Medical College of Wisconsin
Research Publication Series:
October 2017 2
Shao-Min Shi, MD
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Witold Karol Subczynski, PhD, DSc
“Selective Denervation for Persistent Knee Pain After Total Knee Arthroplasty: A Report of 50 Cases” “Organization of Lipids in Fiber-Cell Plasma Membranes of the Eye Lens”
Krishna Acharya, MBBS, MPH
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“Major Anomalies and Birth-Weight Influence NICU Interventions and Mortality in Infants with Trisomy 13 or 18”
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Julie K. Freed, MD, PhD
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Ben Weston, MD, MPH
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Laxman Mainali, PhD
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Moua Yang
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“Communication Is Key: Mechanisms of Intercellular Signaling in Vasodilation” “Does an Individualized Feedback Mechanism Improve Quality of Out-of-Hospital CPR?” “Changes in the Properties and Organization of Human Lens Lipid Membranes Occurring with Age” “Platelet CD36 Promotes Thrombosis by Activating Redox Sensor ERK5 in Hyperlipidemic Conditions”
Pradeep Kannampalli, PhD “Neonatal Bladder Inflammation Induces Long-Term Visceral Pain and Altered Responses of Spinal Neurons in Adult Rats”
Tylor Lewis “Cos2/Kif7 and Osm-3/Kif17 Regulate Onset of Outer Segment Development in Zebrafish Photoreceptors through Distinct Mechanisms”
Erin Kropp, PhD “Cardiomyocyte Differentiation Promotes Cell Survival During Nicotinamide Phosphoribosyltransferase Inhibition Through Increased Maintenance of Cellular Energy Stores”
Jennifer A. Campbell, MPH “Trends of Medical Expenditures and Quality of Life in US Adults with Diabetes: The Medical Expenditure Panel Survey, 2002-2011”
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Shao-Min Shi, MD Distinguished Professor Hand Microsurgery Department of Orthopaedic Surgery Medical College of Wisconsin
I joined the Department of Orthopaedic Surgery at MCW in 1992 as an Assistant Professor, and was named Distinguished Professor of Orthopaedic Surgery in 2007. I received my Medical Degree from the Fourth Military Medical University in Xian, China in 1973, where I earned my Masters’ Degree and PhD in Orthopaedic Surgery. I completed my residency in Orthopaedic Surgery at Xijing Hospital. I then completed my Hand and Microsurgery Fellowship in Michigan in 1988, followed by a hand surgery scholarship in Kentucky, where I was the recipient of the Hand Scholar Award in 1991. My research and clinical interests include hand and microsurgery, free tissue transfer and peripheral nerve injury. I am also a member of the American Society for Reconstructive Microsurgery.
“Selective Denervation for Persistent Knee Pain After Total Knee Arthroplasty: A Report of 50 Cases” Journal of Arthroplasty. 2017;32(3):968-973. Despite the general success of TKA, up to 20% of patients report dissatisfaction following surgery. One potential cause of this dissatisfaction is residual neuroma pain. We found that up to 9.7% of patients exhibited pain attributable to neuroma. Despite the high incidence little is known about the diagnosis or treatment. Between 2011 and 2014, 50 patients with neuroma pain following TKA underwent selective knee denervation. 64% patients rated their outcome as excellent, 20% as good, 6% as fair, and 4% reported no change. The mean pain score was improved from 9.4 to 1.1 (P .001). The mean Knee Society Scores increased from 45.5 to 94.1 points (P .0001). Average follow-up duration was 24 months. Our study suggests that selective denervation provides an effective and long-lasting option for the management. Figure 6. The visual analog scale pain score Mean analog pain score was reduced from 9.4 to 1.1 (P ≤ .0001). Excellent: no pain; good: some pain but no medication; fair: better but pain medication still required; poor: no improvement.
Figure 7. Knee Society Score Increased from a mean of 45.5 ± 14.3 to 94.1 ± 8.6 points (P ≤ .0001) postoperatively. Excellent: 90°-100°; good: 75°90°; fair: 60°-75°; poor: <60°.
