likewise, excellent outcome (modified Rankin Score 0-1) was achieved in 47.4% (236/498) of direct patients versus 38.0% (155/408) of transfer patients (odds ratio, 1.47; 95% confidence interval, 1.13-1.92; =0.005). Mortality did not differ between the 2 groups (15.1% for direct, 13.7% for transfer; =0.55). Intravenous tissue plasminogen activator did not impact outcomes. Hypothetical bypass modeling for all transferred patients suggested that intravenous tissue plasminogen activator would be delayed by 12 minutes, but MT would be performed 91 minutes sooner if patients were routed directly to endovascular-capable centers. If bypass is limited to a 20-mile radius from onset, then intravenous tissue plasminogen activator would be delayed by 7 minutes and MT performed 94 minutes earlier.

Conclusions: In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large-vessel occlusion and direct routing to endovascular-capable centers for patients with severe stroke may improve outcomes.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02239640.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732640PMC
December 2017

Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke: Primary Results of the STRATIS Registry.

Stroke 2017 10 22;48(10):2760-2768. Epub 2017 Aug 22.

From the Advanced Neuroscience Network/Tenet South Florida (N.H.M.-K., R.K.); St Vincent Mercy Hospital, Toledo, OH (O.O.Z.); Vanderbilt University Medical Center, Nashville, TN (M.T.F., R.C.); University of California Los Angeles (R.J., J.L.S., D.S.L., S. Starkman); Brigham and Women's Hospital, Boston, MA (M.A.A.-S.); Methodist Hospital, Houston, TX (R.P.K.); Florida Hospital Neuroscience Institute, Winter Park (F.R.H., R.H.G.); University of Miami Miller School of Medicine/Jackson Memorial Hospital, FL (D.R.Y., E.C.P.); Norton Neuroscience Institute, Norton Healthcare, Louisville, KY (T.L.Y., S.R.D.); University of Pittsburgh Medical Center, PA (A.P.J.); WellStar Neurosciences Network, WellStar Kennestone Regional Medical Center, Marietta, GA (R.G.); Valley Baptist Medical Center, Harlingen, TX (A.E.H.); St Luke's Hospital of Kansas City, MO (C.O.M.); Oregon Health and Science University Hospital, Portland, OR (H.B.); Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA (R.G.N., D.C.H.); Baptist Health Lexington/Central Baptist, KY (C.A.G.); South Broward Hospital, Hollywood, FL (B.P.M.); Providence St Vincent Medical Center, Portland, OR (V.D.); Baptist Hospital of Miami, FL (I.L.); St Dominic's-Jackson Memorial Hospital, MS (S.H.M.); University of Tennessee Medical Center, Knoxville (P.K.); Advocate Christ Medical Center, Oak Lawn, IL (T.J.G.); Cleveland Clinic, OH (M.S.H.); Baylor University Medical Center, Dallas, TX (I.T.); OhioHealth Riverside Methodist Hospital, Columbus (N.V.); Memorial Hermann Texas Medical Center, Houston (P.R.C.); Swedish Medical Center First Hill Campus, Seattle, WA (S.J.M.); Maine Medical Center, Portland (R.D.E.); Geisinger Clinic, Danville, PA (C.M.S.); Baptist Medical Center-Jacksonville, FL (E.S.); Baptist Hospital Louisville, KY (A.A.-C.); Barnes Jewish Hospital, St Louis, MO (C.P.D.); Mercy San Juan Medical Center and Mercy General, Carmichael, CA (L.M.); Presence St Joseph Medical Center, Joliet, IL (A. Badruddin); Buffalo General Medical Center, NY (A.H.S.); University of Arizona Medical Center, Tucson (T.M.D.); University of Kentucky Hospital, Lexington (A.A.); Los Robles Medical Center, Thousand Oaks, CA (M.A.T.); Aurora Hospital, Milwaukee, WI (K.A.); West Virginia University/Ruby Memorial Hospital, Morgantown, WV (J.C.); Albany Medical Center, NY (A. Boulos); University of Maryland Medical Center, Baltimore (G.J.); University of Massachusetts Memorial Medical Center, Worcester (A.S.P.); Crouse Hospital, Syracuse, NY (E.M.D.); Virginia Mason Medical Center, Seattle, WA (D.H.R.); Mayo Clinic-Rochester, MN (D.F.K.); Erlanger Medical Center, Chattanooga, TN (B.W.B.); ProMedica Toledo Hospital, OH (M.A.J.); Banner University Medical Center, Phoenix, AZ (P.S.); McLaren Flint, MI (A.M.); California Pacific Medical Center, San Francisco (J.D.E.); University of California, Irvine, Orange (S. Suzuki); St John Providence Hospital, Detroit, MI (R.D.F.); Abbott Northwestern Hospital, Minneapolis, MN (J.E.D.A.); and Carolinas Medical Center, Charlotte, NC (J.C.M.).

Background And Purpose: Mechanical thrombectomy with stent retrievers has become standard of care for treatment of acute ischemic stroke patients because of large vessel occlusion. The STRATIS registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) aimed to assess whether similar process timelines, technical, and functional outcomes could be achieved in a large real world cohort as in the randomized trials.

Methods: STRATIS was designed to prospectively enroll patients treated in the United States with a Solitaire Revascularization Device and Mindframe Capture Low Profile Revascularization Device within 8 hours from symptom onset. The STRATIS cohort was compared with the interventional cohort of a previously published SEER patient-level meta-analysis.

