All rights reserved. Contents are the property of the authors and/or journals cited. Cover Image from “Management of Type 1 Diabetes in the Hospital Setting�
Oleg Palygin, PhD Assistant Professor Department of Physiology Medical College of Wisconsin
My research is focused on ion channels and ion transport in the kidney. I use electrophysiological, molecular biology and microscopy methods to address unresolved questions about the physiological mechanisms responsible for the regulation of renal function in health and disease. The kidney plays a fundamental role in the regulation of blood pressure and sodium and water balance. As such, renal dysfunction is a key component of hypertension and the associated cardiovascular diseases. In recent years advances in molecular and cellular biology has furthered our understanding of renal function, and how these processes may become disordered in conditions such as chronic kidney disease, hypertension, polycystic kidney disease and diabetes mellitus. Our lab is interested in several aspects of the kidney: its ability to control and regulate body electrolytes, its vulnerability to genetically related mutations, oxidative stress, albuminuria and the role that transport potassium channels, protease activated receptors and purines, e.g. ATP, play in these processes.
“Acute In Vivo Analysis of ATP Release in Rat Kidneys in Response to Changes of Renal Perfusion Pressure” Palygin O, Evans LC, Cowley AW, Staruschenko A. Journal of the American Heart Association. 2017;6(9):e006658. ATP and derivatives are recognized to be essential agents of paracrine signaling. Information on the sources of ATP, the mechanisms of its release, and its relationship to blood pressure has been limited by the inability to precisely measure dynamic changes in intrarenal ATP levels in vivo. In this paper we used amperometric biosensots, developed by Sarissa Biomedical (UK), to assess alterations in cortical ATP concentrations in response to changes in renal perfusion pressure (RPP) in anesthetized Sprague–Dawley rats. Changes in RPP directly correlate with renal sodium excretion and the elevation of cortical ATP. Given the known effects of ATP on regulation of glomerular filtration and tubular transport, the data support a role for ATP release in the rapid natriuretic responses to acute increases in RPP. The current report represents an important technical advance in which we used microenzymatic biosensors to measure in vivo changes in cortical ATP in real time. The data implicate ATP as a key regulator of the pressure‐natriuresis mechanism. This research was recently supported by an American Heart Association Scientist Development Grant (17SDG33660149).
Renal perfusion pressure induced changes of interstitial ATP concentration in the kidney cortex. Surgical preparation for the assessment of renal function and ATP concentrations in vivo. Schematic images show experimental setup. A, Experimental protocol, 5×15‐min manipulation periods. Changes in mean arterial pressure (MAP) and ATP levels during pressure manipulation by ligation occlusion/release (note the direction of the signal shown in the left‐hand panel). B, Summary graphs represent changes in ATP concentration from the baseline (control) value detected by microenzymatic biosensors in kidney cortex.
Sabrina Hofmeister, DO Assistant Professor Associate Program Director Department of Family & Community Medicine Medical College of Wisconsin
I am a family physician practicing full spectrum family medicine at a residency training clinic in Milwaukee. At this clinic, I see a large amount of patients and families who are affected by incarceration. I have an interest in creating optimal care transitions for patients recently released from incarceration. I am going to be tracking health outcomes for this population to advocate on a state and national level to prioritize care transitions for the recently released, particularly those with significant chronic illness, mental illness or substance abuse history. I also have an interest in training family medicine residents to work with these patients and families to provide care that is traumainformed and sensitive to their needs.
“Teaching Resident Physicians to Work with the Previously Incarcerated Patient” Hofmeister S, Soprych A. International Journal of Psychiatry in Medicine. 2017;52(3):277-285. The United States has the highest incarceration rate in the world. A large number of these individuals return to the community each year. This population has an elevated burden of chronic disease and lower socioeconomic status. Residency training about care of incarcerated or previously incarcerated patients is significantly lacking. This article describes an “educate the educators” workshop presented at a 2016 national conference. Attendees participated in exercises addressing assumptions, expectations, bias, and worldview and increased their ability for self-reflection when interacting with these patients. Strategies were identified that focused on engaging the patient. Future development includes a formal curriculum for training in this area, incorporation into existing rotations, and establishment of structured transition clinics where residents can be exposed to this population and improve their overall health outcomes. Figure 1. Workshop Activity Timeline & Tip Sheet Samples
How we frame our work
How we talk to our patient
Special Considerations: Criminal Record
Patient Focused
Physician Focused
The patient makes the decisions
You make the decisions
The plan is created together
You create the plan
The problem is solved together
You solve the problem
Is about what the patient can do
Is about what you can do
Non-Judgmental
Judgmental
I’m not following you… help me understand…
That doesn’t make sense
That’s one option, here are my concerns…
That will never work
What motivated you to do that?
