UW Neurological Surgery Recent PubMed Publications

Preclinical Profile of AB-423, an Inhibitor of Hepatitis B Virus Pregenomic RNA Encapsidation.

Antimicrob Agents Chemother. 2018 06;62(6):

Authors: Mani N, Cole AG, Phelps JR, Ardzinski A, Cobarrubias KD, Cuconati A, Dorsey BD, Evangelista E, Fan K, Guo F, Guo H, Guo JT, Harasym TO, Kadhim S, Kultgen SG, Lee ACH, Li AHL, Long Q, Majeski SA, Mao R, McClintock KD, Reid SP, Rijnbrand R, Snead NM, Micolochick Steuer HM, Stever K, Tang S, Wang X, Zhao Q, Sofia MJ

Abstract
AB-423 is a member of the sulfamoylbenzamide (SBA) class of hepatitis B virus (HBV) capsid inhibitors in phase 1 clinical trials. In cell culture models, AB-423 showed potent inhibition of HBV replication (50% effective concentration [EC50] = 0.08 to 0.27 μM; EC90 = 0.33 to 1.32 μM) with no significant cytotoxicity (50% cytotoxic concentration > 10 μM). Addition of 40% human serum resulted in a 5-fold increase in the EC50s. AB-423 inhibited HBV genotypes A through D and nucleos(t)ide-resistant variants in vitro Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pregenomic RNA and relaxed circular DNA (rcDNA), indicating that it is a class II capsid inhibitor. In a de novo infection model, AB-423 prevented the conversion of encapsidated rcDNA to covalently closed circular DNA, presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer-dimer interface of core protein. In vitro dual combination studies with AB-423 and anti-HBV agents, such as nucleos(t)ide analogs, RNA interference agents, or interferon alpha, resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher levels of accumulation in the liver. A 7-day twice-daily administration of AB-423 in a hydrodynamic injection mouse model of HBV infection resulted in a dose-dependent reduction in serum HBV DNA levels, and combination with entecavir or ARB-1467 resulted in a trend toward antiviral activity greater than that of either agent alone, consistent with the results of the in vitro combination studies. The overall preclinical profile of AB-423 supports its further evaluation for safety, pharmacokinetics, and antiviral activity in patients with chronic hepatitis B.

PMID: 29555628 [PubMed - indexed for MEDLINE]

A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite.

Nat Med. 2018 05;24(4):408-416

Authors: Kisalu NK, Idris AH, Weidle C, Flores-Garcia Y, Flynn BJ, Sack BK, Murphy S, Schön A, Freire E, Francica JR, Miller AB, Gregory J, March S, Liao HX, Haynes BF, Wiehe K, Trama AM, Saunders KO, Gladden MA, Monroe A, Bonsignori M, Kanekiyo M, Wheatley AK, McDermott AB, Farney SK, Chuang GY, Zhang B, Kc N, Chakravarty S, Kwong PD, Sinnis P, Bhatia SN, Kappe SHI, Sim BKL, Hoffman SL, Zavala F, Pancera M, Seder RA

Abstract
Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.

PMID: 29554083 [PubMed - indexed for MEDLINE]

National Football League Head, Neck and Spine Committee's Concussion Diagnosis and Management Protocol: 2017-18 season.

Br J Sports Med. 2018 Jul;52(14):894-902

Authors: Ellenbogen RG, Batjer H, Cardenas J, Berger M, Bailes J, Pieroth E, Heyer R, Theodore N, Hsu W, Nabel E, Maroon J, Cantu R, Barnes R, Collins J, Putukian M, Lonser R, Solomon G, Sills A

Abstract
One of the National Football League's (NFL) Head, Neck and Spine Committee's principal goals is to create a 'best practice' protocol for concussion diagnosis and management for its players. The science related to concussion diagnosis and management continues to evolve, thus the protocol has evolved contemporaneously. The Fifth International Conference on Concussion in Sport was held in Berlin in 2016, and guidelines for sports concussion diagnosis and management were revised and refined. The NFL Head, Neck and Spine Committee has synthesised the most recent empirical evidence for sports concussion diagnosis and management including the Berlin consensus statement and tailored it to the game played in the NFL. One of the goals of the Committee is to provide a standardised, reliable, efficient and evidence-based protocol for concussion diagnosis and management that can be applied in this professional sport during practice and game day. In this article, the end-of-season version of the 2017-18 NFL Concussion Diagnosis and Management Protocol is described along with its clinical rationale. Immediate actions for concussion programme enhancement and research are reviewed. It is the Committee's expectation that the protocol will undergo refinement and revision over time as the science and clinical practice related to concussion in sports crystallise.

PMID: 29549147 [PubMed - indexed for MEDLINE]

CaBP1 regulates Cav1 L-type Ca2+ channels and their coupling to neurite growth and gene transcription in mouse spiral ganglion neurons.

