Novel Antiviral Strategies Targeting the Human Immunodeficiency Virus Type 1 (HIV-1) Viral Protein R and Its Cellular Partner, the Glucocorticoid Receptor

Most highly active anti-retroviral treatment (HAART) regimens eventually fail to provide complete and long-term suppression of virus replication due to the inability to fully clear virus from cellular reservoirs. The HIV-1 viral protein R, Vpr, increases virus replication in T cells and is necessary for the optimal infection of primary monocytes/macrophages and other non-dividing cells. In this essay, it is demonstrated that Vpr interacts with the cellular Glucocorticoid Receptor (GR) and transactivates the HIV-1 LTR through GRE and that this event can be blocked by the GR antagonist, mifepristone. Based on these observations, it is shown that targeting Vpr-mediated virus transcription with the glucocorticoid antagonist, mifepristone, can demonstrate a potent anti-retroviral therapy. Results demonstrated that Vpr-induced transactivation of both autologous and heterologous promoters was inhibited by mifepristone in a dose-dependent manner by >90% at a 1 µM concentration. Infectivity assays using T-tropic, dual-tropic, and macrophage-tropic viruses demonstrated antiviral effects on a dose-dependent regimen of mifepristone. The effects of mifepristone were also tested in HIV-1 latent cells that could be activated with extracellular viral protein and results exhibited a greater than 90% inhibition of re-activation in the presence of this antagonist. Cytotoxic effects of mifepristone demonstrated a CT50 from 10 to 100 µM in normal human primary cells, HeLa, HEK293, and CV-1 cells. Statement of Public Health Relevance: By utilizing the interaction between Vpr and the glucocortoicoid receptor, glucocorticoid antagonists such as mifepristone hold promise for anti-retroviral therapy by both preventing viral transactivation in currently-infected cell populations as well as preventing the reactivation of latent virus

The Road Rage and Aggressive Driving Dichotomy: Personality and Attribution Factors in Driver Aggression

Aggressive driving is not clearly and consistently defined in the literature, neither in terms of the specific behaviors chosen for inclusion nor the degree to which the emotional state of the driver is taken into account. Principally, the aim of this current research is to determine the extent to which aggressive driving and road rage overlap. This will be accomplished primarily by applying two well-supported dichotomies in aggression research: hostile/instrumental and impulsive/premeditated. Relevant personality traits will also be measured to help discern the aggressive driving- road rage overlap and to explore secondary areas of interest, such as sex and age differences in driver aggression

The Surficial Geologic Maps of Connecticut Illustrated by a Field Trip in Central Connecticut

Guidebook for field trips in Connecticut and south central Massachusetts: New England Intercollegiate Geological Conference 74th annual meeting, University of Connecticut, Storrs Connecticut , October 2 and 3, 1982: Trip Q-

Effect of introducing the mucosal atomization device for fentanyl use in out-of-hospital pediatric trauma patients

Background: Pain associated with pediatric trauma is often under-assessed and undertreated in the out-of-hospital setting. Administering an opioid such as fentanyl via the intranasal route is a safe and efficacious alternative to traditional routes of analgesic delivery and could potentially improve pain management in pediatric trauma patients. Objective: The study sought to examine the effect of introducing the mucosal atomization device (MAD) on analgesia administration as an alternative to intravenous fentanyl delivery in pediatric trauma patients. The hypothesis for the study is that the introduction of the MAD would increase the administration of fentanyl in pediatric trauma patients. Methods: The research utilized a 2-group design (pre-MAD and post-MAD) to study 946 pediatric trauma patients (age ,16) transported by a large, urban EMS agency to one of eight hospitals in Marion County, which is located in Indianapolis Indiana. Two emergency medicine physicians independently determined whether the patient met criteria for pain medication receipt and a third reviewer resolved any disagreements. A comparison of the rates of fentanyl administration in both groups was then conducted. Results: There was no statistically significant difference in the rate of fentanyl administration between the pre-MAD (30.4%) and post-MAD groups (37.8%) (P5.238). A subgroup analysis showed that age and mechanism of injury were stronger predictors of fentanyl administration. Conclusion: Contrary to the hypothesis, the addition of the MAD device did not increase fentanyl administration rates in pediatric trauma patients. Future research is needed to address the barriers to analgesia administration in pediatric trauma patients

Intervention and Outcomes of Children in Different Types of Listening and Spoken Language Programs