Why did you do that
How does that relate to this?
That has nothing to do with this
I’d like you to do… One option I see is…
You should do…
Do
Don’t
Treat the person the same as any other person
Assume guilt or what they’ve been through based on their record
Look at underlying issues that led to record
Assume malicious intent
Recognize that consequences of having a record can make it difficult to fully participate in society
Confine a person’s identity to their criminal record
Carlos Mendez, MD, FACP Associate Professor of Medicine Section of Perioperative & Consultative Medicine Medical College of Wisconsin Division of Diabetes and Endocrinology Zablocki VA Medical Center
I am an Associate Professor of Medicine specialized in diabetes management within the Section of Perioperative and Consultative Medicine at Froedtert & MCW and the Division of Endocrinology at the Clement Zablocki Veterans Affairs Medical Center. My research aims to study and develop novel strategies to improve clinical outcomes in patients with diabetes. My contributions have provided notable advances in the understanding, as well as in the development of new approaches, for the management of diabetes and hyperglycemia in the inpatient, outpatient, and perioperative settings.
“Management of Type 1 Diabetes in the Hospital Setting� Mendez CE, Umpierrez GE. Current Diabetes Reports. 2017;17(10):98. Due to the increased prevalence and life expectancy of patients with type 1 diabetes, a growing number of these patients require hospitalization every year. Inpatient diabetes management is complex and is best provided by a multidisciplinary diabetes team. In the absence of such resource, providers and health care staff must become familiar with the features of this condition to avoid complications such as severe hyperglycemia, ketoacidosis, hypoglycemia, or glycemic variability. We reviewed most recent guidelines and relevant literature in the topic to provide practical recommendations for the inpatient management of patients with Type 1 diabetes. Figure 3. Recommendations on the course of action for hospitalized patient with type 1 diabetes wearing insulin pumps
Jonathan M. Bock, MD Associate Professor Division of Laryngology & Professional Voice Department of Otolaryngology Medical College of Wisconsin
I am an academic surgeon with interests in voice pathology, laryngeal function, and swallowing disorders. My interest in vocal cord pathology stems from my personal background as a musician, singer, and performer. My practice here at the Medical College of Wisconsin focuses on adult patients with voice, airway, and swallowing disorders and my current research focuses on clinical extensions of that work. I practice at Froedtert Hospital and the Zablocki VA hospital. I’m also a proud Medical College of Wisconsin graduate (MD ’01).
“Evaluation of the Natural History of Patients Who Aspirate” Bock JM, Varadarajan V, Brawley MC, Blumin JH. Laryngoscope. 2017;127(S8):S1-S10. The study shows long term follow-up data (up to 3.5 yrs) for patients with documented unsensed penetration or aspiration on swallowing study evaluations at Froedtert Hospital. The effects of interventions to improve swallowing, specific etiology of dysphagia, severity of swallowing dysfunction, and other patient-related factors were studied to assess impact on overall mortality (all cause) and rates of pulmonary events in our cohort. We show a very high overall mortality for patients with documented aspiration without significant change seen based on interventions or severity of initial swallow dysfunction. We were additionally able to show significant variations in survival and pneumonia rates based on initial etiology/diagnosis of dysphagia. Figure 7. Survival Predicted by Dysphagia Etiology
Figure 8. Impact of Etiology on Survival Hazard Ratio and 95% CL
Ji-Geng Yan, MD, PhD Associate Professor Director, Plastic Surgery Research Lab Department of Plastic Surgery Medical College of Wisconsin
I am an Associate Professor and Director of the Research Lab in the Department of Plastic Surgery. I am primarily interested in peripheral nerve injury. My major goals are to build on our previous work on the effects of excessive calcium influx and the use of calcium modulating agents with regard to peripheral nerve injury. For over 100 years, the outcomes of nerve repair have been unsatisfactory, even with advanced microsurgical techniques. This is because we lack understanding of the nerve injury cascade process and the cellular and molecular mechanism involved in nerve degeneration and regeneration. Our published studies have shown that an overwhelming calcium influx occurs after a crush injury and there is a strong correlation between nerve functional recovery and calcium absorption.