Witold Karol Subczynski, PhD, DSc Professor Department of Biophysics Medical College of Wisconsin
After obtaining my MSc degree in Physics (1969) and PhD in Biophysics (1976) from the Department of Biophysics, Lomonosov Moscow State University, I joined the Department of Biophysics, Jagiellonian University, Krakow, Poland. There, I received my DSc degree in Natural Sciences (1984) and the title Professor of Biophysics (awarded in 1995 by the President of Poland). Since my first visit to MCW in 1980, I have been here about 50% of the time. I emigrated to the USA and joined the MCW faculty as an Assistant Professor (2000), then went on to become an Associate Professor (2002), and finally a Professor of Biophysics (2010). My research focuses on understanding how lipid composition, its properties, and the organization of the lipid bilayer portion of biological membranes are involved in regulating a variety of cellular functions.
“Organization of Lipids in Fiber-Cell Plasma Membranes of the Eye Lens” Experimental Eye Research. 2017;156:79-86. This paper summarizes the research performed in my lab during three R01 grant cycles (beginning in 2004) on the properties of the lipid bilayer portion of the eye lens’s fiber-cell plasma membrane, and their connections with cataract development. Major attention was paid to cholesterol’s role in eye lens health. We used the electron paramagnetic resonance (EPR) spin-labeling methods developed at the National Biomedical EPR Center, which provide information about the lateral organization of membranes, allowing us to discriminate coexisting domains and obtain several important membrane properties as a function of membrane depth. We concluded that high cholesterol content, formation of cholesterol bilayer domains, and formation of cholesterol crystals should not be regarded as major predispositions for the development of age-related cataracts.
Schematic drawing of the human lens fiber-cell plasma membranes. Lipid domains, induced by high cholesterol content and the presence of integral membrane proteins, are indicated. The tightly adherent cell–cell junctions formed by membrane proteins (AQP0, Cx46, and Cx50) permit communication between tightly packed layers of fiber cells. The lipid bilayer portion of the membrane provides a high hydrophobic barrier that protect against the uncontrolled leaking of small polar molecules. Note that cholesterol is excluded from boundary lipids.
I am an Assistant Professor of Pediatrics in the Division of Neonatology at MCW. I am interested in understanding the epidemiology, medical management, and outcomes of infants with birth defects using large data analysis. My additional interests are in prenatal counseling of mothers with high-risk pregnancies, including the accuracy of prenatal predictions about fetal or neonatal outcomes, and how prenatal counseling influences parental decision-making.
Krishna Acharya, MBBS, MPH Assistant Professor Department of Pediatrics Division of Neonatology Medical College of Wisconsin
“Major Anomalies and Birth-Weight Influence NICU Interventions and Mortality in Infants with Trisomy 13 or 18” Journal of Perinatology. 2017;37(4):420-426. There is ongoing debate about the extent of neonatal intensive care unit (NICU) interventions that should be provided for infants with trisomy 13 (T13) or trisomy 18 (T18). In order to understand the contemporary neonatal management and outcomes of neonates with T13 and T18, we used a large national NICU database. We found that infants with T13 or T18 received a wide range of NICU medical interventions. The majority of infants have birth defects that necessitate medical decision-making, but few require immediate surgical intervention. VLBW infants or those with a neonatal surgical anomaly had twice the mortality rate of infants without those risk factors. Infants who received NICU medical interventions did not have improved survival to NICU discharge; in fact, the majority of infants discharged home receive minimal NICU medical intervention. NICU neonatal intensive care unit. VLBW very low birth weight. Table 1. NICU Mortality Among Infants with T13 or T18 by Receipt of Intervention. Anomaly Category
