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BACKGROUND: Lymphocyte inhibition by antagonism of α4 integrins is a validated therapeutic approach for relapsing multiple sclerosis (RMS). OBJECTIVE: Investigate the effect of CDP323, an oral α4-integrin inhibitor, on lymphocyte biomarkers in RMS. METHODS: Seventy-one RMS subjects aged 18-65 years with Expanded Disability Status Scale scores ≤6.5 were randomized to 28-day treatment with CDP323 100 mg twice daily (bid), 500 mg bid, 1000 mg once daily (qd), 1000 mg bid, or placebo. RESULTS: Relative to placebo, all dosages of CDP323 significantly decreased the capacity of lymphocytes to bind vascular adhesion molecule-1 (VCAM-1) and the expression of α4-integrin on VCAM-1-binding cells. All but the 100-mg bid dosage significantly increased total lymphocytes and naive B cells, memory B cells, and T cells in peripheral blood compared with placebo, and the dose-response relationship was shown to be linear. Marked increases were also observed in natural killer cells and hematopoietic progenitor cells, but only with the 500-mg bid and 1000-mg bid dosages. There were no significant changes in monocytes. The number of samples for regulator and inflammatory T cells was too small to draw any definitive conclusions. CONCLUSIONS: CDP323 at daily doses of 1000 or 2000 mg induced significant increases in total lymphocyte count and suppressed VCAM-1 binding by reducing unbound very late antigen-4 expression on lymphocytes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00726648.

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OBJECTIVE: Due to the challenges inherent in performing clinical trials in children, a systematic review of published clinical trials was performed to determine whether the efficacy of antiepileptic drugs (AEDs) in adults can be used to predict the efficacy of AEDs in the pediatric population. METHODS: Medline/PubMed, EMBASE, and Cochrane library searches (1970-January 2010) were conducted for clinical trials of partial-onset seizures (POS) and primary generalized tonic-clonic seizures (PGTCS) in adults and in children <2 and 2-18 years. Independent epidemiologists used standardized search and study evaluation criteria to select eligible trials. Forest plots were used to investigate the relative strength of placebo-subtracted effect measures. RESULTS: Among 30 adjunctive therapy POS trials in adults and children (2-18 years) that met evaluation criteria, effect measures were consistent between adults and children for gabapentin, lamotrigine, levetiracetam, oxcarbazepine, and topiramate. Placebo-subtracted median percent seizure reduction between baseline and treatment periods (ranging from 7.0% to 58.6% in adults and from 10.5% to 31.2% in children) was significant for 40/46 and 6/6 of the treatment groups studied. The ≥50% responder rate (ranging from 2.0% to 43.0% in adults and from 3.0% to 26.0% in children) was significant for 37/43 and 5/8 treatment groups. In children <2 years, an insufficient number of trials were eligible for analysis. CONCLUSIONS: This systematic review supports the extrapolation of efficacy results in adults to predict a similar adjunctive treatment response in 2- to 18-year-old children with POS.

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OBJECTIVE: Prehospital care of stroke and chest pain patients is dependent on adequate emergency medical services (EMS) education and evidence-based protocols. We sought to describe the amount of education offered, community outreach implemented, and protocols established for stroke and for chest pain among North Carolina EMS agencies and personnel. METHODS: A survey was developed to measure EMS system characteristics regarding the prehospital care of stroke and chest pain patients. Each of the 83 primary EMS agencies in North Carolina was asked to participate. RESULTS: Of the 83 agencies surveyed, 72 (87%) responded. Both advanced life support (ALS) and basic life support (BLS) services were provided by 54% of agencies; 44% offered ALS only and 1% offered BLS only. While 89% of the EMS agencies provided stroke education to EMS personnel and 96% chest pain education to EMS personnel in the previous two years, the median hours devoted to stroke was one-half that for chest pain (6.0 vs. 12.0 hours, respectively). In the previous six months, 14% of EMS agencies had conducted community outreach programs for stroke compared with 17% for chest pain. The majority of EMS agencies had protocols specifically for managing stroke (83%) and for managing chest pain (99%). Diagnostic scales to identify stroke patients were used by 54% of agencies (20% Los Angeles Prehospital Stroke Screen, 20% Cincinnati Prehospital Stroke Scale, and 14% a locally developed scale). Thrombolytic checklists were used to identify eligible stroke patients at 37% of the EMS agencies, compared with 28% for eligible chest pain patients. CONCLUSIONS: In North Carolina, primary EMS agencies appear to have stroke and chest pain protocols in approximately the same frequency, yet their personnel receive only one-half as much education about stroke as they do about chest pain. Many stroke protocols were lacking basic components and would benefit from standardization across the state. Community outreach programs for both stroke and chest pain are minimal.