“Effect of Calcitonin on Cultured Schwann Cells” Yan JG, Zhang LL, Agresti MA, et al. Muscle & Nerve. 2017;56(4):768-772. After nerve injury, calcium concentrations in intranerve fibers quickly increase. We have shown that functional recovery of injured nerves correlates with calcium absorption. A slight increase in calcium reduces the number of Schwann cells present. Calcitonin therapy greatly improves regeneration by accelerating calcium absorption. We examined the effect of adding calcitonin to higher concentration calcium media on cultured Schwann cells. Methods: The cells, isolated from intact sciatic nerves, were cultured with normal or higher concentration calcium media with or without calcitonin. Schwann cells were incubated with anti–S100, goat–antimouse, and propidium iodide and then viewed through fluorescent light and phase-contrast microscopy for observation and analysis. Results: The cells in each calcitonin-containing medium showed many Schwann cells, however, the cells in the higher concentration calcium media showed fewer and more defective Schwann cells. Conclusion: These results show that calcitonin protects against the harmful effects of excessive calcium encountered in peripheral nerve injury. FIGURE 1. Schwann cell (SC) growth in different media. (A) SC growth in normal media, with dense SCs and other cells. The white arrows indicate normal spindle-shaped SCs with large, bright-yellow nuclei and long cytoplasmic processes. Red arrows indicate larger fibroblast cells with multiple irregular cytoplasmic processes, red ovoid nuclei, and evident nucleoli. (B) SC growth normal medium with calcitonin (CT), with a slightly denser distribution of SCs than in normal medium without CT. (C) SC growth in high-calcium medium with CT. The SC distribution and morphological features are similar to those in (A) and (B). White arrows indicate normal SCs. Red arrows indicate larger fibroblast cells. Slightly brighter green cytoplasm with longer and thicker axons can be seen in the SCs. (D) SC growth with high calcium only. There are a few unhealthy SCs and other cells in this high-calcium medium. The right white arrow indicates an SC cytoplasmic process defect; left white arrow indicates SC with short cytoplasmic processes. The right red arrow indicates 2 fibroblast cells with sparse cytoplasmic processes; the left red arrow indicates 3 fibroblast cells with irregular nuclei. Series of anti–S-100 immunological stain. Bar550 mm.
“Metabolically Derived Lysine Acylations and Neighboring Modifications Tune the Binding of the BET Bromodomains to Histone H4” Olp MD, Zhu N, Smith BC. Biochemistry. 2017;56(41):5485-5495. Recent proteomic studies discovered histone lysines are modified by acylations beyond acetylation. These acylations derive from acyl-CoA metabolites, potentially linking metabolism to transcription. Bromodomains bind lysine acylation on histones and other nuclear proteins to influence transcription. However, the extent to which bromodomains bind non-acetyl acylations is largely unknown. Using peptide arrays, binding assays, sucrose gradients, and computational methods, we quantified differential binding of the bromodomain and extraterminal domain (BET) family toward 10 distinct acyl-lysine histone marks. Our results suggest cellular acyl-CoA levels tune recruitment of the BET bromodomains to histones, integrating metabolism with bromodomain-mediated transcription.
Michael D. Olp MSTP Student Department of Biochemistry: Smith Lab
Michael Mashock, PhD Postdoctoral Research Fellow Department of Pathology
“Evaluation of Copan FecalSwab as Specimen Type for Use in Xpert C. difficile Assay” Mashock MJ, Faron ML, Buchan BW, Ledeboer NA. Journal of Clinical Microbiology. 2017;55(10):3123-3129. Liquid based microbiology (LBM) devices with flocked swabs and preservative media eases the transport of specimens and can improve specimen yield when compared to traditional fiber wound swabs. However, the performance of LBM collection devices has not been evaluated in many molecular assays. The positive and negative percent agreement of specimens inoculated with the LBM device (FecalSwab™) was 97.0% and 99.4%, respectively, compared to reference results obtained using unpreserved stool. This high positive and negative percent agreement shows that stool in preserved media yields equivalent results to unpreserved stool, enabling clinical laboratories to adopt this LBM collection device.