This study explores the impact of the type and dosage of listening and spoken language (LSL) services on speech and language outcomes in children with cochlear implants or hearing aids in two LSL programs. Identical demographic variables were collected across the two programs for use in the statistical analyses. Speech and language outcomes were examined at ages 3 and 5 using standardized test measures. At age 3, significant differences in LSL outcomes existed between programs for children using cochlear implants but not for children using binaural hearing aids. However, at age five, outcomes were similar between the different LSL programs for children with hearing aids and cochlear implants. Total hours of LSL services do not serve as a predictor of LSL outcomes at five years of age. However, early identification of hearing loss, early amplification, and early enrollment in a LSL program were highly influential factors affecting LSL outcomes at three and five years of age. Non-verbal IQ and maternal education levels also influence LSL outcomes. Children with earlier access to hearing technology and LSL intervention may need fewer hours of LSL services to achieve age-appropriate LSL outcomes. Overall, both of these LSL programs supported age-appropriate speech and language outcomes by age 5

Assessing Patient Satisfaction and Confidence After Use of Educational Video to Augment Surgical Consent for Thyroid Surgery

Introduction: Informed consent is a crucial aspect of ethical patient care, yet the increase in surgical complexity presents a challenge in achieve this properly. This study explores the use of an educational video to help standardize the consent process, increase patient retention of information, and promote patient understanding by allowing patients to replay the information remotely as often as needed. Methods: This is a perspective, survey-based study of adult patients undergoing thyroid surgery. A novel video detailing thyroid surgery containing the standard contents of informed consent was shown to patients after traditional informed consent followed by a survey on their level of comfort of the information before and after the video. Data on patient age, education level, previous surgical experience was collected. Results: Preliminary data shows that there is an increase in confidence, benefits, and knowledge of risk of the patients’ operation. We expect to find that with the addition of an educational video to the thyroid surgery consent process, patients will report a higher level of satisfaction as well as confidence in regards to their surgery. Discussion: The process of informed consent has not evolved with the complexity of procedures. The use of multimedia has been demonstrated as a valuable teaching tool in addition to traditional informed. Our study reinforces that there is a place for multimedia, specifically educational videos in informed consent for thyroid surgery as it may help patients better understand their procedure. Future aims of this study include evaluating patient comprehension with the addition of an educational video to informed consent, as well as the creation of more educational videos for head and neck surgery consent

Inhibitors of Foot and Mouth Disease Virus Targeting a Novel Pocket of the RNA-Dependent RNA Polymerase

Foot-and-Mouth Disease Virus (FMDV) is a picornavirus that infects cloven-hoofed animals and leads to severe losses in livestock production. In the case of an FMD outbreak, emergency vaccination requires at least 7 days to trigger an effective immune response. There are currently no approved inhibitors for the treatment or prevention of FMDV infections.Using a luciferase-based assay we screened a library of compounds and identified seven novel inhibitors of 3Dpol, the RNA-dependent RNA polymerase of FMDV. The compounds inhibited specifically 3Dpol (IC(50)s from 2-17 µM) and not other viral or bacterial polymerases. Enzyme kinetic studies on the inhibition mechanism by compounds 5D9 and 7F8 showed that they are non-competitive inhibitors with respect to NTP and nucleic acid substrates. Molecular modeling and docking studies into the 3Dpol structure revealed an inhibitor binding pocket proximal to, but distinct from the 3Dpol catalytic site. Residues surrounding this pocket are conserved among all 60 FMDV subtypes. Site directed mutagenesis of two residues located at either side of the pocket caused distinct resistance to the compounds, demonstrating that they indeed bind at this site. Several compounds inhibited viral replication with 5D9 suppressing virus production in FMDV-infected cells with EC(50) = 12 µM and EC(90) = 20 µM).We identified several non-competitive inhibitors of FMDV 3Dpol that target a novel binding pocket, which can be used for future structure-based drug design studies. Such studies can lead to the discovery of even more potent antivirals that could provide alternative or supplementary options to contain future outbreaks of FMD

Proprioceptive Coupling within Motor Neurons Drives C. Elegans Forward Locomotion

Locomotion requires coordinated motor activity throughout an animal’s body. In both vertebrates and invertebrates, chains of coupled central pattern generators (CPGs) are commonly evoked to explain local rhythmic behaviors. In C. elegans, we report that proprioception within the motor circuit is responsible for propagating and coordinating rhythmic undulatory waves from head to tail during forward movement. Proprioceptive coupling between adjacent body regions transduces rhythmic movement initiated near the head into bending waves driven along the body by a chain of reflexes. Using optogenetics and calcium imaging to manipulate and monitor motor circuit activity of moving C. elegans held in microfluidic devices, we found that the B-type cholinergic motor neurons transduce the proprioceptive signal. In C. elegans, a sensorimotor feedback loop operating within a specific type of motor neuron both drives and organizes body movement.Chemistry and Chemical BiologyPhysic