Lauren A. O’Donnell

STAT1-Independent Control of a Neurotropic Measles Virus Challenge in Primary Neurons and Infected Mice

Neurons are chiefly nonrenewable; thus, cytolytic immune strategies to clear or control neurotropic viral infections could have lasting neurologic consequences. IFN-γ is a potent antiviral cytokine that is critical for noncytolytic clearance of multiple neurotropic viral infections, including measles virus (MV); however, the downstream pathways through which IFN-γ functions in neurons have not been defined. Unlike most cell types studied to date in which IFN-γ affects gene expression via rapid and robust activation of STAT1, basal STAT1 levels in primary hippocampal neurons are constitutively low, resulting in attenuated STAT1 activation and consequently slower kinetics of IFN-γ–driven STAT1-dependent gene expression. Given this altered expression and activation of STAT1 in neurons, we sought to determine whether STAT1 was required for IFN-γ–mediated protection from infection in neurons. To do so, we evaluated the consequences of MV challenge of STAT1-deficient mice and primary hippocampal neurons explanted from these mice. Surprisingly, the absence of STAT1 did not restrict the ability of IFN-γ to control viral infection either in vivo or ex vivo. Moreover, the canonical IFN-γ–triggered STAT1 gene expression profile was not induced in STAT1-deficient neurons, suggesting that IFN-γ regulates neuronal STAT1-independent pathways to control viral replication.

Blue moon neurovirology: the merits of studying rare CNS diseases of viral origin.

While measles virus (MV) continues to have a significant impact on human health, causing 150,000–200,000 deaths worldwide each year, the number of fatalities that can be attributed to MV-triggered central nervous system (CNS) diseases are on the order of a few hundred individuals annually (World Health Organization 2009). Despite this modest impact, substantial effort has been expended to understand the basis of measles-triggered neuropathogenesis. What can be gained by studying such a rare condition? Simply stated, the wealth of studies in this field have revealed core principles that are relevant to multiple neurotropic pathogens, and that inform the broader field of viral pathogenesis. In recent years, the emergence of powerful in vitro systems, novel animal models, and reverse genetics has enabled insights into the basis of MV persistence, the complexity of MV interactions with neurons and the immune system, and the role of immune and CNS development in virus-triggered disease. In this review, we highlight some key advances, link relevant measles-based studies to the broader disciplines of neurovirology and viral pathogenesis, and propose future areas of study for the field of measles-mediated neurological disease.

Influence of Dosage Form, Formulation, and Delivery Device on Olfactory Deposition and Clearance: Enhancement of Nose-to-CNS Uptake

Nose-to-central nervous system (CNS) drug delivery has shown promising results in preclinical efficacy models and exploratory human clinical trials. There are two primary limitations to direct CNS uptake of drugs following intranasal administration. Firstly, non-specific deposition in the nasal cavity leads to systemic absorption instead of CNS absorption, altering CNS bioavailability. Secondly, mucociliary clearance affects the residence time of the formulation at the site of deposition. In vivo results have demonstrated that therapeutic agents targeted to the olfactory region can translocate directly into the CNS via neuronal uptake. In this review, liquid and solid formulations are investigated for their effect on olfactory deposition and clearance based on their physical properties. The influence of delivery device and mode of administration is also reviewed. Case examples are provided to illustrate the importance of optimal deposition in olfactory region.

The intersection of antimicrobial stewardship and microbiology: educating the next generation of health care professionals

&NA; With the alarming rise of antibiotic resistance, clinical professionals are called upon to manage antibiotic therapies using the most relevant and recent clinical and laboratory data. To this end, antimicrobial stewardship (AMS) programs aim to reduce unnecessary or suboptimal use of antibiotics while maximizing outcomes for the patient. For AMS programs to succeed, the active participation of clinical professionals at all levels of patient care is required. Although programs exist to train established clinicians in AMS, there is a paucity of literature on how and when to integrate AMS concepts and skills in pre‐clinical and clinical coursework. Here, we discuss the crucial microbiology concepts and proficiencies that are necessary for building and supporting an AMS program. We provide recommendations for key points to include in clinical curricula in order to develop the necessary microbiology interpretation skills to participate in AMS. The influence of AMS programs on local organism susceptibility patterns is emphasized. The importance of antibiograms, rapid diagnostic testing and the practical interpretations of microbiology laboratory reporting are discussed in regard to prioritization in clinical curricula. We also review the current literature on instructional strategies for introducing AMS into clinical programs, and propose concepts that should be included in didactic coursework in order to provide a foundation for AMS education.

