Publication Type
March Total
Articles
123
Editorial Material
14
Reviews
23
Biographical/News Items
2
Total
162
Publications in Top Quartile Journals 103 out of 162 (63.6%)
Total Publications Fiscal Year to Date: 1,220
All rights reserved. Contents are the property of the authors and/or journals cited. Cover Image from “Transcriptional and Epigenetic Regulation of Effector and Memory CD8 T Cell Differentiation�
John D. Imig, PhD Professor of Pharmacology & Toxicology Director, Drug Discovery Center Medical College of Wisconsin
My laboratory conducts research and therapeutic development efforts to understand the mechanisms by which certain fatty acids “eicosanoids” influence kidney and cardiovascular function and develop drugs that target eicosanoids to treat diseases. Our research group has successfully worked with pharmaceutical and biotechnology companies through research and licensing agreements to move these drugs forward. Over the past decade, the Imig laboratory and collaborators have developed novel eicosanoid-based drugs to treat diseases including hypertension, stroke, heart attacks, diabetes, fatty liver disease, and kidney diseases. These novel drugs have tremendous potential as a therapy for cardiovascular, metabolic, and kidney diseases.
“Prospective for Cytochrome P450 Epoxygenase Cardiovascular and Renal Therapeutics” Imig, JD. Pharmacology & Therapeutics. 2018;192:1-19. This article highlights how drugs targeting eicosanoid enzymes and metabolites have evolved rapidly over the last two decades. A comprehensive examination of eicosanoid drugs in preclinical animal models and initial human trials provides evidence that these drugs are worthy of pursuing as therapeutics in renal and cardiovascular diseases. There are new vistas that are in the beginning stages and remain largely unexplored for eicosanoid drugs. These areas include the expansion to eicosanoid drugs that are bifunctional, expanding therapeutic indications for eicosanoid drugs, and targeting other novel epoxy fatty acid metabolites. Even though challenges remain, there is a high likelihood that a eicosanoid drug will be prescribed to treat a cardiovascular or kidney disease in the next decade. Fig. 5. Epoxyeicosatrienoic acid (EET) analogs and soluble epoxide hydrolase (sEH) inhibitors combat cardiovascular diseases.
EET analogs and sEH inhibitors decrease cardiac cell inflammation and oxidative stress. Cardiac cell signaling mechanisms leading to fibrosis, endoplasmic reticulum stress and hypertrophy are combated by EET analogs and sEH inhibitors to opposed heart diseases.
Fig. 6. Epoxyeicosatrienoic acid (EET) analogs and soluble epoxide hydrolase (sEH) inhibitors combat renal diseases.
Renal hemodynamic actions, epithelial cell actions, and anti-inflammatory are responsible for EET analogs and sEH inhibitors ability to oppose kidney diseases. EET analogs and sEH inhibitors improve endothelial responses, enhance sodium excretion, decrease apoptosis, and oppose epithelial to mesenchymal transition mediated fibrosis.
I am board certified in General Pediatrics and Child Abuse Pediatrics. My clinical duties include the provision of medical care to children and adolescents when there are suspicions of physical or sexual abuse or neglect. My research interests involve the assessment of initiatives to prevent and recognize child maltreatment, assessing the knowledge and confidence of medical providers in recognizing and responding to youth at risk for commercial sexual exploitation, and in the assessment of educational programs meant to address knowledge gaps in these areas. I have also directed several multidisciplinary initiatives in Wisconsin to develop protocols for the investigative, medical, and advocacy response to potential victims of maltreatment.