Results: A total of 984 patients treated at 55 sites were analyzed. The mean National Institutes of Health Stroke Scale score was 17.3. Intravenous tissue-type plasminogen activator was administered in 64.0%. The median time from onset to arrival in the enrolling hospital, door to puncture, and puncture to reperfusion were 138, 72, and 36 minutes, respectively. The Core lab-adjudicated modified Thrombolysis in Cerebral Infarction ≥2b was achieved in 87.9% of patients. At 90 days, 56.5% achieved a modified Rankin Scale score of 0 to 2, all-cause mortality was 14.4%, and 1.4% suffered a symptomatic intracranial hemorrhage. The median time from emergency medical services scene arrival to puncture was 152 minutes, and each hour delay in this interval was associated with a 5.5% absolute decline in the likelihood of achieving modified Rankin Scale score 0 to 2.

Conclusions: This largest-to-date Solitaire registry documents that the results of the randomized trials can be reproduced in the community. The decrease of clinical benefit over time warrants optimization of the system of care.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02239640.
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http://dx.doi.org/10.1161/STROKEAHA.117.016456DOI Listing
October 2017

Flow Diverter Treatment of Tandem Intracranial Aneurysms.

World Neurosurg 2017 Nov 3;107:142-147. Epub 2017 Aug 3.

Cerebrovascular Center, Cleveland Clinic, Cleveland, Ohio, USA. Electronic address:

Objective: To assess technical success and clinical and imaging outcomes of flow diversion (FD) treatment of multiple, tandem intracranial aneurysms.

Methods: Retrospective analysis was performed of patients treated with FD for tandem intracranial aneurysms.

Results: Twenty female patients with a mean (±SD) age of 60 (±12) years were included. One patient was treated after subarachnoid hemorrhage. In 22 separate procedures, 47 aneurysms, all located in the intracranial internal carotid artery, were treated. In 3 cases, treatment was performed for aneurysm recurrence after previous endovascular treatment. All aneurysms were successfully treated in 1 session. A single stent was used in most (82%) cases, with no adjunctive coiling. There were no intraprocedural complications. Three patients experienced mild, transient neurologic symptoms after the procedure with no long-term neurologic deficits. Follow-up imaging with digital subtraction angiography and/or contrast-enhanced magnetic resonance angiography was available in 18/20 (90%) patients at an average (±SD) of 18.8 (±11.2) months. Of 40 aneurysms with follow-up imaging, 34 (85%) were completely occluded. Clinical follow-up, available in 20/20 (100%) patients, showed that 19/20 (95%) achieved a modified Rankin Scale score of 0-2. There were no cases of aneurysm rupture after treatment, and no patients required retreatment at last available follow-up.

Conclusions: FD appears technically feasible, safe, and effective for treatment of tandem intracranial aneurysms, with potential advantages over traditional endovascular or surgical treatment modalities. Larger studies are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.wneu.2017.07.146DOI Listing
November 2017

Reduction in time to treatment in prehospital telemedicine evaluation and thrombolysis.

Neurology 2017 Apr 8;88(14):1305-1312. Epub 2017 Mar 8.

From the Cerebrovascular Center (A.T., R.C., A.I., S.W., M.B., M.M.D., Z.K., D.W., J.A.F., A.N.R., P.R., K.U., M.S.H.), Department of Neurology (N.O., A.B.B., L.S., S.-M.C.), and Critical Care Transport Team (A.P.R., F.M.H., D.M.K.), Cleveland Clinic, OH; and Department of Epidemiology and Biostatistics, School of Medicine (F.B.S.B.), and Frances Payne Bolton School of Nursing (A.P.R.), Case Western Reserve University, Cleveland, OH.

Objective: To compare the times to evaluation and thrombolytic treatment of patients treated with a telemedicine-enabled mobile stroke treatment unit (MSTU) vs those among patients brought to the emergency department (ED) via a traditional ambulance.

Methods: We implemented a MSTU with telemedicine at our institution starting July 18, 2014. A vascular neurologist evaluated each patient via telemedicine and a neuroradiologist and vascular neurologist remotely assessed images obtained by the MSTU CT. Data were entered in a prospective registry. The evaluation and treatment of the first 100 MSTU patients (July 18, 2014-November 1, 2014) was compared to a control group of 53 patients brought to the ED via a traditional ambulance in 2014. Times were expressed as medians with their interquartile ranges.

Results: Patient and stroke severity characteristics were similar between 100 MSTU and 53 ED control patients (initial NIH Stroke Scale score 6 vs 7, = 0.679). There was a significant reduction of median alarm-to-CT scan completion times (33 minutes MSTU vs 56 minutes controls, < 0.0001), median alarm-to-thrombolysis times (55.5 minutes MSTU vs 94 minutes controls, < 0.0001), median door-to-thrombolysis times (31.5 minutes MSTU vs 58 minutes controls, = 0.0012), and symptom-onset-to-thrombolysis times (97 minutes MSTU vs 122.5 minutes controls, = 0.0485). Sixteen patients evaluated on MSTU received thrombolysis, 25% of whom received it within 60 minutes of symptom onset.

Conclusion: Compared with the traditional ambulance model, telemedicine-enabled ambulance-based thrombolysis resulted in significantly decreased time to imaging and treatment.
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http://dx.doi.org/10.1212/WNL.0000000000003786DOI Listing
April 2017

Safety and outcomes of simultaneous vasospasm and endovascular aneurysm treatment (SVAT) in subarachnoid hemorrhage.

J Neurointerv Surg 2017 May 27;9(5):482-485. Epub 2016 Oct 27.

Department of Neurology, Albany Medical College, Albany, New York, USA.

