Kimberly M Vellano

Emory University, Atlanta, Georgia, United States

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Publications (5)26.82 Total impact

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    ABSTRACT: Each year, approximately 300,000 persons in the United States experience an out-of-hospital cardiac arrest (OHCA); approximately 92% of persons who experience an OHCA event die. An OHCA is defined as cessation of cardiac mechanical activity that occurs outside of the hospital setting and is confirmed by the absence of signs of circulation. Whereas an OHCA can occur from noncardiac causes (i.e., trauma, drowning, overdose, asphyxia, electrocution, primary respiratory arrests, and other noncardiac etiologies), the majority (70%--85%) of such events have a cardiac cause. The majority of persons who experience an OHCA event, irrespective of etiology, do not receive bystander-assisted cardiopulmonary resuscitation (CPR) or other timely interventions that are known to improve the likelihood of survival to hospital discharge (e.g., defibrillation). Because nearly half of cardiac arrest events are witnessed, efforts to increase survival rates should focus on timely and effective delivery of interventions by bystanders and emergency medical services (EMS) personnel. This is the first report to provide summary data from an OHCA surveillance registry in the United States. This report summarizes surveillance data collected during October 1, 2005-- December 31, 2010. In 2004, CDC established the Cardiac Arrest Registry to Enhance Survival (CARES) in collaboration with the Department of Emergency Medicine at the Emory University School of Medicine. This registry evaluates only OHCA events of presumed cardiac etiology that involve persons who received resuscitative efforts, including CPR or defibrillation. Participating sites collect data from three sources that define the continuum of emergency cardiac care: 911 dispatch centers, EMS providers, and receiving hospitals. OHCA is defined in CARES as a cardiac arrest that occurred in the prehospital setting, had a presumed cardiac etiology, and involved a person who received resuscitative efforts, including CPR or defibrillation. During October 1, 2005--December 31, 2010, a total of 40,274 OHCA records were submitted to the CARES registry. After noncardiac etiology arrests and missing hospital outcomes were excluded from the analysis (n = 8,585), 31,689 OHCA events of presumed cardiac etiology (e.g., myocardial infarction or arrhythmia) that received resuscitation efforts in the prehospital setting were analyzed. The mean age at cardiac arrest was 64.0 years (standard deviation [SD]: 18.2); 61.1% of persons who experienced OHCA were male (n = 19,360). According to local EMS agency protocols, 21.6% of patients were pronounced dead after resuscitation efforts were terminated in the prehospital setting. The survival rate to hospital admission was 26.3%, and the overall survival rate to hospital discharge was 9.6%. Approximately 36.7% of OHCA events were witnessed by a bystander. Only 33.3% of all patients received bystander CPR, and only 3.7% were treated by bystanders with an automated external defibrillator (AED) before the arrival of EMS providers. The group most likely to survive an OHCA are persons who are witnessed to collapse by a bystander and found in a shockable rhythm (e.g., ventricular fibrillation or pulseless ventricular tachycardia). Among this group, survival to discharge was 30.1%. A subgroup analysis was performed among persons who experienced OHCA events that were not witnessed by EMS personnel to evaluate rates of bystander CPR for these persons. After exclusion of 3,400 OHCA events that occurred after the arrival of EMS providers, bystander CPR information was analyzed for 28,289 events. In this group, whites were significantly more likely to receive CPR than blacks, Hispanics, or members of other racial/ethnic populations (p<0.001). Overall survival to hospital discharge of patients whose events were not witnessed by EMS personnel was 8.5%. Of these, patients who received bystander CPR had a significantly higher rate of overall survival (11.2%) than those who did not (7.0%) (p<0.001). CARES data have helped identify opportunities for improvement in OHCA care. The registry is being used continually to monitor prehospital performance and selected aspects of hospital care to improve quality of care and increase rates of survival following OHCA. CARES data confirm that patients who receive CPR from bystanders have a greater chance of surviving OHCA than those who do not. Medical directors and public health professionals in participating communities use CARES data to measure and improve the quality of prehospital care for persons experiencing OHCA. Tracking performance longitudinally allows communities to better understand which elements of their care are working well and which elements need improvement. Education of public officials and community members about the importance of increasing rates of bystander CPR and promoting the use of early defibrillation by lay and professional rescuers is critical to increasing survival rates. Reporting at the state and local levels can enable state and local public health and EMS agencies to coordinate their efforts to target improving emergency response for OHCA events, regardless of etiology, which can lead to improvement in OHCA survival rates.