Mol Cell Neurosci. 2018 04;88:342-352

Authors: Yang T, Choi JE, Soh D, Tobin K, Joiner ML, Hansen M, Lee A

Abstract
CaBP1 is a Ca2+ binding protein that is widely expressed in neurons in the brain, retina, and cochlea. In heterologous expression systems, CaBP1 interacts with and regulates voltage-gated Cav Ca2+ channels but whether this is the case in neurons is unknown. Here, we investigated the cellular functions of CaBP1 in cochlear spiral ganglion neurons (SGNs), which express high levels of CaBP1. Consistent with the role of CaBP1 as a suppressor of Ca2+-dependent inactivation (CDI) of Cav1 (L-type) channels, Cav1 currents underwent greater CDI in SGNs from mice lacking CaBP1 (C-KO) than in wild-type (WT) SGNs. The coupling of Cav1 channels to downstream signaling pathways was also disrupted in C-KO SGNs. Activity-dependent repression of neurite growth was significantly blunted and unresponsive to Cav1 antagonists in C-KO SGNs in contrast to WT SGNs. Moreover, Cav1-mediated Ca2+ signals and phosphorylation of cAMP-response element binding protein were reduced in C-KO SGNs compared to WT SGNs. Our findings establish a role for CaBP1 as an essential regulator of Cav1 channels in SGNs and their coupling to downstream pathways controlling activity-dependent transcription and neurite growth.

PMID: 29548764 [PubMed - indexed for MEDLINE]

Current approach to meningiomas of the medial sphenoid wing and the cavernous sinus.

Neurol India. 2018 Mar-Apr;66(2):335-341

Authors: Sekhar LN, Qazi Z

PMID: 29547151 [PubMed - indexed for MEDLINE]

A better approach to in vivo developmental neurotoxicity assessment: Alignment of rodent testing with effects seen in children after neurotoxic exposures.

Toxicol Appl Pharmacol. 2018 09 01;354:176-190

Authors: Vorhees CV, Sprowles JN, Regan SL, Williams MT

Abstract
High throughput screens for developmental neurotoxicity (DN) will facilitate evaluation of chemicals and can be used to prioritize those designated for follow-up. DN is evaluated under different guidelines. Those for drugs generally include peri- and postnatal studies and juvenile toxicity studies. For pesticides and commercial chemicals, when triggered, include developmental neurotoxicity studies (DNT) and extended one-generation reproductive toxicity studies. Raffaele et al. (2010) reviewed 69 pesticide DNT studies and found two of the four behavioral tests underperformed. There are now many epidemiological studies on children showing adverse neurocognitive effects, yet guideline DN studies fail to assess most of the functions affected in children; nor do DN guidelines reflect the advances in brain structure-function relationships from neuroscience. By reducing the number of test ages, removing underperforming tests and replacing them with tests that assess cognitive abilities relevant to children, the value of DN protocols can be improved. Testing for the brain networks that mediate higher cognitive functions need to include assessments of working memory, attention, long-term memory (explicit, implicit, and emotional), and executive functions such as cognitive flexibility. The current DNT focus on what can be measured should be replaced with what should be measured. With the wealth of data available from human studies and neuroscience, the recommendation is made for changes to make DN studies better focused on human-relevant functions using tests of proven validity that assess comparable functions to tests used in children. Such changes will provide regulatory authorities with more relevant data.

PMID: 29544898 [PubMed - indexed for MEDLINE]

Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial.