Background: Simultaneous vasospasm and endovascular aneurysm treatment (SVAT) has been shown to be effective with good clinical outcomes in small series, but these studies have not examined predictive factors for clinical outcome after treatment.

Objective: To identify the safety and efficacy of SVAT in a large multicenter patient cohort and evaluate prognostic markers of clinical outcome following SVAT.

Methods: This study retrospectively enrolled 50 consecutive patients undergoing SVAT at 11 different centers. We analyzed Hunt and Hess and Fisher grades, aneurysm location, angiographic vasospasm grade, Glasgow Outcome Scale (GOS) at discharge, and 90-day modified Rankin Scale (mRS) scores.

Results: A total of 50 patients undergoing SVAT between the years 2003 and 2009 were identified. Patients presented, on average, 6.48±4.45 days after subarachnoid hemorrhage. Hunt and Hess and Fisher grades were 1 (n=7), 2 (n=12), 3 (n=14), 4 (n=15), 5 (n=2), and 3 and 4 (n=33), respectively. Aneurysm location was distributed as follows: anterior (n=32), posterior (n=16), anterior and posterior (n=2). Patients with good clinical condition (Hunt and Hess score 1-3) had significantly higher odds of surviving (OR=17.5, 95% CI 1.9 to 161.5), favorable GOS (OR=4.2, 95% CI 1.2 to 14.8), and favorable 90-day mRS (OR=4.2, 95% CI 1.2 to 14.8).

Conclusions: SVAT is safe, with the majority of patients achieving good clinical outcome. Patients with lower Hunt and Hess grades have higher odds of surviving and favorable clinical prognosis.
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http://dx.doi.org/10.1136/neurintsurg-2016-012714DOI Listing
May 2017

The Combination of Clinical Features, Transcranial Doppler, and Alberta Stroke Program Early Computed Tomography Score (Computed Tomography Angiography) in Predicting Outcome in Intravenous Recombinant Tissue Plasminogen Activator-Treated Patients.

J Stroke Cerebrovasc Dis 2016 Aug 27;25(8):2019-23. Epub 2016 May 27.

Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta, Canada.

Background: Little data exist on using combined baseline clinical neuroimaging and transcranial Doppler (TCD) information in predicting clinical outcome in stroke patients treated with intravenous (IV) thrombolysis.

Methods: Stroke patients received IV recombinant tissue plasminogen activator (rt-PA) and had diagnostic TCD within 3 hours of symptom onset. The TCD result was interpreted using the thrombolysis in brain ischemia (TIBI) flow grading system. Following multiple regression analysis, a grading system was created with 1 point for each of the following: National Institutes of Health Stroke Scale (NIHSS) score of 16 or higher, TIBI score of 1 or lower, and Alberta Stroke Program Early CT Score (ASPECTS) of 6 or lower. The patients' scores were compared to modified Rankin Scale (mRS) scores at 90 days.

Results: A total of 349 patients were included. In unvaried analysis, age of 80 years or older (P = .002), an ASPECTS of 6 or lower (P < .001), an NIHSS score of 16 or higher (P < .001), a TIBI score of 1 or lower (P < .001), and a glucose level ≥ 200 mg/dl (P = .04) were associated with poor outcome (mRS score > 2). In the multiple regression analysis, age of 80 years or older, an ASPECTS of 6 or lower, an NIHSS score of 16 or higher, and hyperglycemia were predictors of poor outcome (P < .05). Based on our scoring system, the patients' odds ratios for poor outcome were 7 (95% confidence interval [CI]: 2-23, P = .003), 8 (95% CI: 3-25, P < .001), and 24 (95% CI: 4-151, P = .001) for scores of 1, 2, and 3, respectively, after adjustment for common stroke risk factors. The mean time to recanalization increased as the score increased (score of 0: 160 ± 45 minutes versus score of 3: 186 ± 38 (P = .70).

Conclusion: A multimodal grading system is useful in predicting outcome in patients treated with IV rt-PA. Those withhigher scores might be candidates for interventional therapy.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.12.013DOI Listing
August 2016

Timeline of blood pressure changes after intra-arterial therapy for acute ischemic stroke based on recanalization status.

J Neurointerv Surg 2017 May 15;9(5):455-458. Epub 2016 Apr 15.

Cerebrovascular Center, Cleveland Clinic, Cleveland, Ohio, USA.

Background: There is sparse literature on the natural history of blood pressure (BP) after intra-arterial therapy (IAT) for acute ischemic stroke (AIS).

Methods: A retrospective analysis was performed of patients with AIS who underwent IAT without endotracheal intubation for internal carotid artery terminus (ICA-T) or M1 middle cerebral artery occlusion from January 2008 to February 2012. Systolic BP (SBP) values at the beginning (First) and end (End) of IAT and for 36 h after the procedure were collected. Successful recanalization was defined as Thrombolysis In Cerebral Infarction (TICI) 2b-3.

Results: Sixty-two patients (14 (22.5%) ICA-T, 46 (74.2%) M1, 2 (3.2%) ICA-T+M1) met the study criteria and 37 (59.7%) achieved successful recanalization. The First and End SBP values were similar in the successful (Group R) and unsuccessful (Group NR) recanalization groups. Taking the whole cohort, End SBP was significantly lower than First SBP, but this decline was significant only in Group R. Subsequently, absolute SBP values in Group R were not significantly different from Group NR. However, when comparing the hourly decline of SBP with First SBP, Group R demonstrated a greater fall than Group NR and the decline was significantly different from hours 8 to 12 post-procedure. The SBP in Group NR then decreased further, and its difference from baseline was similar to Group R from hour 14 onwards. Mean SBP and SBP variability over 36 h were similar between the two groups.