    MMWR. Surveillance summaries: Morbidity and mortality weekly report. Surveillance summaries / CDC 07/2011; 60(8):1-19.
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    ABSTRACT: NMDA receptors are tetrameric complexes of NR1 and NR2A-D subunits that mediate excitatory synaptic transmission and have a role in neurological disorders. In this article, we identify a novel subunit-selective potentiator of NMDA receptors containing the NR2C or NR2D subunit, which could allow selective modification of circuit function in regions expressing NR2C/D subunits. The substituted tetrahydroisoquinoline CIQ (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone) enhances receptor responses two-fold with an EC(50) of 3 μM by increasing channel opening frequency without altering mean open time or EC(50) values for glutamate or glycine. The actions of CIQ depend on a single residue in the M1 region (NR2D Thr592) and on the linker between the N-terminal domain and agonist binding domain. CIQ potentiates native NR2D-containing NMDA receptor currents from subthalamic neurons. Our identification of a subunit-selective NMDA receptor modulator reveals a new class of pharmacological tools with which to probe the role of NR2C- and NR2D-containing NMDA receptors in brain function and disease.
    Nature Communications 10/2010; 1:90. DOI:10.1038/ncomms1085 · 10.74 Impact Factor
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    ABSTRACT: We describe a new class of subunit-selective antagonists of N-methyl D-aspartate (NMDA)-selective ionotropic glutamate receptors that contain the (E)-3-phenyl-2-styrylquinazolin-4(3H)-one backbone. The inhibition of recombinant NMDA receptor function induced by these quinazolin-4-one derivatives is noncompetitive and voltage-independent, suggesting that this family of compounds does not exert action on the agonist binding site of the receptor or block the channel pore. The compounds described here resemble CP-465,022 ((S)-3-(2-chlorophenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one), a noncompetitive antagonist of AMPA-selective glutamate receptors. However, modification of ring substituents resulted in analogues with greater than 100-fold selectivity for recombinant NMDA receptors over AMPA and kainate receptors. Furthermore, within this series of compounds, analogues were identified with 50-fold selectivity for recombinant NR2C/D-containing receptors over NR2A/B containing receptors. These compounds represent a new class of noncompetitive subunit-selective NMDA receptor antagonists.
    Journal of Medicinal Chemistry 08/2010; 53(15):5476-90. DOI:10.1021/jm100027p · 5.48 Impact Factor
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    ABSTRACT: N-Methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca(2+)-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism.
    Journal of Pharmacology and Experimental Therapeutics 03/2010; 333(3):650-62. DOI:10.1124/jpet.110.166256 · 3.86 Impact Factor
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    ABSTRACT: We have studied relative efficacies of NR1 agonists glycine and d-cycloserine (DCS), and found efficacy to be dependent on the NR2 subunit. DCS shows partial agonism at NR1/NR2B but has higher relative efficacy than glycine at NR1/NR2C receptor. Molecular dynamics (MD) simulations of the NR1/NR2B and NR1/NR2C agonist binding domain dimer suggest only subtle differences in the interactions of DCS with NR1 binding site residues relative to glycine. The most pronounced differences were observed in the NR1/NR2C simulation between the orientation of helices F and G of the NR1 subunit. Interestingly, Helix F was previously proposed to influence receptor gating and to adopt an orientation depending on agonist efficacy. MD simulations and site-directed mutagenesis further suggest a role for residues at the agonist binding domain dimer interface in regulating DCS efficacy. To relate the structural rearrangements to receptor gating, we recorded single-channel currents from outside-out patches containing a single active NR1/NR2C receptor. DCS increased the mean open time and open probability of NR1/NR2C receptors compared with glycine. Maximum likelihood fitting of a gating model for NR1/NR2C receptor activation to the single-channel data suggests that DCS specifically accelerates the rate constant governing a fast gating step and reduces the closing rate. These changes appear to reflect a decreased activation energy for a pregating step and increased stability of the open states. We suggest that the higher efficacy of DCS at NR1/NR2C receptors involves structural rearrangements at the dimer interface and an effect on NR1/NR2C receptor pregating conformational changes.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2010; 30(7):2741-54. DOI:10.1523/JNEUROSCI.5390-09.2010 · 6.75 Impact Factor