Ebola Virus Disease Roles and Considerations for Pharmacists

Ebola virus disease (EVD) poses significant clinical care implications for pharmacists. Emergency preparedness efforts should be undertaken to ensure vital response to EVD. Pharmacists should consider factors such as enhanced use of resources for front-line EVD patient care along with procurement of investigational medications. Appropriate and timely preparation, distribution, and administration of treatment for patients with EVD in the setting of substantial critical illness as well as infection control measures are essential. Aggressive supportive care and early, goal-directed therapy are cornerstones of therapy, whereas investigational treatments for EVD will likely play a larger, more well-defined role as future clinical trials are conducted.

Teaching Pharmacology Graduate Students how to Write an NIH Grant Application

Objective. To fill the gap in grant writing training in pharmacology graduate education using an active-learning strategy. Design. Graduate students wrote subsections of a grant according to NIH guidelines. Students revised their applications based on multiple rounds of critiques from professors and peers throughout a semester-long scientific writing course. Assessment. Prerevision and postrevision grant drafts were graded. Students were provided with questionnaires assessing their perception of the process. To determine the impact of feedback on the proposals, the quality of the pre/postrevision drafts was assessed by professors who were blinded and unaffiliated with the course. Conclusion. Student grades improved significantly upon resubmission. Perceptions of the proposals by blinded faculty members favored revised submissions based on multiple criteria. Survey feedback indicated an increase in student confidence in grant writing ability. The results of 3 independent measures demonstrate that intensive feedback on scientific writing improved the quality of student proposals.

Development and Implementation of a Global Health Elective with a Drug Discovery Game for Pharmacy Students

Interest in global health education within the pharmacy curriculum has increased significantly in recent years. However, discussion of different models and methods to evaluate course structures are limited. The overall objective was to (1) describe the structure of our global health elective for pharmacy students, and (2) assess educational outcomes related to perceived/formal knowledge and attitudes associated with global health. Our elective was designed using a competency-centered approach to global health education, incorporating reflection, projects, service and game-learning. In addition to course assessments, a pre-post survey questionnaire assessing attitudes, knowledge perception, formalized knowledge and opinions was utilized. Overall, students demonstrated appropriate performance on course assessments, temporally improving throughout longitudinal projects. The survey demonstrated significant increases in knowledge perception as a result of the course; however, no change in formalized knowledge was evident through the survey assessment. Additionally, the incorporation of game-learning into the course was well received by students. Future iterations of the course will focus on utilization of different assessment methods to meet learning outcomes.

Measles Virus and Subacute Sclerosing Panencephalitis

The measles–mumps–rubella (MMR) vaccine has nearly eliminated subacute sclerosing panencephalitis (SSPE), a rare complication of measles, and other measles-virus-related neurological disorders in populations with compulsory vaccination programs (http://www.cdc.gov/measles/about/history.html). Nonetheless, the neurological complications of measles, including SSPE, remain threats to unimmunized persons, especially children who live in measles-endemic regions and acquire measles at young ages. This chapter summarizes current information regarding the epidemiology, virology, clinical manifestations, diagnosis, and management of measles and its neurological complications, focusing on SSPE.

Predicting Hemagglutinin MHC-II Ligand Analogues in Anti-TNFα Biologics: Implications for Immunogenicity of Pharmaceutical Proteins

The purpose of this study was to evaluate the extent of overlapping immunogenic peptides between three pharmaceutical biologics and influenza viruses. Clinical studies have shown that subsets of patients with rheumatoid arthritis (RA) develop anti-drug antibodies towards anti-TNFα biologics. We postulate that common infectious pathogens, including influenza viruses, may sensitize RA patients toward recombinant proteins. We hypothesize that embedded within infliximab (IFX), adalimumab (ADA), and etanercept (ETN) are ligands of class II major histocompatibility complex (MHC-II) that mimic T cell epitopes derived from influenza hemagglutinin (HA). The rationale is that repeated administration of the biologics would reactivate HA-primed CD4 T cells, stimulating B cells to produce cross-reactive antibodies. Custom scripts were constructed using MATLAB to compare MHC-II ligands of HA and the biologics; all ligands were predicted using tools in Immune Epitope Database and Resources (IEDB). We analyzed three HLA-DR1 alleles (0101, 0401 and 1001) that are prominent in RA patients, and two alleles (0103 and 1502) that are not associated with RA. The results indicate that 0401 would present more analogues of HA ligands in the three anti-TNFα biologics compared to the other alleles. The approach led to identification of potential ligands in IFX and ADA that shares sequence homology with a known HA-specific CD4 T cell epitope. We also discovered a peptide in the complementarity-determining region 3 (CDR-3) of ADA that encompasses both a potential CD4 T cell epitope and a known B cell epitope in HA. The results may help generate new hypotheses for interrogating patient variability of immunogenicity of the anti-TNFα drugs. The approach would aid development of new recombinant biologics by identifying analogues of CD4 T cell epitopes of common pathogens at the preclinical stage.