Search

Depression (major depressive disorder) is a common but serious mood disorder. When traditional medication treatment does not reduce symptoms, transcranial magnetic stimulation (TMS) has been approved by the Food and Drug Administration (FDA), neuromodulation has become increasingly relevant to clinical research. However, TMS has significant drawback in the lack of depth and special specificity. In the last few years low-intensity focused ultrasound pulsation (LIFUP) has been used to be focused noninvasively through the skull anywhere within the brain, together with functional magnetic resonance imaging (fMRI) guided techniques, LIFUP can be applied to deep structures with greater spatial precision. In this manuscript, combination of TMS and fMRI-guided LIFUP on the treatment of depression was proposed to achieve the benefits of both. The data of the combined methods demonstrate significantly better clinical results in comparison to the control group, as measured by the Hamilton Rating Scale for Depression (HAM-D) scale, Geriatric Depression scale (GDS) and the Pittsburgh Sleep Quality Index (PSQI) with low adverse reaction.

Background: Acute Ischemic Stroke (AIS) treatment is time sensitive. Many hospitals lack neurology expertise on site to assess patients and assist emergency medicine colleagues with administration of thrombolytic therapy. Telestroke services have been shown to be as safe for administering thrombolytic therapy as on-site neurological expertise. Neurologists covering acute stroke services on-site and via telemedicine are in short supply. Advance Practice Registered Nurses (APRNs) specializing in stroke and cerebrovascular disease have helped fill the gap, however, data are lacking on APRN acute telestroke coverage, thrombolytic administration, and patient outcomes. Purpose: The aim was to determine whether cerebrovascular trained APRNs covering our 24/7/365 CSC telestroke service could accurately and safely administer alteplase as well as our neurology physician colleagues. Methods: All consecutive AIS telestroke consults were reviewed at 2 rural community hospital spoke sites from 1/1/17-7/1/19. Telestroke call was shared among neurologists and 2 APRNs. Both APRNs have > 10 years of cerebrovascular disease experience. Nationally accepted AHA guidelines for inclusion/exclusion for alteplase (tPA) administration were followed and documented accordingly up to 4.5 hours from onset. Results: A total of 1,515 telestroke consults were performed (427 MD, 1088 APRN). Of those, 121 were diagnosed with suspected AIS, met criteria for tPA, and it was administered. Conclusions: APRNs at our CSC providing telestroke coverage at 2 rural community hospitals resulted in no statistical difference in stroke care delivery and patient outcomes compared to our physician colleagues. Incorporating APRNs into telestroke call coverage needs further study to better define necessary telehealth training, curriculum, standardized professional competencies, and consideration of state laws.

Introduction: Mechanical thrombectomy (MT) is a part of the standard treatment of LVO stroke. Peri-interventional blood pressure variability may impact the outcomes of MT. In this study, we assessed whether lower mean blood pressure levels for longer than 12 hours has any impact on the short-term functional outcomes of MT. Methods: With the approval of the Human Studies Committee at the University of Louisville (IRB #: 13.0396), we performed a retrospective analysis of LVO stroke MT patients from 2016-18 (n=86). Blood pressure (BP) data collected at admission baseline, precanalization, immediate post-canalization, and 24 hours post-canalization. Baseline and post-canalization 24-hour BP data collected hourly. MBP lower than 20% of the “mean baseline” values recorded in the first few hours of admission was considered as “ clinically low ” BP, and a total of 12 hours of clinically low MBP levels within the first 24-hour of post-thrombectomy period was considered as “ potentially hypoperfused ”. Changes in NIHSS within the first 24 hours post canalization and NIHSS at discharge were assessed as main outcomes. Results: Mean age was 65±13 years. About 83% of patients TICI 2b/3 was accomplished. Baseline MBP levels were 103 ± 16mmHg. When the “ potentially hypoperfused ” patients (MBP12 hours) were compared with the patients who were not (n=29 vs. n=57), the change in NIHSS at 24 hours and the NIHSS score at discharge were statistically significantly worse in patients who were potentially hypoperfused . (Table) Discussion: In this retrospective analysis, we assessed the contribution of clinically lower MBP levels after MT to the short-term functional outcome. Our preliminary results showed that the patients who were exposed to hypoperfusion for longer than 12 hours had worse NIHSS scores. Impact of maintaining baseline blood pressure needs to be further studied under prospective and controlled study designs.