Intervention Received
Neonatal surgical Non-neonatal surgical Minor
Birth Weight Group
Total
<1500g
1500-2499g
>2500g
Died
p
Died
p
Died
p
Died
p
No
25/46 (54%)
0.360
6/10 (60%)
0.379
16/32 (50%)
0.653
3/4 (75%)
0.755
Yes
61/96 (64%)
No
70/271 (26%)
Yes
153/274 (56%)
No
58/121 (48%)
Yes
22/33 (67%)
26/35 (74%) <0.001
16/30 (53%)
27/49 (55%) 0.077
57/80 (71%) 0.076
18/19 (95%) 10/16 (63%)
43/179 (24%)
8/12 (67%) <0.001
72/144 (50%) 0.018
33/76 (43%) 9/11 (82%)
13/62 (21%)
0.002
24/50 (48%) 0.017
7/26 (27%)
0.272
3/6 (50%)
NICU mortality among infants with T13 or T18. The left column lists anomaly categories: neonatal surgical = an infant with a major anomaly that requires surgery during the neonatal hospitalization for survival; non-neonatal surgical = an infant with a major anomaly that does not necessarily require surgery during the neonatal hospitalization for survival; minor = infants without major anomalies. The second column lists whether the infant received NICU medical interventions, including mechanical ventilation, surfactant, postnatal steroids, inhaled nitric oxide, vasopressors, paralytics, or prostaglandin (for infants with ductal-dependent cardiac lesions). Subsequent columns list the number of infants in each group who died divided by the total number of infants in each group, and the percentage of infants who died before NICU discharge. p values represent chi squared or Fisher’s exact tests, as appropriate. Grey bars highlight the “lowest-risk” infants: those without neonatal surgical anomalies who weighed >1500g at birth and did not receive NICU medical interventions.
Julie K. Freed, MD, PhD Assistant Professor Department of Anesthesiology Cardiovascular Center Medical College of Wisconsin
My research primarily focuses on the role that sphingolipids have in the development of endothelial dysfunction in the human microcirculation. Elevated plasma levels of ceramide, a prototypical sphingolipid, is a known independent risk factor for major adverse cardiovascular events in otherwise healthy people. My lab, located in the Cardiovascular Center, is currently investigating how these bioactive lipids are regulated in human endothelial cells. A potential way ceramide could adversely affect outcomes is by its recently discovered effect on flow-induced dilation (FID). The changing population demographics (higher percentage of elderly individuals, obesity epidemic, and increased incidence of cancer) will ignite an overall increase in surgical procedures over the next decade. As a cardiac anesthesiologist, I am also interested in translating our work in the lab through interdisciplinary collaboration to improve outcomes for surgical patients.
“Communication Is Key: Mechanisms of Intercellular Signaling in Vasodilation” Journal of Cardiovascular Pharmacology. 2017;69(5):264-272. Following exposure to ceramide, arterioles collected from healthy patients, dilate in response to flow by generating hydrogen peroxide, a pro-inflammatory and pro-atherosclerotic mediator as opposed to nitric oxide (NO), the anti-inflammatory, anti-atherosclerotic mediator. We have discovered that sphingosine-1-phosphate (S1P), also within the sphingolipid family and a metabolite of ceramide, promotes NO-dependent FID in vessels collected from patients with cardiovascular disease.¹ We have also found that ceramide is a potent trigger for the formation of endothelial microvesicles, which are also capable of causing vascular dysfunction in arterioles from healthy patients.² Our data supports that Neutral Ceramidase (NCdase), an enzyme that hydrolyzes ceramide and promotes the formation of S1P, regulates the sphingolipid balance within the endothelial cell. Finally, the vasculoprotective effect of adiponectin, may be partially due to activation of NCdase. Diagram of Pathways. NCdase determines the mediator of FID in health versus disease.