Angela L. Rabbitt, DO, FAAP Associate Professor of Pediatrics Medical College of Wisconsin Child Abuse Pediatrician Program Director, Child Advocacy and Protection Fellowship Children’s Hospital of Wisconsin
“Assessment of Maternal Knowledge and Confidence about Abusive Head Trauma and Coping with Infant Crying Before and After Infant Safety Education in the Neonatal Intensive Care Unit (NICU)” Rabbitt AL, Bretl D, Parker M, Yan K, Zhang L. The Journal of Perinatal & Neonatal Nursing. 2018;32(4):373-381. Infants with a history of perinatal illness are at higher risk for abusive head trauma (AHT). Crying is a common trigger for physical abuse, and education on coping with infant crying is an important component of AHT prevention. This study assesses the effects of education in the NICU on mothers’ knowledge about AHT and infant crying, self-efficacy in applying the education to infant cares, and the quality of AHT and infant crying education after discharge. Mothers received a standardized education program about AHT and infant crying and completed a pre-survey, post-survey, and 4-5-month follow-up survey. Education on AHT and crying in the NICU produced significant sustained increases in mothers’ knowledge and confidence, but few received recommended education after discharge. The effectiveness may be improved by addressing unique barriers to education in this population.
Percent Confident
Figure 3. Changes in Confidence in Coping with Infant Crying 120 100 80 60 40 20 0
83
96a
96
#1: I know what to do when my infant cries.
83
92a
92 71
90a
94
96
96
95
96
98
97
#2: I can settle my baby even when I #3: I can walk away and let my baby cry #4: I can talk to other people who care #5: I can talk to other people who care am tired or stressed. if I am frustrated. for my baby about what to do when my for my baby about the dangers of baby cries. shaking a baby.
Pre-education Survey Post-education Survey Follow-up Survey
Box 1. Key messages for improvement in the delivery of education about AHT and coping with crying in the NICU 1. 2. 3. 4. 5. 6. 7.
Discuss that infant crying peaks at 6wks corrected age when providing anticipatory guidance for preterm infants. Caregivers should be encouraged to seek medical care if they are concerned about crying, but reassured that once physical illness is excluded, even vigorous crying can be normal and does not necessarily indicate the baby is ill or in pain. Even “good parents” sometimes can not stop the crying. Infant crying is a part of normal development, not an indication of poor parenting or a “spoiled” infant. Verbal education and allowing caregivers to practice soothing the infant with immediate feedback during their NICU admission may improve confidence more than providing written and audiovisual educational materials alone. Education on AHT and coping with crying should be reinforced at well child visits throughout infancy. Include fathers and other caregivers in education whenever possible and encourage parents to share the information with others who care for the infant. Healthcare providers should be prepared to provide additional education and parent support resources to families who are regularly seeking medical care for crying related complaints or seem frustrated with the crying.
Nirav Shah, MD, MSHP Assistant Professor Department of Medicine Division of Hematology & Oncology Medical College of Wisconsin
I am an Assistant Professor of Medicine in the Division of Hematology and Oncology. I have a clinical practice focusing on patients with lymphomatous malignancies and on those needing cell based therapies, and autologous/ allogeneic transplantation. My research focus includes patients with non-Hodgkin lymphoma, and on the development of novel cellular therapies for patients with refractory B-cell malignancies, specifically using CAR-T cell technology.
“Early positron emission tomography/computed tomography as a predictor of response after CTL019 chimeric antigen receptor -T-cell therapy in B-cell non-Hodgkin lymphomas� Shah NN, Nagle SJ, Torigian DA, et al. Cytotherapy. 2018;20(12):1415-1418. This was a pilot clinical trial to determine the clinical utility of early Positron emission tomography/computed tomography (PET/CT) as a predictor of long-term response for patients with relapsed, refractory non-Hodgkin lymphoma treated with CTL019 (anti-CD19 CAR-T cell therapy). In this small study, PET/CT was found to be a predictor of long-term response with all patients achieving a complete response (CR) at Day 28, remaining in CR up to 2 years posttreatment. Figure 1. Representative subject 19 FDG-PET/CT coronal maximum intensity projection (MIP) images before (left) and 30 days after (right) CTL019 CAR-T cell immunotherapy demonstrating interval complete.