Introduction: Ischemic stroke (IS) is a medical emergency with a high risk of morbidity, leading to disability, and mortality. IS’s impact on our patients’ lives and healthcare system make it essential to optimize its immediate management, triage requirements, and plans for transfer to comprehensive stroke centers. In this study, we hypothesized that it is possible to predict the mortality of IS patients within the first hour of hospital admission. Methods: With the approval of the Human Studies Committee (IRB #: 13.0396), we performed a retrospective analysis from the Stroke Quality Database. Patients who were admitted between 2007-2012 were included. In-hospital mortality was the main outcome of the study. Patients’ demographics, baseline illnesses, home medications, baseline neurological assessment scores, and basic laboratory values on admission were included in the analysis as potential factors. Multivariate analysis was performed to assess the independent contributing factors. Data is presented as odds ratio and 95% confidence intervals. Results: IS in-hospital mortality was about 10% in our study population. Multivariate analysis was performed in 2,131 patients. NIH Stroke Scale on admission, recurrent stroke, high WBC levels (>11K), elderly age, AHA Stage II hypertension, baseline use of Ca-channel blockers, and beta-blockers, admission glucose levels and albumin levels independently contributed to in-hospital mortality (Table). Conclusions: IS patients’ baseline characteristics, hospital admission assessment scales, and laboratory values on admission contributed to prediction of in-hospital mortality. Therefore, it is essential to rapidly initiate acute care for high-risk and complex stroke patients. Additionally, focusing on the modifiable factors such as blood pressure management, treating acute infections, and managing glucose levels may help to decrease acute IS mortality.

Introduction: Evidence-based practice shows that the earlier a patient presenting with an acute ischemic stroke receives IV-tpa the better the outcomes. The stroke clinical operations nurse role was developed to help streamline door-to-needle (DTN) time for patients being treated with Alteplase (IV-tPA). Adding experienced, stroke trained, critical care nurses, or Stroke Clinical Operations Nurses, on the stroke team as part of the response to acute stroke patients presenting within 12 hours of stroke, our hospital has been able to drive DTN time down and increase the number of patients treated within the 45 and 60 minute window since implementation. Method: Retrospective review of all patients who received IV-tPA from Jan 2013 –June 2017. January 2013- June 2016 is the pre-implementation data and July 2016- June 2017 is post implementation data. We compared DTN time and percentage of DTN less than 45 minutes after implementation of stroke dedicated nursing service. Mean and median were calculated. Two-tailed student T-test was used for comparison and a statistical significance was determined at 0.05 level. Results: Total of 313 patients who received Iv-tPA from 2013 to June 2016, and 85 patients from July 2016 to June 2017. There was significant decrease in mean (44.5 ± 0.6 vs 41.6+1.3 min) and median (45 vs 40 min) of DTN within 60 min after the start of the service. Meanwhile, there was a significant increase of percentage of DTN within 45 min (37.7% vs 49.4%). There was a significant decrease in DTN time (mean: 37.5 ± 0.5 vs 35.0 ± 1 min; and median: 39 vs 36.7 min) in groups of DTN within 45 min. Conclusion: Implementation of the SCON decreased the Door-to-Needle (DTN) time and improves the number of patients being treated with IV Alteplase in the 45 and 60 minute time window goals. The implementation of the SCON will serve as a new model for early management of patients with acute ischemic stroke to deliver the highest quality patient services across the state and nationwide.

Background & Purpose: It has been well established that intravenous alteplase (IVa) administration for treatment of acute ischemic stroke (AIS) improves clinical outcome at 3 months, and earlier treatment is more likely to result in a favorable outcome with reduced symptomatic intracranial hemorrhage (sICH). A platelet count (PC) of Methods: We retrospectively reviewed charts of patients who received IVa from January, 2009 to July, 2017 at our facility. Patients were identified and treated based on standard FDA approved guidelines. We identified patients with admission PC Results: 511 patients received IVa for treatment of AIS at our facility during the study period. Four patients (0.97%) with a PC of Conclusion: IVa treatment in AIS with PC

In this paper, we propose peak-valley ratio and spectral centroid frequency features, and use them as supplements to baseline system to speech detection. The two features are related to the peaks and the formant frequencies of speech spectra, which are robust to noise. Detection results also justify that the proposed two supplementary features improve the performance of baseline system.