Conclusions: SBP falls significantly in patients with AIS with large vessel occlusion who recanalize with IAT. While SBP in non-recanalized patients also drops from baseline, it occurs to a lesser degree and stays higher only for a short period of time before falling to similar levels as in recanalized patients.
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http://dx.doi.org/10.1136/neurintsurg-2016-012369DOI Listing
May 2017

Lower Intraprocedural Systolic Blood Pressure Predicts Good Outcome in Patients Undergoing Endovascular Therapy for Acute Ischemic Stroke.

Interv Neurol 2016 Mar 25;4(3-4):151-7. Epub 2016 Feb 25.

Cerebrovascular Center, Cleveland Clinic, Cleveland, Ohio, USA.

Background: It is unknown if intraprocedural blood pressure (BP) influences clinical outcomes and what BP parameter best predicts outcomes in acute ischemic stroke (AIS) patients who undergo intra-arterial therapy (IAT) for emergent large vessel occlusion.

Methods: We retrospectively reviewed 147 patients who underwent IAT for anterior circulation AIS from January 2008 to December 2012 at our institution. Baseline demographics, stroke treatment variables, and detailed intraprocedural hemodynamic variables were collected.

Results: The entire cohort consisted of 81 (55%) females with a mean age of 66.9 ± 15.6 years and a median National Institutes of Health Stroke Scale (NIHSS) score of 16 (IQR 11-21). Thirty-six (24.5%) patients died during hospitalization, 25 (17%) achieved a 30-day modified Rankin Scale score of 0-2, and 24 (16.3%) suffered symptomatic parenchymal hematoma type 1/2 hemorrhage. Patients who achieved a good outcome had a significantly lower admission NIHSS score, a higher baseline CT ASPECTS score, and a lower rate of ICA terminus occlusions. Successful recanalization was more frequent in the good-outcome group, while symptomatic hemorrhages occurred only in poor-outcome patients. The first systolic BP (SBP; 146.5 ± 0.2 vs. 157.7 ± 25.6 mm Hg, p = 0.042), first mean arterial pressure (MAP; 98.1 ± 20.8 vs. 109.7 ± 20.3 mm Hg, p = 0.024), maximum SBP (164.6 ± 27.6 vs. 180.9 ± 18.3 mm Hg, p = 0.0003), and maximum MAP (125.5 ± 18.6 vs. 138.5 ± 24.6 mm Hg, p = 0.0309) were all significantly lower in patients who achieved good outcomes. A lower maximum intraprocedural SBP was an independent predictor of good outcome (adjusted OR 0.929, 95% CI 0.886-0.963, p = 0.0005). Initial NIHSS score was the only other independent predictor of a good outcome.

Conclusion: Lower intraprocedural SBP was associated with good outcome in patients undergoing IAT for AIS, and maximum SBP was an independent predictor of good outcome. SBP may be the optimal hemodynamic variable to monitor intraprocedurally during IAT and may predict outcome.
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http://dx.doi.org/10.1159/000444098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817385PMC
March 2016

Performance of CT Angiography on a Mobile Stroke Treatment Unit: Implications for Triage.

J Neuroimaging 2016 07 30;26(4):391-4. Epub 2016 Mar 30.

Cerebrovascular Center, Cleveland Clinic, Cleveland, OH.

Background: There is a strong inverse relationship between outcome in patients with acute ischemic stroke from emergent large vessel occlusion (ELVO), and time to reperfusion from intra-arterial therapy. Delay in transferring patients to thrombectomy-capable centers is currently a major limitation. The mobile stroke unit (MSU) concept with onboard portable computed tomography (CT) scanner enables rapid performance of CT angiography (CTA) of the intracranial vessels to detect ELVO in the field, and allows for rapid triage of patients to interventional-capable centers.

Methods: Our institution implemented a mobile stroke treatment unit (MSTU) program that started on July 2014, and CTA capability was added on April 2015. The eligibility criteria, equipment, and method of CTA imaging are described. We report the first case of CTA being performed in the field in the United States to aid in triage of ELVO patients.

Results: MSTU was dispatched for reported new onset of right hemiparesis in a patient. Teleneurological assessment detected findings consistent with a severe left middle cerebral artery (MCA) syndrome. Noncontrast CT head revealed left lenticulostriate hypoattenuation. A CTA was performed subsequently on the MSTU that showed an MCA cutoff. Based on these findings, patient was immediately transferred to the main hospital with neurointerventional capability, where he underwent successful recanalization with improvement in symptoms.

Conclusion: CTA is possible on an MSTU, enabling rapid detection and triage of ELVO cases directly to thrombectomy-capable centers, which significantly reduces time to endovascular treatment.
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http://dx.doi.org/10.1111/jon.12346DOI Listing
July 2016

Telemedicine in Prehospital Stroke Evaluation and Thrombolysis: Taking Stroke Treatment to the Doorstep.

JAMA Neurol 2016 Feb;73(2):162-8

Cerebrovascular Center, Cleveland Clinic, Cleveland, Ohio.

Importance: Mobile stroke treatment units (MSTUs) with on-site treatment teams that include a vascular neurologist can provide thrombolysis in the prehospital setting faster than treatment in the hospital. These units can be made more resource efficient if the need for an on-site neurologist can be eliminated by relying solely on telemedicine for physician presence.

Objective: To test whether telemedicine is reliable and remote physician presence is adequate for acute stroke treatment using an MSTU.