JAMA Oncol. 2018 05 10;4(5):e180013

Authors: Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH

Abstract
Importance: Therapeutic options are needed for patients with advanced gastric cancer whose disease has progressed after 2 or more lines of therapy.
Objective: To evaluate the safety and efficacy of pembrolizumab in a cohort of patients with previously treated gastric or gastroesophageal junction cancer.
Design, Setting, and Participants: In the phase 2, global, open-label, single-arm, multicohort KEYNOTE-059 study, 259 patients in 16 countries were enrolled in a cohort between March 2, 2015, and May 26, 2016. Median (range) follow-up was 5.8 (0.5-21.6) months.
Intervention: Patients received pembrolizumab, 200 mg, intravenously every 3 weeks until disease progression, investigator or patient decision to withdraw, or unacceptable toxic effects.
Main Outcomes and Measures: Primary end points were objective response rate and safety. Objective response rate was assessed by central radiologic review per Response Evaluation Criteria in Solid Tumors, version 1.1, in all patients and those with programmed cell death 1 ligand 1 (PD-L1)-positive tumors. Expression of PD-L1 was assessed by immunohistochemistry. Secondary end points included response duration.
Results: Of 259 patients enrolled, most were male (198 [76.4%]) and white (200 [77.2%]); median (range) age was 62 (24-89) years. Objective response rate was 11.6% (95% CI, 8.0%-16.1%; 30 of 259 patients), with complete response in 2.3% (95% CI, 0.9%-5.0%; 6 of 259 patients). Median (range) response duration was 8.4 (1.6+ to 17.3+) months (+ indicates that patients had no progressive disease at their last assessment). Objective response rate and median (range) response duration were 15.5% (95% CI, 10.1%-22.4%; 23 of 148 patients) and 16.3 (1.6+ to 17.3+) months and 6.4% (95% CI, 2.6%-12.8%; 7 of 109 patients) and 6.9 (2.4 to 7.0+) months in patients with PD-L1-positive and PD-L1-negative tumors, respectively. Forty-six patients (17.8%) experienced 1 or more grade 3 to 5 treatment-related adverse events. Two patients (0.8%) discontinued because of treatment-related adverse events, and 2 deaths were considered related to treatment.
Conclusions and Relevance: Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment. Durable responses were observed in patients with PD-L1-positive and PD-L1-negative tumors. Further study of pembrolizumab for this group of patients is warranted.
Trial Registration: clinicaltrials.gov Identifier: NCT02335411.

PMID: 29543932 [PubMed - indexed for MEDLINE]

THE SUCCESS OF INTRAVITREAL INJECTIONS.

Ulster Med J. 2017 May;86(2):149-150

Authors: O'Donnell M, Williams M

PMID: 29535495 [PubMed - in process]

Association of Early Myocardial Workload and Mortality Following Severe Traumatic Brain Injury.

Crit Care Med. 2018 06;46(6):965-971

Authors: Krishnamoorthy V, Vavilala MS, Chaikittisilpa N, Rivara FP, Temkin NR, Lele AV, Gibbons EF, Rowhani-Rahbar A

Abstract
OBJECTIVES: To examine the impact of early myocardial workload on in-hospital mortality following isolated severe traumatic brain injury.
DESIGN: Retrospective cohort study.
SETTING: Data from the National Trauma Databank, a multicenter trauma registry operated by the American College of Surgeons, from 2007 to 2014.
PATIENTS: Adult patients with isolated severe traumatic brain injury (defined as admission Glasgow Coma Scale < 8 and head Abbreviated Injury Score ≥ 4).
INTERVENTIONS: Admission rate-pressure product, categorized into five levels based on published low, normal, and submaximal human thresholds: less than 5,000; 5,000-9,999; 10,000-14,999; 15,000-19,999; and greater than 20,000.
MEASUREMENTS AND MAIN RESULTS: Data from 26,412 patients were analyzed. Most patients had a normal rate-pressure product (43%), 35% had elevated rate-pressure product, and 22% had depressed rate-pressure product at hospital admission. Compared with the normal rate-pressure product group, in-hospital mortality was 22 percentage points higher in the lowest rate-pressure product group (cumulative mortality, 50.2%; 95% CI, 43.6-56.9%) and 11 percentage points higher in the highest rate-pressure product group (cumulative mortality, 39.2%; 95% CI, 37.4-40.9%). The lowest rate-pressure product group was associated with a 50% increased risk of mortality, compared with the normal rate-pressure product group (adjusted relative risk, 1.50; 95% CI, 1.31-1.76%; p < 0.0001), and the highest rate-pressure product group was associated with a 25% increased risk of mortality, compared with the normal rate-pressure product group (adjusted relative risk, 1.25; 95% CI, 1.18-1.92%; p < 0.0001). This relationship was blunted with increasing age. Among patients with normotension, those with depressed and elevated rate-pressure products experienced increased mortality.
CONCLUSIONS: Adults with severe traumatic brain injury experience heterogeneous myocardial workload profiles that have a "U-shaped" relationship with mortality, even in the presence of a normal blood pressure. Our findings are novel and suggest that cardiac performance is important following severe traumatic brain injury.

PMID: 29509569 [PubMed - indexed for MEDLINE]

Coagulopathy induced by traumatic brain injury: systemic manifestation of a localized injury.

Blood. 2018 05 03;131(18):2001-2006

Authors: Zhang J, Zhang F, Dong JF

Abstract
Traumatic brain injury (TBI)-induced coagulopathy is a common and well-recognized risk for poor clinical outcomes, but its pathogenesis remains poorly understood, and treatment options are limited and ineffective. We discuss the recent progress and knowledge gaps in understanding this lethal complication of TBI. We focus on (1) the disruption of the brain-blood barrier to disseminate brain injury systemically by releasing brain-derived molecules into the circulation and (2) TBI-induced hypercoagulable and hyperfibrinolytic states that result in persistent and delayed intracranial hemorrhage and systemic bleeding.