Kevin Bozymski, PharmD, BCPS, BCPP Assistant Professor Department of Clinical Sciences, School of Pharmacy Department of Psychiatry & Behavioral Medicine, School of Medicine Medical College of Wisconsin
I am an Assistant Professor in the MCW School of Pharmacy. I also work as a Board Certified Psychiatric Pharmacist (BCPP) and Pharmacotherapy Specialist (BCPS) in the Department of Psychiatry and Behavioral Medicine, both at Froedtert/MCW Tosa Health Center and Community Memorial Hospital. My research broadly focuses on improving the holistic care of individuals with mental illness through evidence-based medicine and innovative clinical pharmacy services. I am also interested in studying pedagogies that reduce mental health stigma in future pharmacists and other healthcare professionals.
“Caffeine Sodium Benzoate for Electroconvulsive Therapy Augmentation” Bozymski KM, Potter TG, Venkatachalam V, Pandurangi AK, Crouse EL. The Journal of ECT. 2018;34(4):233-239. Electroconvulsive therapy (ECT) has demonstrated efficacy in treatment-resistant mental illness. Pretreatment with caffeine sodium benzoate (CSB) has been used to improve seizure response, though most evidence is limited to case reports. Our retrospective chart review investigated use of CSB compounded for ECT at an academic medical center due to a nationwide drug shortage. The primary outcome was change in electroencephalogram (EEG) seizure duration between pre- and initial caffeine ECT sessions. Duration significantly increased for 71 subjects undergoing an index ECT course, with more subjects achieving a 30-second goal. CSB’s effects persisted across remaining sessions, with no clinically significant changes in hemodynamic parameters. These findings reaffirm CSB’s usefulness for ECT, including when compounded by a pharmacy. The Journal of ECT recognized this work as one of its top 3 articles of 2018. Table 4. Primary and Secondary Outcomes
Nicholas D. Young, PhD Assistant Professor Division of Child & Adolescent Psychiatry Department of Psychiatry & Behavioral Medicine Children’s Hospital of Wisconsin Medical College of Wisconsin
I provide scientific and clinical leadership for the Children’s Hospital of Wisconsin Integrated Behavioral Health Program, the state’s flagship model for pediatric primary care services. My research and applied interests center on behavioral health consultation, integrated primary care, judgment/databased decision making, and behavioral economics. I completed undergraduate training at the University of Wisconsin-Madison and graduate training at the University of Nebraska-Lincoln. I completed my internship at the University of Nebraska Medical Center Munroe-Meyer Institute, and postdoctoral fellowship at Children’s Hospital Colorado Pediatric Mental Health Institute.
“Sequential Screening to Improve Behavioral Health Needs Detection in Primary Care” Young ND, Takala CR. Journal of the American Academy of Child and Adolescent Psychiatry. 2018;57(8):603-609. This study examined sequential screening to improve behavioral health needs detection in pediatric primary care (a setting that often functions as the “de facto” behavioral health system for children). Innovative research methodology was used to evaluate population health costs/benefits across several model iterations (i.e., programs) by leveraging known technical properties of common screening instruments and estimates of psychopathology. Results revealed that screening outcomes were differentially impacted by measure choice, administration order, and technical properties (see Figure 1). Certain screening programs performed best at lower base rates of psychopathology, despite observed net sensitivity/specificity that was comparable to other programs. The counterintuitive results help inform high stakes decisions surrounding behavioral health screening program development in pediatric primary care.
Figure 1. Visualized Power Regression Results for Ratio of Reduced Referrals to Net False Negatives Across Each Sequential Screening Program
Using Initial Base Rate as the Predictor, With Solid Lines Representing Exact Model Fit and Dotted Lines Representing 95% Prediction Bands. CBCL = Child Behavior Checklist; PSC = Pediatric Symptom Checklist; RRFN = ratio of reduced referrals to false negatives; SDQ = Strengths and Difficulties Questionnaire.