Design, Setting, And Participants: Prospective observational study conducted between July 18 and November 1, 2014. The dates of the study analysis were November 1, 2014, to March 30, 2015. The setting was a community-based study assessing telemedicine success of the MSTU in Cleveland, Ohio. Participants were the first 100 residents of Cleveland who had an acute onset of stroke-like symptoms between 8 am and 8 pm and were evaluated by the MSTU after the implementation of the MSTU program at the Cleveland Clinic. A vascular neurologist evaluated the first 100 patients via telemedicine, and a neuroradiologist remotely assessed images obtained by mobile computed tomography (CT). Data were entered into the medical record and a prospective registry.

Main Outcomes And Measures: The study compared the evaluation and treatment of patients on the MSTU with a control group of patients brought to the emergency department via ambulance during the same year. Process times were measured from the time the patient entered the door of the MSTU or emergency department, and any problems encountered during his or her evaluation were recorded.

Results: Ninety-nine of 100 patients were evaluated successfully. The median duration of telemedicine evaluation was 20 minutes (interquartile range [IQR], 14-27 minutes). One connection failure was due to crew error, and the patient was transported to the nearest emergency department. There were 6 telemedicine disconnections, none of which lasted longer than 60 seconds or affected clinical care. Times from the door to CT completion (13 minutes [IQR, 9-21 minutes]) and from the door to intravenous thrombolysis (32 minutes [IQR, 24-47 minutes]) were significantly shorter in the MSTU group compared with the control group (18 minutes [IQR, 12-26 minutes] and 58 minutes [IQR, 53-68 minutes], respectively). Times to CT interpretation did not differ significantly between the groups.

Conclusions And Relevance: An MSTU using telemedicine is feasible, with a low rate of technical failure, and may provide an avenue for reducing the high cost of such systems.
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http://dx.doi.org/10.1001/jamaneurol.2015.3849DOI Listing
February 2016

Brain Imaging Using Mobile CT: Current Status and Future Prospects.

J Neuroimaging 2016 Jan-Feb;26(1):5-15. Epub 2015 Nov 23.

Cerebrovascular Center, Cleveland Clinic, Cleveland, OH.

Computed tomography (CT) is an invaluable tool in the diagnosis of many clinical conditions. Several advancements in biomedical engineering have achieved increase in speed, improvements in low-contrast detectability and image quality, and lower radiation. Portable or mobile CT constituted one such important advancement. It is especially useful in evaluating critically ill, intensive care unit patients by scanning them at bedside. A paradigm shift in utilization of mobile CT was its installation in ambulances for the management of acute stroke. Given the time sensitive nature of acute ischemic stroke, Mobile stroke units (MSU) were developed in Germany consisting of an ambulance equipped with a CT scanner, point of care laboratory system, along with teleradiological support. In a radical reconfiguration of stroke care, the MSU would bring the CT scanner to the stroke patient, without waiting for the patient at the emergency room. Two separate MSU projects in Saarland and Berlin demonstrated the safety and feasibility of this concept for prehospital stroke care, showing increased rate of intravenous thrombolysis and significant reduction in time to treatment compared to conventional care. MSU also improved the triage of patients to appropriate and specialized hospitals. Although multiple issues remain yet unanswered with the MSU concept including clinical outcome and cost-effectiveness, the MSU venture is visionary and enables delivery of life-saving and enhancing treatment for ischemic and hemorrhagic stroke. In this review, we discuss the development of mobile CT and its applications, with specific focus on its use in MSUs along with our institution's MSU experience.
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http://dx.doi.org/10.1111/jon.12319DOI Listing
January 2017

Emergent mechanical thrombectomy for acute stroke using the Mindframe Capture LP system: initial single-center experience.

J Neurointerv Surg 2016 Nov 13;8(11):1178-1180. Epub 2015 Nov 13.

Cerebrovascular Center, Cleveland Clinic, Cleveland, Ohio, USA.

Background: Mechanical thrombectomy using stentrievers is the standard of care for emergent large vessel occlusion stroke. Data on the use of stentrievers in smaller caliber vessels are sparse.

Objective: To present our initial experience with the Mindframe Capture LP device, which was designed for mechanical thrombectomy in small cerebral arteries.

Methods: A retrospective chart review was conducted of patients who underwent Mindframe device assisted emergent thrombectomy. Clinical, imaging, procedural and early follow-up data were obtained.

Results: Nine patients met inclusion criteria (5 men, median age 62 years). Median National Institute of Health Stroke Scale (NIHSS) score was 18 (IQR 9-22), and 6 patients received intravenous tissue plasminogen activator. Six patients had M2 segment occlusions, and 2 patients had distal M1 segment occlusions of the middle cerebral artery. One had distal basilar artery occlusion. Median vessel diameter at the thrombus was 1.7 mm (IQR 1.5-2.5). In all 9 patients the Mindframe device was used together with manual aspiration, with median groin puncture to recanalization time of 35 min (IQR 27-54), and median procedural time of 67 min (IQR 51-91). Final Thrombolysis in Cerebral Infarction score was 3 and 2b in 4 patients each (89% total), and 2a in 1 patient. No patient had any postprocedural complications or symptomatic intracerebral hemorrhage. Median postprocedure and discharge NIHSS were 4 and 1, respectively.

Conclusions: Our data suggest that the Mindframe device is safe and effective for rapid treatment of acute strokes involving small caliber intracranial vessels. Further study in a larger cohort is warranted.
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http://dx.doi.org/10.1136/neurintsurg-2015-012078DOI Listing
November 2016

Safety and Hemodynamic Profile of Propofol and Dexmedetomidine Anesthesia during Intra-arterial Acute Stroke Therapy.