PMID: 29507078 [PubMed - indexed for MEDLINE]

Implementation of the 2017 Berlin Concussion in Sport Group Consensus Statement in contact and collision sports: a joint position statement from 11 national and international sports organisations.

Br J Sports Med. 2018 May;52(10):635-641

Authors: Patricios JS, Ardern CL, Hislop MD, Aubry M, Bloomfield P, Broderick C, Clifton P, Echemendia RJ, Ellenbogen RG, Falvey ÉC, Fuller GW, Grand J, Hack D, Harcourt PR, Hughes D, McGuirk N, Meeuwisse W, Miller J, Parsons JT, Richiger S, Sills A, Moran KB, Shute J, Raftery M

Abstract
The 2017 Berlin Concussion in Sport Group Consensus Statement provides a global summary of best practice in concussion prevention, diagnosis and management, underpinned by systematic reviews and expert consensus. Due to their different settings and rules, individual sports need to adapt concussion guidelines according to their specific regulatory environment. At the same time, consistent application of the Berlin Consensus Statement's themes across sporting codes is likely to facilitate superior and uniform diagnosis and management, improve concussion education and highlight collaborative research opportunities. This document summarises the approaches discussed by medical representatives from the governing bodies of 10 different contact and collision sports in Dublin, Ireland in July 2017. Those sports are: American football, Australian football, basketball, cricket, equestrian sports, football/soccer, ice hockey, rugby league, rugby union and skiing. This document had been endorsed by 11 sport governing bodies/national federations at the time of being published.

PMID: 29500252 [PubMed - indexed for MEDLINE]

The interdependence of excitation and inhibition for the control of dynamic breathing rhythms.

Nat Commun. 2018 02 26;9(1):843

Authors: Baertsch NA, Baertsch HC, Ramirez JM

Abstract
The preBötzinger Complex (preBötC), a medullary network critical for breathing, relies on excitatory interneurons to generate the inspiratory rhythm. Yet, half of preBötC neurons are inhibitory, and the role of inhibition in rhythmogenesis remains controversial. Using optogenetics and electrophysiology in vitro and in vivo, we demonstrate that the intrinsic excitability of excitatory neurons is reduced following large depolarizing inspiratory bursts. This refractory period limits the preBötC to very slow breathing frequencies. Inhibition integrated within the network is required to prevent overexcitation of preBötC neurons, thereby regulating the refractory period and allowing rapid breathing. In vivo, sensory feedback inhibition also regulates the refractory period, and in slowly breathing mice with sensory feedback removed, activity of inhibitory, but not excitatory, neurons restores breathing to physiological frequencies. We conclude that excitation and inhibition are interdependent for the breathing rhythm, because inhibition permits physiological preBötC bursting by controlling refractory properties of excitatory neurons.

PMID: 29483589 [PubMed - indexed for MEDLINE]

Lawful physician-hastened death: AAN position statement.

Neurology. 2018 02 27;90(9):420-422

Authors: Russell JA, Epstein LG, Bonnie RJ, Conwit R, Graf WD, Kirschen M, Kurek JA, Larriviere DG, Pascuzzi RM, Rizzo M, Sattin JA, Simmons Z, Taylor L, Tsou A, Williams MA, Ethics, Law, and Humanities Committee (a joint committee of the AAN, ANA, and CNS), Ethics, Law and Humanities Committee, a joint committee of the AAN, ANA and CNS

PMID: 29483313 [PubMed - indexed for MEDLINE]

Endovascular stent-coiling of a giant basilar artery aneurysm through a previous radial artery bypass.

J Clin Neurosci. 2018 May;51:100-102

Authors: Ozdemir B, Kelly CM, Levitt MR, Kim LJ

Abstract
Giant, partially-thrombosed basilar artery (BA) aneurysms are extraordinarily difficult to treat. Due to the high risk of rupture exclusion of these aneurysms from the circulation is imperative. In certain instances, direct clipping is unsuitable, and high-flow bypass and proximal parent vessel clip occlusion is required. We report a case of a recurrent partially-thrombosed giant BA apex aneurysm treated with endovascular stent-coiling through a previous radial artery bypass graft. Following the initial bypass and aneurysm trapping six years prior, the patient was neurologically stable until three months prior to admission when he developed new diplopia and left third nerve palsy. Imaging studies demonstrated interval enlargement of the thrombosed portion of the aneurysm and increased size in the filling portion of the aneurysm. In the present case, the existing radial artery bypass graft between left VA and left PCA permitted successful stent-assisted embolization of the recurrent BA aneurysm. To our knowledge, this is the first published case of endovascular stent-coiling of a BA aneurysm through a radial artery bypass graft. This novel technique can be a useful alternative for endovascular aneurysm treatment in these challenging lesions.

PMID: 29483014 [PubMed - indexed for MEDLINE]