Additional References: 1. Freed JK, Beyer AM, LoGiudice JA, Hockenberry JC, Gutterman DD: Ceramide changes the mediator of flow-induced vasodilation from nitric oxide to hydrogen peroxide in the human microcirculation. Circ Res 2014; 115: 525-32. 2. Freed JK, Durand MJ, Hoffmann BR, Densmore JC, Greene AS, Gutterman DD: Mitochondria-regulated formation of endothelium-derived extracellular vesicles shifts the mediator of flow-induced vasodilation. Am J Physiol Heart Circ Physiol 2017; 312: H1096-H1104
Ben Weston, MD, MPH Assistant Professor Director, Mass Gathering & Event Medicine Section of EMS and Disaster Medicine Department of Emergency Medicine Medical College of Wisconsin
I am an Assistant Professor in the Department of Emergency Medicine at MCW. I serve as Director of Mass Gathering and Event Medicine as well as Associate Director of Medical Services for Milwaukee County EMS. I have provided medical direction and oversight for events including NFL, NBA, MLB, IndyCar, and USA Triathlon as well as other concerts and competitive sporting events. Clinically, I practice in the emergency department at Froedtert Hospital. I received my baccalaureate degree at Lawrence University, my medical degree and master in public health from the University of Wisconsin School of Medicine and Public Health, and completed my emergency medicine residency at Hennepin County Medical Center. I am dual board-certified in Emergency Medicine as well as Emergency Medical Services by the American Board of Emergency Medicine after completing my Emergency Medical Services Fellowship at MCW.
â&#x20AC;&#x153;Does an Individualized Feedback Mechanism Improve Quality of Out-ofHospital CPR?â&#x20AC;? Resuscitation. 2017;113:96-100. Despite its prevalence, survival from out-of-hospital cardiac arrest remains low. High quality CPR has been associated with improved survival in cardiac arrest patients. In early 2014, a program was initiated to provide feedback on CPR quality to prehospital providers after every treated cardiac arrest. Our aim in this study was to assess whether individualized CPR feedback was associated with improved CPR quality measures in the prehospital setting. This before and after retrospective review compared CPR quality measures prior to and after the initiation of the CPR feedback program. We found that individual CPR feedback is associated with marginally improved quality of CPR in the prehospital setting. Further investigation with larger samples is warranted to better quantify this effect.
“Changes in the Properties and Organization of Human Lens Lipid Membranes Occurring with Age” Current Eye Research. 2017;42(5):721-731 This research documents the changes in the organization and properties of human lens lipid membranes that occur with age. In the eye lens, cholesterol bilayer domains (CBDs) are formed within the fiber-cell plasma membranes and play a positive physiological role, maintaining lens transparency and possibly protecting against cataract formation. Our research findings show that the properties of pure CBDs changed significantly with the age of the human donor and were related to the size of the CBD, which increased with the donor’s age and was greater in nuclear than in cortical membranes.
Laxman Mainali, PhD Research Scientist II Department of Biophysics
Moua Yang Graduate Student (Graduate School) Department of Cell Biology, Neurobiology, and Anatomy
“Platelet CD36 Promotes Thrombosis by Activating Redox Sensor ERK5 in Hyperlipidemic Conditions” Blood. 2017;129(21):2917-2927. Atherothrombosis can cause life-threatening complications. Platelet reactivity in this setting is enhanced when platelet scavenger receptor CD36 recognizes oxidized lipids in LDL particles (oxLDL). In this study, we found that atherogenic conditions promote CD36 signaling by generating specific reactive oxygen species to activate redox sensitive MAP Kinase ERK5. This activation is through a signaling pathway requiring Src kinases and NADPH oxidase. Pharmacologic inhibition and targeted genetic deletion of ERK5 in murine platelets prevented platelet activation, aggregation, and thrombus formation by oxLDL or high fat diet-fed hyperlipidemic conditions. These findings suggest an important role for ERK5 in promoting platelet CD36-mediated thrombosis in atherogenic conditions.