“IL-13 promotes in vivo neonatal cardiomyocyte cell cycle activity and heart regeneration” Wodsedalek DJ, Paddock SJ, Wan TC, et al. American Journal of Physiology-Heart and Circulatory Physiology. 2019;316(1):H24-H34. We studied the effects of cytokine IL-13 in promoting neonatal cardiomyocyte (CM) heart regeneration. Using an IL-13 knockout mouse model (IL-13-/-), we showed these mice lacked the ability to regenerate injured heart tissue after apical resection compared with wild-type mice. After surgery, IL-13-/- CMs displayed lower levels of proliferative markers and increased hypertrophy. Administration of recombinant IL-13 reversed these phenotypes by increasing CM proliferation markers and reducing hypertrophy severity. RNA-sequencing data from primary neonatal CMs treated with IL-13 prompted us to examine and subsequently find increased activation of ERK1/2 and Akt pathways associated with pro-proliferative and anti-apoptotic regulation respectively.
Dylan Wodsedalek Research Technologist II Department of Physiology
Kyle Stoltz 1st Year IDP Graduate Student Department of Microbiology & Immunology
Christopher N. Jondle, PhD Postdoctoral Fellow Department of Microbiology & Immunology
“Tumor suppressor Interferon Regulatory Factor 1 selectively blocks expression of endogenous retrovirus” Stoltz KP, Jondle CN, Pulakanti K, et al. Virology. 2019;526:52-60. Endogenous retroviruses (ERVs) comprise 10% of the genome and normally are transcriptionally silenced post early-embryogenesis. However, several stimuli, including exogenous virus infection and cellular transformation, can reactivate ERV expression via a poorly understood mechanism. We identified Interferon Regulatory Factor 1 (IRF-1) and IRF-3 as suppressors of ERV expression. Each factor decreased expression of distinct ERV families both in vitro and in vivo. Given the emerging appreciation of the physiological relevance of ERV expression in cancer, IRF-1-mediated suppression of specific ERVs may contribute to the overall tumor suppressor activity this factor is known for.
“Use Of Ankle Immobilization In Evaluating Treatments To Promote Longitudinal Muscle Growth In Mice” Tinklenberg J, Beatka M, Bain JLW, et al. Muscle & Nerve. 2018;58(5):718-725. Early immobilization of ankles in prepuberal mice was used to produce deformities similar to congenital contractures. Stretch treatment, electrostimulation, and local intramuscular injection of a follistatin analog were assessed as interventions for these deformities. Ankle immobilization at full plantarflexion and 90° created tendon lengthening and muscle shortening in the tibialis anterior and soleus. Stretch treatment produced minimal evidence for muscle growth and electrostimulation provided no additional benefit. Stretch with FST‐288 produced greater longitudinal muscle growth and less tendon lengthening, constituting the best treatment response. Ankle immobilization recapitulates features of congenital contracture and can be mitigated by stretch and pharmacological approaches.
Jennifer Tinklenberg, MS Graduate Student Department of Physiology
Yao Chen 3rd Year Graduate Student Department of Microbiology & Immunology
“Transcriptional and Epigenetic Regulation of Effector and Memory CD8 T Cell Differentiation” Chen Y, Zander R, Khatun A, Schauder DM, Cui W. Frontiers in Immunology. 2018;9:2826.
Immune protection and lasting memory are accomplished through the generation of phenotypically and functionally distinct CD8 T cell subsets. In this review, we summarized the current understanding of CD8 T cell differentiation upon acute infection, with a focus on the transcriptional and epigenetic regulation of cell fate decision and memory formation. Moreover, we highlighted the importance of high throughput sequencing approaches and single cell technologies in providing insight into genome-wide investigations and the heterogeneity of individual CD8 T cells. Such findings will undoubtedly have an impact on T cell-based therapies and vaccine designs.