“Removal of a Consensus Proline Is Not Sufficient to Allow Tetratricopeptide Repeat Oligomerization” Bakkum AL, Hill RB. Protein Science. 2017;26(10):1974-1986.
Fis1 is a mitochondrial tetratricopeptide repeat (TPR) protein that is conserved in all species that contain mitochondria. TPR domains are ubiquitous protein interaction domains. We use the consensus sequence of TPR proteins to identify a proline that might be important for Fis1 and other TPR protein dimerization. We show that mutation of the native proline in the human Fis1 sequence does not allow dimerization, suggesting that the role of the TPR proline is not to prevent oligomerization. Further analysis of all available TPR protein structures reveal that the presence of the consensus proline might favor short turns between repeats.
Amber L. Bakkum Graduate Student Department of Biochemistry
Ninh Doan, MD, PhD Resident Physician Department of Neurosurgery
“Acid Ceramidase Confers Radioresistance to Glioblastoma Cells” Doan NB, Nguyen HS, Al-Gizawiy MM, et al. Oncology Reports. 2017;38(4):1932-1940. Glioblastoma multiforme (GBM) is the most common primary, intracranial malignancy of the central nervous system. The standard treatment protocol, which involves surgical resection, and concurrent radiation with adjuvant temozolomide (TMZ), still imparts a grim prognosis. Ultimately, all GBMs exhibit recurrence or progression, developing resistance to standard treatment. This study demonstrates that GBMs acquire resistance to radiation via upregulation of acid ceramidase (ASAH1) and sphingosine 1-phosphate (Sph-1P). Moreover, inhibition of ASAH1 and Sph-1P, either with humanized monoclonal antibodies, small molecule drugs (i.e. carmofur), or a combination of both, led to suppression of GBM cell growth. These results suggest that ASAH1 and Sph-1P may be excellent targets for the treatment of new GBMs and recurrent GBMs, especially since the latter overexpresses ASAH1.
“Growth- and Stress-Induced PASTA Kinase Phosphorylation in Enterococcus faecalis” Labbe BD, Kristich CJ. Journal of Bacteriology. 2017;199(21):e00363-17. Transmembrane Ser/Thr kinases containing extracellular PASTA domains are ubiquitous among Actinobacteria and Firmicutes and regulate critical processes. The prevailing model for signaling by “PASTA kinases” has not been rigorously tested in vivo. We show that the PASTA kinase IreK of Enterococcus faecalis responds to cell wall stress in vivo by enhancing its phosphorylation, and that of a downstream substrate. This response requires the PASTA domains and phosphorylatable residues in the kinase domain. Thus, our results provide in vivo evidence, with an intact full-length PASTA kinase in its native physiological environment, which supports the prevailing model of PASTA kinase signaling.
Ben Labbe Doctoral Candidate Department of Microbiology & Immunology
Daniel Walden, BS MD Candidate (2018) Medical Student
“Antiproliferative and Apoptotic Effects of Xanthohumol in Cholangiocarcinoma” Walden D, Kunnimalaiyaan S, Sokolowski K, Clark TC, Kunnimalaiyaan M. Oncotarget. 2017;8(50):88069-88078. We analyzed the effects of xanthohumol, a prenylated chalcone, on cholangiocarcinoma. Xanthohumol potently reduced cellular proliferation, colony formation, and cell confluency through cell cycle arrest as well as apoptosis through the reduction of cell cycle regulatory proteins as well as an increase in pro-apoptotic markers (cleaved poly ADP ribose polymerase, cleaved caspase-3) and a decrease in anti-apoptotic markers (X-linked inhibitor of apoptosis and survivin). Xanthohumol reduced Notch1 and AKT expression. Additionally, xanthohumol significantly restricted cholangiocarcinoma growth in cholangiocarcinoma derived mice xenografts. We show xanthohumol significantly reduces cholangiocarcinoma growth in-vitro and in-vivo.