Mechanisms underlying the clinical benefits of glatiramer acetate (GA) for patients with multiple sclerosis (MS) remain elusive. A prevailing hypothesis is that GA can induce Th2-polarized T cells, which cross-recognize myelin-specific epitopes and can inhibit myelin-reactive autoaggression in Th1 T cells, a process referred to as 'bystander suppression.' To test whether the efficacy of GA is indeed mediated by Th2 T cells, we have utilized an animal model for MS: experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. GA therapy conferred moderate protection from EAE. GA-reactive T cells from these mice were not Th2 polarized, and the Th1 cytokine reduction of myelin-reactive T cells in GA-treated mice was comparable to that in untreated control mice. Significantly, the protective effects of GA against EAE were also observed in IL-4-, IL-10-deficient and IL-4/IL-10 double-deficient mice. Similar to wild-type mice, GA therapy in IL-4- and IL-10-deficient mice was associated with diminished myelin-reactive T cell expansion and reduced production of myelin antigen-induced IFN-gamma and tumor necrosis factor-alpha. Thus, despite the absence of two prominent Th2 cytokines, IL-4 and IL-10, either alone or combined, GA was still beneficial in suppressing EAE. Our results caution against the notion that Th2 cells and bystander suppression account for the effect of GA on EAE and suggest that an alternative mechanism may operate in GA-treated MS patients.

Background— Estimation of ventricular volume and mass is important for baseline and serial evaluation of fetuses with normal or abnormal hearts. Direct measurement of chamber wall volumes and mass can be made without geometric assumptions by 3D fetal echocardiography. Our goals were to determine the feasibility of using fast nongated 3D echocardiography for fetal volumetric and mass assessments, to validate the accuracy of the ultrasound system and the measurement technique, and if satisfactory, to develop normal values for fetal ventricular mass during the second and third trimesters. Methods and Results— This was a prospective outpatient study of 90 consecutive normal pregnancies during routine obstetric services at Oregon Health & Science University (Portland). Optimized 3D volumes of the fetal thorax and cardiac chambers were rapidly acquired and later analyzed for right and left ventricular mass by radial summation technique from manual epicardial and endocardial traces. Experiments to validate the ultrasound system and measurement technique were performed with modified small balloon models and in vivo and ex vivo small animal experiments. Our study established the feasibility of fetal ventricular mass measurements with 3D ultrasound technology and developed normal values for right and left ventricular mass from 15 weeks’ gestation to term. Conclusions— Nongated fast 3D fetal echocardiography is an acceptable modality for determination of cardiac chamber wall volume and mass with good accuracy and acceptable interobserver variability. The method should be especially valuable as an objective serial measurement in clinical fetal studies with structurally or functionally abnormal hearts.