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OBJECTIVE: We describe the development and implementation of the North Carolina Rapid Response to Stroke (NCRRS) project--a community-based online education project developed for 911 telecommunicators and EMS personnel. METHODS: Two online courses, one for 911 telecommunicators and one for EMS personnel, were designed to provide timely and accessible continuing education on stroke assessment and care. Eight county-based emergency management systems, representing 15 agencies, were recruited for participation in a 4-month trial of the online courses in 2003. A total of 150 telecommunicators and 208 EMS personnel completed the courses. RESULTS: Results showed high levels of participant satisfaction with the program and improvements in posttest scores; agency leaders also provided positive feedback on the project. Motivators to complete the education identified by participants included peers, agency support, and materials provided by the NCRRS project. Courses were revised on the basis of feedback and successfully sustained online through August 2006, providing free stroke education for almost 1,000 additional 911 telecommunicators and EMS personnel in North Carolina. CONCLUSIONS: We describe the process of development and implementation that ensured project success. The results of this study show the need for and value of online stroke education for emergency services personnel and describe the challenges of developing and implementing online continuing education for this population. Similar education programs should be developed. Programs should incorporate comprehensive recruitment programs and community-based networks that sustain interest and promote full participation in educational offerings.

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Patient delay in seeking treatment for acute coronary syndrome and stroke symptoms is the major factor limiting delivery of definitive treatment in these conditions. Despite decades of research and public education campaigns aimed at decreasing patient delay times, most patients still do not seek treatment in a timely manner. In this scientific statement, we summarize the evidence that (1) demonstrates the benefits of early treatment, (2) describes the extent of the problem of patient delay, (3) identifies the factors related to patient delay in seeking timely treatment, and (4) reveals the inadequacies of our current approaches to decreasing patient delay. Finally, we offer suggestions for clinical practice and future research.

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OBJECTIVE: We conducted a statewide survey of communication centers regarding practices, training, and outreach for stroke and myocardial infarction (MI) and explored differences for those that were Emergency Medical Dispatch (EMD) certified or not. METHODS: A survey was mailed to all 115 centers that dispatched for emergency medical services (EMS) in North Carolina. Seventy-four percent (85/115) returned the survey. RESULTS: For 31% of centers, all telecommunicators were EMD-certified, 28% of centers had some personnel certified, and 41% had no personnel certified. Forty-four percent of centers used dispatch guides or algorithms to aid telecommunicators. If telecommunicators suspected a stroke, 47% of the centers provided prearrival instructions and if they suspected an MI, 49% provided prearrival instructions. In the past 2 years, 27% of the telecommunicators received stroke-specific training and 29% received MI-specific training. Stroke or MI training for telecommunicators was more common among the EMD centers (51% stroke; 51% MI) than among the non-EMD centers (5% stroke; 9% MI). Only one center conducted a community outreach program about stroke or MI in the last 6 months. CONCLUSIONS: Our results suggest that the development of statewide telecommunication training program to improve knowledge and care for suspected stroke or MI is needed in North Carolina. Dispatching for stroke and MI could be enhanced by requiring all communication centers to be EMD-certified and by creating consistent and standard dispatching practices across the state, using triage algorithms. Implementing these changes could improve rapid response and care for acute stroke and MI patients.