“Delayed Retroclival and Cervical Spinal Subdural Hematoma Complicated by Preexisting Chiari Malformation in Adult Trauma Patient” Nguyen HS, Choi H, Kurpad S, Soliman H. World Neurosurgery. 2017;105:1039.e1-1039.e5.
Traumatic spinal subdural hematoma (sSDH) involving the retroclival region and upper cervical spine is rare, with only 2 prior cases in an adult trauma patient. A 30-year-old trauma patient sustained injuries to occipital condyle, tectorial membrane, and transverse ligament, with pre-existing Chiari 1. Three days later, she exhibited apneic episodes, bradycardia, and hypertension. Imaging showed interval hydrocephalus and a new ventral hematoma spanning the retroclival region to C7. She underwent decompressive surgery; postoperatively, she was intact. This pathology can lead to bulbar signs and obstructive hydrocephalus. High-energy craniocervical trauma, disruption of the tectorial membrane, and anticoagulation may be risk factors.
Ha Son Nguyen, MD Resident Physician Department of Neurosurgery
Natasha Moussouras, BA MSTP Student Department of Microbiology & Immunology: Dwinell & Volkman Labs
“Differences in Sulfotyrosine Binding amongst CXCR1 and CXCR2 Chemokine Ligands” Moussouras NA, Getschman AE, Lackner ER, Veldkamp CT, Dwinell MB, Volkman BF. Int’l Journal of Molecular Sciences. 2017;18(9):p1894. Chemokines are small globular proteins that coordinate the migration of immune cells via activation of their receptors, which often contain post-translational modifications such as tyrosine sulfation. Binding pocket prediction servers identified a cleft containing the canonical sulfotyrosine-binding pocket as a hot spot for ligand binding on the structures of the chemokines CXCL1, CXCL2, CXCL7, and CXCL8, but not CXCL5. Sulfotyrosine titrations monitored via NMR spectroscopy correspondingly showed specific binding to CXCL8, but not to CXCL5. The lack of CXCL5–sulfotyrosine interaction and the presence of CXCL8– sulfotyrosine binding suggests a role for receptor post-translational modifications in regulating ligand selectivity.
“Morbidity of Curative Cancer Surgery and Suicide Risk” Jayakrishnan TT, Sekigami Y, Rajeev R, Gamblin TC, Turaga KK. Psycho-oncology. 2017;26(11):1792-1798. Although surgery is perceived as improving cancer patients’ prognoses, curative cancer operations lead to debility and loss of autonomy in a population vulnerable to suicide. We used patient-based data (SEER Database) to understand the effect of surgical morbidity on suicide risk. The incidence of suicide among patients that underwent curative surgery was 16.58/100 000 person-years. Significant risk factors included male sex and age>65 years. When stratified by 30-day overall postoperative morbidity, a significantly higher incidence of suicide was found for patients that undergo high-morbidity surgeries. The identification of this high-risk cohort should motivate adoption of appropriate post-operative screening measures.
Thejus Jayakrishnan, MD General Surgery Resident PGY3 Department of Surgery
Lezlie España, BS Research Technologist II Brain Injury Research Department of Neurosurgery
“Serial Assessment of Gray Matter Abnormalities after Sport-Related Concussion” España LY, Lee RM, Ling JM, Jeromin A, Mayer AR, Meier TB. Journal of Neurotrauma. 2017;34(22):3143-3152. There is a need to characterize the acute physiological effects of sport-related concussions (SRC) to inform recovery decisions for athletes. We investigated the effects of SRC on gray matter structure and diffusion imaging metrics in collegiate athletes at multiple time points post-concussion. We found that acute SRC was associated with acute changes in diffusion metrics (mean diffusivity and fractional anisotropy) in gray matter compared to healthy athletes, without differences in gray matter volume or thickness. Results highlight the utility of diffusion imaging for the determination of the physiological effects of SRC.
Medical College of Wisconsin Office of Research 8701 W Watertown Plank Road Milwaukee, WI 53226-0509 mcw.edu/office-of-research.htm