Sergiy V Kushchayev,1 Tejas Sankar,1 Laura L Eggink,4,5 Yevgeniya S Kushchayeva,5 Philip C Wiener,1,5 J Kenneth Hoober,5,6 Jennifer Eschbacher,3 Ruolan Liu,2 Fu-Dong Shi,2 Mohammed G Abdelwahab,4 Adrienne C Scheck,4 Mark C Preul11Neurosurgery Research Laboratory, 2Neuroimmunology Laboratory, 3Department of Pathology, 4Neurooncology Research, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, 5School of Life Sciences, Arizona State University, Tempe, 6Susavion Biosciences, Inc, Tempe, AZ, USAObjectives: Immunotherapy with immunostimulants is an attractive therapy against gliomas. C-type lectin receptors specific for galactose/N-acetylgalactosamine (GCLR) regulate cellular differentiation, recognition, and trafficking of monocyte-derived cells. A peptide mimetic of GCLR ligands (GCLRP) was used to activate blood monocytes and populations of myeloid-derived cells against a murine glioblastoma.Methods: The ability of GCLRP to stimulate phagocytosis by human microglia and monocyte-derived cells of the brain (MDCB) isolated from a human glioblastoma was initially assessed in vitro. Induction of activation markers on blood monocytes was assayed by flow cytometry after administration of GCLRP to naive mice. C57BL/6 mice underwent stereotactic intracranial implantation of GL261 glioma cells and were randomized for tumor size by magnetic resonance imaging, which was also used to assess increase in tumor size. Brain tumor tissues were analyzed using flow cytometry, histology, and enzyme-linked immunosorbent assay with respect to tumor, peritumoral area, and contralateral hemisphere regions.Results: GCLRP exhibited strong stimulatory effect on MDCBs and blood monocytes in vitro and in vivo. GCLRP was associated with an increased percentage of precursors of dendritic cells in the blood (P = 0.003), which differentiated into patrolling macrophages in tumoral (P = 0.001) and peritumoral areas (P = 0.04), rather than into dendritic cells, as in control animals. Treatment with GCLRP did not result in a significant change in survival of mice bearing a tumor.Conclusions: In vitro and in vivo activation of monocytes was achieved by administration of GCLR to mice. GCLRP-activated blood monocytes were recruited to the brain and exhibited specific phenotypes corresponding with tumor region (glioma, peritumoral zone, and contralateral glioma-free hemisphere). GCLRP treatment alone was associated with increased glioma mass as the result of the infiltration of phagocytic cells. Regional specificity for MDCB may have significant tumor treatment implications.Keywords: microglia, macrophages, peptide, brain tumor, glioblastoma, mouse, C-type lectin receptors, galactose/N-acetylgalactosamine, immunotherapy

Natural killer (NK) cells are large, granular lymphocytes that represent an important component of the innate immune system and operate through cytolytic activity and cytokine secretion. Both NK cell cytolytic activity and cytokine secretion have been exploited for immunotherapy of cancer and, more recently, autoimmune diseases 1–5. Long-term, low-dose infusion of IL-2 results in selective expansion of the CD56bright NK cell subpopulation 6. Surprisingly, IL-2R blockade in vivo also expands the same NK cell population 1, 3, 6. Based on these findings, the humanized anti-IL-2R α-chain mAb daclizumab has been developed and subsequently employed for treatment of autoimmune diseases, including MS and autoimmune uveitis1, 3–5 The beneficial clinical effects of daclizumab in these diseases have been attributed, at least in part, to its capacity to expand CD56bright NK cells 2, 7, which are believed to exhibit immunoregulatory functions 8. The use of daclizumab therapy has provoked interest in further exploring the benefits of NK cell-based therapies in human organ-specific inflammatory and autoimmune diseases. This approach has also elicited several questions that are critical for understanding the role of NK cells in autoimmune diseases. First, to what extent do NK cells contribute to the protective effects of daclizumab against autoimmunity? Since lymphocytes that bear IL-2 receptors and have potential suppressive functions, such as NKT cells, CD8+ T cells and CD4+CD25+ regulatory T cells, might also be altered by IL-2 or anti-IL-2 mAb based therapies. Second, in which anatomical compartments do NK cells demonstrate their immunosuppressive activities? Because daclizumab likely affects NK cells in all organ systems, its beneficial effects on autoimmunity might be due to events that occur in the periphery, in target organs (brain, spinal cord, or eye), or both. Third, daclizumab is only partially effective in reducing disease activity in MS. If disease attenuation is indeed linked to NK cells, will agents that have higher efficacy in inducing NK cells further improve the clinical outcome? Last, what is (are) the mechanism(s) underlying NK cell-mediated suppression of CNS pathology? To address these questions, we first studied here the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting MS. We compared the efficacy of IL-2, anti-IL-2 mAb and IL-2/anti-IL-2 mAb complexes in expanding NK cells in relation to the clinical manifestations of EAE, and we defined the anatomical site of action. To translate our findings to the clinical situation, we investigated the effects of the human version of IL-2 and anti-IL-2 mAb on subsets of human NK cells and to modulate disease expression in a human-mouse chimera model.