J Stroke Cerebrovasc Dis 2015 Oct 29;24(10):2397-403. Epub 2015 Jul 29.

Cerebrovascular Center, Cleveland Clinic, Cleveland, Ohio.

Background: There is limited data on the safety, hemodynamic profile, and outcome of patients undergoing intra-arterial therapy (IAT) for acute ischemic stroke (AIS) under sedation with dexmedetomidine (DEX) versus propofol (PROP).

Methods: Retrospective study of patients with anterior circulation AIS, who underwent IAT without intubation, and received either DEX or PROP between January 2008 and December 2012, was performed. Demographics, stroke treatments, time metrics, anesthesia, intraprocedural hemodynamics, vasopressor use, infarct volumes, recanalization status, and intracerebral hemorrhage were collected.

Results: Seventy-two patients met inclusion criteria, of which 35 received DEX and 37 PROP. There was no difference in baseline demographics, stroke treatments, successful recanalization, hemorrhages, infarct volume growth, good clinical outcome (mRS ≤ 2 [19% versus 22%, P = .742]), or in-hospital mortality (18% versus 8%, P = .225) between DEX and PROP. The DEX group had lower intraprocedural minimum systolic blood pressure (103 ± 27 versus 114 ± 18 mm Hg, P = .032) and minimum mean arterial pressure (MAP; 67 ± 17 versus 77 ± 10 mm Hg, P = .006). More patients in the DEX group experienced episodes of hypotension (MAP < 60 mm Hg; 24% versus 3%; P = .010) and had higher vasopressor requirement (phenylephrine: 1825 ± 2390 versus 491 ± 884 mcg, P = .007) compared to PROP.

Conclusions: There was no difference in good clinical outcome or in-hospital mortality in patients undergoing IAT for AIS using DEX versus PROP sedation. However, hemodynamic instability and vasopressor requirement were significantly higher in the DEX group. DEX should be cautiously utilized in IAT.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.06.041DOI Listing
October 2015

A Mobile Stroke Treatment Unit for Field Triage of Patients for Intraarterial Revascularization Therapy.

J Neuroimaging 2015 Nov-Dec;25(6):940-5. Epub 2015 Jul 14.

Cerebrovascular Center, Cleveland Clinic, Cleveland, OH.

Introduction: Favorable outcomes in intraarterial therapy (IAT) for acute ischemic stroke (AIS) are related to early vessel recanalization. The mobile stroke treatment unit (MSTU) is an on-site, prehospital, treatment team, laboratory, and CT scanner that reduces time to treatment for intravenous thrombolysis and may also shorten time to IAT.

Methods: Using our MSTU database, we identified patients that underwent IAT for AIS. We compared the key time metrics to historical controls, which included patients that underwent IAT at our institution six months prior to implementation of the MSTU. We further divided the controls into two groups: (1) transferred to our institution for IAT and (2) directly presented to our emergency room and underwent IAT.

Results: After 164 days of service, the MSTU transported 155 patients of which 5 underwent IAT. We identified 5 historical controls that were transferred to our center for IAT. Substantial reduction in times including median door to initial CT (12 minute vs. 32 minute), CT to IAT (82 minute vs. 165 minute), and door to MSTU/primary stroke center departure (37 minute vs. 106 minute) were noted among the two groups. Compared to the 6 patients who presented to our institution directly, the MSTU process times were also shorter.

Conclusion: Our initial experience shows that MSTU may help in early triage and shorten the time to IAT for AIS.
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http://dx.doi.org/10.1111/jon.12276DOI Listing
December 2016

Large deep white matter lesions may predict futile recanalization in endovascular therapy for acute ischemic stroke.

Interv Neurol 2015 Jan;3(1):48-55

Cerebrovascular Center, Cleveland Clinic, Cleveland, Ohio, USA.

Objective: This study investigated whether large ischemic lesions in the deep white matter (DWM) on pretreatment diffusion-weighted MRI (DWI) predict futile recanalization.

Methods: Consecutive acute stroke patients with anterior circulation ischemia who underwent successful arterial recanalization with thrombolysis in cerebral infarction grade 2b or 3 were enrolled. A large DWI-DWM lesion was defined as a hyperintense lesion in the DWM on initial DWI, located mainly between the anterior and posterior horns of the lateral ventricle. The Alberta Stroke Program Early CT score on CT and DWI and stroke volume on initial DWI were recorded. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) score. Futile recanalization was defined as a 30-day modified Rankin scale score of 3-6 despite successful recanalization. Univariate and multivariate regression analyses were performed to identify predictors of futile recanalization.

Results: In 35 of 46 patients (76%) with successful recanalization, futile recanalization was observed in 20 patients (57%). Patients with futile recanalization were older (median age 74 vs. 58 years; p = 0.053), had higher initial NIHSS scores (median 17 vs. 9; p = 0.042), and a higher prevalence of large DWI-DWM lesions (45 vs. 9%; p = 0.022). Logistic regression analysis showed that a large DWI-DWM lesion was an independent predictor of futile recanalization (OR 13.97; 95% CI 1.32-147.73; p = 0.028).

Conclusion: Patients with large preintervention DWI-DWM lesions may be poor candidates for endovascular therapy.
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http://dx.doi.org/10.1159/000369835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4436528PMC
January 2015

Initial Experience Using the 5MAX™ ACE Reperfusion Catheter in Intra-arterial Therapy for Acute Ischemic Stroke.