“Neonatal Bladder Inflammation Induces Long-Term Visceral Pain and Altered Responses of Spinal Neurons in Adult Rats” Neuroscience. 2017;346:349-364. Interstitial cystitis/bladder pain syndrome (IC/BPS) affect between 3-8 million women and between 1-4 million men in the United States. Painful events early in life have been shown to increase the incidence of IC/PBS in adulthood. However, the intrinsic mechanism is not well studied. We previously reported that neonatal bladder inflammation causes molecular disruption of spinal GABAergic system in adulthood. The present study investigates whether these molecular changes affect the integrative function and responses of bladder-sensitive primary afferent and spinal neurons. Neonatal bladder inflammation was induced by intravesicular injection of zymosan during postnatal (P) days 14-16. At adulthood (P60), the viscero-motor response (VMR) to visceral stimuli was found to be significantly inhibited by HZ166 (GABAAα-2 agonist) only in neonatally saline-treated, but not in neonatally zymosan-treated rats. HZ166 also inhibited the responses of bladder-responsive lumbosacral (LS) spinal neurons to urinary bladder distension (UBD) and slow infusion (SI) in neonatally saline-treated rats. The drug did not attenuate the responses of UBD-sensitive pelvic nerve afferent (PNA) fibers to UBD and SI in either group of rats tested. These findings indicate that neonatal bladder inflammation leads to functional and molecular alteration of spinal GABAAα-2 receptor subtype, which results in chronic visceral hyperalgesia in adulthood.
Pradeep Kannampalli, PhD Postdoctoral Fellow Department of Medicine Division of Gastroenterology & Hepatology
Tylor Lewis Research Assistant: Besharse Lab Department of Cell Biology, Neurobiology, and Anatomy
“Cos2/Kif7 and Osm-3/Kif17 regulate onset of outer segment development in zebrafish photoreceptors through distinct mechanisms” Developmental Biology. 2017;425(2):176-190. Proper development of the photoreceptor outer segment, a modified cilium concentrated in phototransductive machinery, is essential for vision. In this work, we study KIF17, a ciliary kinesin motor that participates in intraflagellar transport within the outer segment. By generating genetic mutants of KIF17 in mice and zebrafish, we show that KIF17 regulates the onset of outer segment development specifically through disc morphogenesis. Additionally, we generate a zebrafish mutant of KIF7, a regulator of the Hedgehog signaling pathway, to show that Hedgehog signaling is important in photoreceptor differentiation. Taken together, we describe a role of two kinesin motors in photoreceptor development.
“Cardiomyocyte Differentiation Promotes Cell Survival During Nicotinamide Phosphoribosyltransferase Inhibition Through Increased Maintenance of Cellular Energy Stores” Stem Cells Translational Medicine. 2017;6(4):1191-1201 This study provides new mechanistic insight into how regulation of cellular NAD and energy pools change with differentiation of human pluripotent stem cells (hPSC) to cardiomyocytes. Furthermore, it informs how inhibition of an NAD synthesis pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT) could be implemented within the context of cardiomyocyte differentiation to eliminate tumorigenic cells. Here we show how to refine approaches for eliminating tumorigenic hPSC by varying treatment duration at specified timepoints during differentiation. These studies show that in vitro cardiomyogenic commitment provides resistance to NAMPT inhibition and cell survival is associated with maintenance of ATP pools despite NAD depletion.
Erin Kropp, PhD Medical Student (M3) Medical Scientist Training Program
Jennifer A. Campbell, MPH Program Coordinator II Center for Patient Care and Outcomes Research
“Trends of Medical Expenditures and Quality of Life in US Adults with Diabetes: The Medical Expenditure Panel Survey, 2002-2011” Health and Quality of Life Outcomes. 2017;15(1):70 Examination of a nationally representative dataset showed a clear gradient between quality of life (QOL) and health expenditures, with increasing physical and mental health related QOL associated with lower costs for U.S. adults with diabetes. Over 10-years, those with the lowest physical related QOL spent on average $7,500 more per year than those with the highest scores; and the lowest mental related QOL spent on average $3,000 more per year than those with the highest scores. This study demonstrates the significant impact poor QOL has on patients, and reveals the burden of disease not reflected when focusing on clinical measures.
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