Objective. This study was designed to validate a slow-sweep real-time 4-dimensional (4D) spatiotemporal image correlation method for producing quantitatively accurate dynamic fetal heart images using an in vitro pulsatileballoon model and apparatus. Methods. To model fetal heart chambers, asymmetric double-walled finger stalls (tips of surgical latex gloves) were used and attached to a laboratory-designed circuit that allowed calibrated changes in the inner balloon volume as well as an intermediate gel mass interposed between the 2 layers. The water-submerged model was attached to a small-volume pulsatile pump to produce phasic changes in volume within the inner balloon at a fixed rate. A sonography system with 4D spatiotemporal image correlation (STIC) capabilities was used for 3-dimensional (3D) and 4D data acquisition. Volume data were analyzed by customized radial summation techniques with 4D data analysis software and compared with known volumes and masses. Results. Fifty-six individual volumes ranging from 2.5 to 10 mL were analyzed. Volume and mass measurements with 4D STIC were highly correlated (R 2 > 0.90). The mean percentage error was better (

Sergiy V Kushchayev,1 Tejas Sankar,1 Laura L Eggink,5,6 Yevgeniya S Kushchayeva,5 Philip C Wiener,1,5 J Kenneth Hoober,5,6 Jennifer Eschbacher,3 Ruolan Liu,2 Fu-Dong Shi,2 Mohammed G Abdelwahab,4 Adrienne C Scheck,4 Mark C Preul11Neurosurgery Research Laboratory, 2Neuroimmunology Laboratory, 3Department of Pathology, 4Neurooncology Research, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, 5School of Life Sciences, Arizona State University, Tempe, 6Susavion Biosciences, Inc, Tempe, AZ, USABackground: A peptide mimetic of a ligand for the galactose/N-acetylgalactosamine-specific C-type lectin receptors (GCLR) exhibited monocyte-stimulating activity, but did not extend survival when applied alone against a syngeneic murine malignant glioma. In this study, the combined effect of GCLRP with radiation was investigated.Methods: C57BL/6 mice underwent stereotactic intracranial implantation of GL261 glioma cells. Animals were grouped based on randomized tumor size by magnetic resonance imaging on day seven. One group that received cranial radiation (4 Gy on days seven and nine) only were compared with animals treated with radiation and GCLRP (4 Gy on days seven and nine combined with subcutaneous injection of 1 nmol/g on alternative days beginning on day seven). Magnetic resonance imaging was used to assess tumor growth and correlated with survival rate. Blood and brain tissues were analyzed with regard to tumor and contralateral hemisphere using fluorescence-activated cell sorting analysis, histology, and enzyme-linked immunosorbent assay.Results: GCLRP activated peripheral monocytes and was associated with increased blood precursors of dendritic cells. Mean survival increased (P < 0.001) and tumor size was smaller (P < 0.02) in the GCLRP + radiation group compared to the radiation-only group. Accumulation of dendritic cells in both the tumoral hemisphere (P < 0.005) and contralateral tumor-free hemisphere (P< 0.01) was associated with treatment.Conclusion: Specific populations of monocyte-derived brain cells develop critical relationships with malignant gliomas. The biological effect of GCLRP in combination with radiation may be more successful because of the damage incurred by tumor cells by radiation and the enhanced or preserved presentation of tumor cell antigens by GCLRP-activated immune cells. Monocyte-derived brain cells may be important targets for creating effective immunological modalities such as employing the receptor system described in this study.Keywords: microglia, macrophages, peptide, brain tumor, glioblastoma, mouse, C-type lectin receptors

A prominent clinical symptom in multiple sclerosis (MS), a progressive disorder of the central nervous system (CNS) due to heightened neuro-inflammation, is learning and memory dysfunction. Here, we investigated the effects of a ketogenic diet (KD) on memory impairment and CNS-inflammation in a murine model of experimental autoimmune encephalomyelitis (EAE), using electrophysiological, behavioral, biochemical and in vivo imaging approaches. Behavioral spatial learning deficits were associated with motor disability in EAE mice, and were observed concurrently with brain inflammation. The KD improved motor disability in the EAE model, as well as CA1 hippocampal synaptic plasticity (long-term potentiation) and spatial learning and memory (assessed with the Morris Water Maze). Moreover, hippocampal atrophy and periventricular lesions in EAE mice were reversed in KD-treated EAE mice. Finally, we found that the increased expression of inflammatory cytokines and chemokines, as well as the production of reactive oxygen species (ROS), in our EAE model were both suppressed by the KD. Collectively, our findings indicate that brain inflammation in EAE mice is associated with impaired spatial learning and memory function, and that KD treatment can exert protective effects, likely via attenuation of the robust immune response and increased oxidative stress seen in these animals.