J Cerebrovasc Endovasc Neurosurg 2014 Dec 30;16(4):350-7. Epub 2014 Dec 30.

Cerebrovascular Center, Cleveland Clinic, Cleveland, OH, United States.

Objectives: The 5MAX ACE is a new large bore aspiration catheter available for vessel recanalization for treatment of acute ischemic stroke (AIS). We report our initial experience with its use.

Methods: A retrospective analysis of patients undergoing intra-arterial therapy for AIS using the 5MAX ACE reperfusion catheter at our institution was performed. Patient demographics, clinical characteristics and procedural data were obtained from chart review. Successful recanlization was defined as achievement of Thrombolysis in Cerebral Infarction score (TICI) 2b-3 and time to recanalization was defined as time from groin puncture to achievement of at least TICI 2b recanalization.

Results: The 5MAX ACE was used in 15 patients from July-October 2013. Direct aspiration was used as the primary technique in 10/15 (67%) patients. Out of these, aspiration alone was sufficient for recanalization in 3 (20%) patients. In the remaining 7 (47%) patients, additional devices were used. In 5/15 (33%) patients, combined aspiration/stentriever thrombectomy using Solitaire™ (3/5 patients) and Penumbra 3D Separator™ (2/5 patients) were used as the primary technique. Successful recanlization (TICI 2b-3) was achieved in 11/15 (73%) patients. Average time from groin puncture to successful recanalization was 46 +/- 30 minutes (range 14-98 minutes). There were no procedural complications.

Conclusion: The 5MAX ACE is a useful recanalization tool, either by direct aspiration or combined stentriever/aspiration. It may be most advantageous with large clots in the internal carotid artery. The potential for effective and faster recanalization using this device alone or in combination may be a good topic for future study.
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http://dx.doi.org/10.7461/jcen.2014.16.4.350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296047PMC
December 2014

Predictors of infarct growth after endovascular therapy for acute ischemic stroke.

J Stroke Cerebrovasc Dis 2015 Feb 12;24(2):401-7. Epub 2014 Dec 12.

Cerebrovascular Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Background: Intra-arterial (IA) thrombectomy for acute ischemic stroke has an excellent recanalization rate but variable outcomes. The core infarct also grows at a variable rate despite recanalization. We aim to study the factors that are associated with infarct growth after IA therapy.

Methods: We reviewed the hyperacute ischemic stroke imaging database at Cleveland Clinic for those undergoing endovascular thrombectomy of anterior circulation from 2009 to 2012. Patients with both pretreatment and follow-up magnetic resonance imaging were included. Seventy-six patients were stratified into quartiles by infarct volume growth from initial to follow-up diffusion-weighted imaging (DWI) measure by a region of interest demarcation.

Results: The median infarct growth of each quartile was .6 cm(3) (no-growth group), 13.8, 37, and 160.2 cm(3) (large-growth group). Pretreatment stroke severity was comparable among groups. Compared with the no-growth group, the large-growth group had larger initial infarct defined by computed tomography (CT) Alberta Stroke Program Early CT score (median 10 versus 8, P = .032) and DWI volume (mean 13.8 versus 29.2 cm(3), P = .034), lack of full collateral vessels on CT angiography (36.8% versus 0%, P = .003), and a lower recanalization rate (thrombolysis in cerebral infarction ≥2b, P = .044). The increase in infarct growth is associated with decrease in favorable outcomes defined by a modified Rankin Scale score of 0-2 at 30 days: 57.9%, 42.1%, 21.1%, and 5.3%, respectively (P < .001). DWI reversal was observed in 11 of 76 patients, translating to 82% favorable outcome.

Conclusions: Infarct evolution after endovascular thrombectomy is associated with an outcome. DWI reversal or no growth translated to a favorable outcome. Small initial ischemic core, good collateral support, and better recanalization grades predict the smaller infarct growth and favorable outcome after endovascular thrombectomy.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.09.004DOI Listing
February 2015

Intra-arterial therapy for acute ischemic stroke under general anesthesia versus monitored anesthesia care.

Cerebrovasc Dis 2014 13;38(4):262-7. Epub 2014 Nov 13.

Cerebrovascular Center, Cleveland Clinic, Cleveland, Ohio, USA.

Background: Recent studies have shown that intra-arterial recanalization therapy (IAT) for acute ischemic stroke (AIS) is associated with worse clinical outcomes when performed under general anesthesia (GA) compared to local anesthesia, with or without conscious sedation. The reasons for this association have not been systematically studied.

Methods: We retrospectively reviewed 190 patients who underwent IAT for anterior circulation AIS from January 2008 to December 2012 at our institution. Baseline demographics, vessels involved, acute stroke treatment including intravenous tissue type plasminogen activator (tPA) use, use of GA vs. monitored anesthesia care (MAC), location of thrombus, recanalization grade, radiologic post-procedural intracerebral hemorrhage, and 30-day outcomes were collected. Relevant clinical time points were recorded. Detailed intra-procedural hemodynamics including maximum/minimum heart rate, systolic blood pressure (BP), diastolic BP, mean BP, use of pressors and episodes of hypotension were collected. Our study's outcomes were as follows: in-hospital mortality, 30-day good outcome (mRS ≤2), successful recanalization and radiologic post-procedural intracerebral hemorrhage.