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Patient delay in seeking treatment for acute coronary syndrome and stroke symptoms is the major factor limiting delivery of definitive treatment in these conditions. Despite decades of research and public education campaigns aimed at decreasing patient delay times, most patients still do not seek treatment in a timely manner. In this scientific statement, we summarize the evidence that (1) demonstrates the benefits of early treatment, (2) describes the extent of the problem of patient delay, (3) identifies the factors related to patient delay in seeking timely treatment, and (4) reveals the inadequacies of our current approaches to decreasing patient delay. Finally, we offer suggestions for clinical practice and future research.

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We report here the results of a chemical genetic screen using small molecules with known pharmacologies coupled with a cortical brain slice-based model for ischemic stroke. We identified a small-molecule compound not previously appreciated to have neuroprotective action in ischemic stroke, the cardiac glycoside neriifolin, and demonstrated that its properties in the brain slice assay included delayed therapeutic potential exceeding 6 h. Neriifolin is structurally related to the digitalis class of cardiac glycosides, and its putative target is the Na(+)/K(+)-ATPase. Other cardiac glycoside compounds tested also showed neuroprotective activity, although with lower apparent potencies. In subsequent whole-animal studies, we found that neriifolin provided significant neuroprotection in a neonatal model of hypoxia/ischemia and in a middle cerebral artery occlusion model of transient focal ischemia. The neuroprotective potential of Na(+)/K(+)-ATPase is of particular interest because of its known "druggability"; indeed, Food and Drug Administration-approved, small-molecule compounds such as digitoxin and digoxin have been in clinical usage for congestive heart failure and arrhythmias for several decades. Thus, an existing cardiac glycoside or closely related compound could provide an accelerated path toward clinical trial testing for ischemic stroke. Our findings underscore the important role that hypothesis-neutral, high-content, tissue-based screens can play in the identification of new candidate drugs and drug targets for the treatment of diseases for which validated therapeutic pathways are not currently available.

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OBJECTIVE: To obtain a better understanding of how stroke events are communicated to 9-1-1 telecommunicators, and how telecommunicators and emergency medical services (EMS) personnel respond to such calls. METHODS: The authors identified 104 patients with a hospital discharge diagnosis of stroke or transient ischemic attack who were transported to hospital by ambulance in two North Carolina counties during 1999 and 2000. Ambulance call reports were abstracted and linked to 9-1-1 call center audiotapes, which were transcribed and verified. RESULTS: Of the 104 calls, 44 were made by medical personnel, 38 by a family member, eight by a bystander or neighbor, five undetermined, and three by other nonmedical personnel. In only six instances (6%) was the call placed by the patient. The most common symptoms reported were altered mental status (40%), trouble walking (32%), impaired speech (27%), and abnormal breathing (27%). Although the word "stroke" was often used (45%), 9-1-1 telecommunicators classified the calls as a stroke in only 31% of cases. However, in the majority of cases (79%), paramedics were dispatched at the highest priority. The median time from dispatch of EMS to patient arrival at the hospital was 41 minutes, approximately half of which was spent at the scene. CONCLUSION: Although typical stroke symptoms are commonly described, calls are often not classified as "strokes" by telecommunicators. Nevertheless, because of the symptoms reported during the calls, the majority of cases are treated as high priority by telecommunicators.

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The landscape of acute stroke care has changed dramatically in the last decade. Even before the approval of tissue plasminogen activator for acute stroke in 1996, organized acute stroke care was initiated at several hospitals and the pharmaceutical industry was deeply entrenched in the search for neuroprotective agents. In the year 2002, acute stroke care continues to demand the attention of neurologists as well emergency physicians. Despite the failures of many neuroprotective agents and the relative lack of use of tPA, the acute treatment of the stroke has gained increasing importance both at an individual and national level. This chapter reviews some of the advances in the acute treatment of stroke, future of acute stroke care and discusses the emerging role of the emergency physician in this area.

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