Results: Ninety-one patients received GA and 99 patients received MAC. There was no significant difference in the NIHSS score between the two groups but the GA group had a higher number of ICA occlusions (31.9 vs. 18.2%, p = 0.043). The time from the start of anesthesia to incision (23.0 ± 12.5 min vs. 18.7 ± 11.3 min, p = 0.020) and the time from the start of anesthesia to recanalization (110 ± 57.2 vs. 92.3 ± 43.0, p = 0.045) was longer in the GA group. The time from incision to recanalization was not significantly different between the two groups. mRS 0-2 was achieved in 22.8% of patients in the MAC group compared to 14.9% in GA (p = 0.293). Higher mortality was seen in the GA group (25.8 vs. 13.3%, p = 0.040). Successful recanalization (TICI 2b-3) was similar between the GA and MAC (57.8 vs. 48.5%, p = 0.182) groups, but GA had a higher number of parenchymal hematomas (26.3 vs. 10.1%, p = 0.003). There was no difference in the intra-procedural hemodynamic variables between the GA and MAC groups. Anesthesia type was an independent predictor for mortality (along with age and initial NIHSS), and the only independent predictor for parenchymal hematomas, with MAC being protective for both.

Conclusion: Our study has confirmed previous findings of GA being associated with poorer outcomes and higher mortality in patients undergoing IAT for AIS. Detailed analysis of intra-procedural hemodynamics did not reveal any significant difference between the two groups. Parenchymal hematoma was the major driver of the difference in outcomes.
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http://dx.doi.org/10.1159/000368216DOI Listing
August 2015

Phospholipases A2: enzymatic assay for snake venom (Naja naja karachiensis) with their neutralization by medicinal plants of Pakistan.

Acta Pol Pharm 2014 Jul-Aug;71(4):625-30

Phospholipases A2 (PLA2) are the most lethal and noxious component of Naja naja karachiensis venom. They are engaged to induce severe toxicities after their penetration in victims. Present study was designed to highlight hydrolytic actions of PLA. in an egg yolk mixture and to encounter their deleterious effects via medicinal plants of Pakistan. PLA2 were found to produce free fatty acids in a dose dependent manner. Venom at concentration of 0.1 mg was found to liberate 26.6 pmoles of fatty acids with a decline in pH1 of 0.2 owing to the presence of PLA2 (133 Unit/mg). When quantity of venom was increased up to 8 mg, it caused to release 133 pmoles of free fatty acids with a decrease in 1.0 pH due to abundance in PLA, (665 Unit/mg). The rest of other doses of venom (0.3-4.0 mg) was found to liberate fatty acids between these two upper and lower limits. Twenty eight medicinal plants (0.1-0.6 mg) were tried to abort PLA, hydrolytic action, however, all were found useful (50-100%) against PLA,. Bauhinia variegate L., Citrus limon (L.). Burm.f. Enicostemnma hyssopifolium (Willd.) Verdoorn, Ocimum sanctum. Psoralea corylifolia L. and Stenolobium stans (L.) D. Don were found excellent in switching off 100% phospholipases A, at their lowest concentration (0.1 mg). Three plants extract were found useful only at lower concentration (0.1 mg), however, their higher doses were seemed to aggravate venom response. Eight medicinal plants failed to neutralize PLA, rather their higher doses were found effective. Standard antidote and rest of other plants extract were able to show maximum of 50% efficiencies. Therefore, it is necessary to identify and isolate bioactive constituent(s) from above cited six medicinal plants to eradicate the problem of snake bite in the future.
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November 2014

Solitary C1 spinal osteochondroma causing vertebral artery compression and acute cerebellar infarct.

Skeletal Radiol 2015 Feb 12;44(2):299-302. Epub 2014 Aug 12.

Department of Pathology, Cleveland Clinic, Cleveland, OH, USA,

Osteochondroma is a common benign bone lesion, usually involving the long bones. Spinal involvement is rare. The clinical presentation of spinal osteochondroma varies according to the site of the lesion. The most common reported clinical presentation is secondary to encroachment of the lesion on the spinal canal or nerve roots. Less common presentations such as a palpable neck mass, dysphagia, sleep apnea, paralysis of left vocal cord or acute respiratory distress have been reported when the lesions compress the anatomic structures anteriorly. We describe a rare case of a young patient who presented with an emergent critical condition of acute cerebellar infarct as a result of vertebral artery compression caused by a solitary C1 spinal osteochondroma.
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http://dx.doi.org/10.1007/s00256-014-1974-7DOI Listing
February 2015

A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family.

Hum Mol Genet 2014 Nov 20;23(22):5940-9. Epub 2014 Jun 20.

Institute of Human Genetics and

Asymmetric cell division is essential for normal human brain development. Mutations in several genes encoding centrosomal proteins that participate in accurate cell division have been reported to cause autosomal recessive primary microcephaly (MCPH). By homozygosity mapping including three affected individuals from a consanguineous MCPH family from Pakistan, we delineated a critical region of 18.53 Mb on Chromosome 1p21.3-1p13.1. This region contains the gene encoding HsSAS-6, a centrosomal protein primordial for seeding the formation of new centrioles during the cell cycle. Both next-generation and Sanger sequencing revealed a homozygous c.185T>C missense mutation in the HsSAS-6 gene, resulting in a p.Ile62Thr substitution within a highly conserved region of the PISA domain of HsSAS-6. This variant is neither present in any single-nucleotide polymorphism or exome sequencing databases nor in a Pakistani control cohort. Experiments in tissue culture cells revealed that the Ile62Thr mutant of HsSAS-6 is substantially less efficient than the wild-type protein in sustaining centriole formation. Together, our findings demonstrate a dramatic impact of the mutation p.Ile62Thr on HsSAS-6 function and add this component to the list of genes mutated in primary microcephaly.
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http://dx.doi.org/10.1093/hmg/ddu318DOI Listing
November 2014