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Medical Univer sity of South Carolina
Department of Medicine
Research Day
2 0 1 2 R e s e a r c h D ay
DEPARTMENT OF MEDICINE RESEARCH DAY
JANUARY 19, 2012
Many thanks to the judges who contributed their time and effort to make the
6th annual Department of Medicine Research Day a successful event.
Richard Silver, M.D.
Alexander Awgulewitsch, Ph.D.
P. Darwin Bell, Ph.D.
Galina Bogatkevich, M.D., Ph.D
Ruth Campbell, M.D., M.S.
Luciano J. Costa, M.D., Ph.D.
Valerie Durkalski, Ph.D.
Hesham El-Shewy, Ph.D.
Valerian L.C. Fernandes, M.B.B.S.
Patrick Flume, M.D.
Robert Gemmill, Ph.D.
Gary Gilkeson, M.D.
Monika Gooz, M.D., Ph.D.
Yan Huang, M.D., Ph.D.
Michael Janech, Ph.D.
Edward Jauch, M.D.
Diane Kamen, M.D., M.S.C.R.
Michael J. Kilby, M.D.
Louis Luttrell, M.D., Ph.D.
Paul J. McDermott, Ph.D.
Roberto Pisoni, M.D.
Joseph Romagnuolo, M.D., M.Sc.
Adam Smolka, Ph.D.
Antine E. Stenbit, M.D., Ph.D.
William Benjamin Wince, M.D.
Xian (John) Zhang, Ph.D.
Gerry Garza, M.B.A.
Jill Griffith, M.B.A.
Meghan Hatfield
SPECIAL THANKS
We would like to thank all the participants for sharing their innovative research, as
well as those who coordinated and attended this event. Your support for our
research mission is greatly appreciated.
Sincerely,
P. Darwin Bell, Ph.D.
Vice Chairman for Research
Professor, Nephrology Division
Edward Jauch, M.D.
Associate Vice Chairman for Research
Professor, Emergency Med Division
DEPARTMENT OF MEDICINE RESEARCH DAY
AWARD RECIPIENTS
2006
Nathanael Pruett, Graduate Student, Rheumatology & Immunology
Mi-Hye Lee, Ph.D., Postdoctoral Basic Science, Endocrinology
Chamion Olivier, M.D., Clinical Fellow, Infectious Diseases
Guangmao Cheng, M.D., M.S., Basic Junior Faculty, Cardiology
JuanManuel Gomez, M.D., M.S.C.R., Clinical Junior Faculty, Infectious Diseases
2007
Arindam Saha, Graduate Student, Gastroenterology & Hepatology
Santhosh Mani, Ph.D., Postdoctoral Basic Science, Cardiology
Deepika Koya, M.D., Clinical Fellow, General Internal Medicine
Hesham El-Shewy, Ph.D., Basic Junior Faculty, Endocrinology
Joseph Romagnuolo, M.D., Clinical Junior Faculty, Gastroenterology & Hepatology
2008
Christopher Potter, Graduate Student, Rheumatology & Immunology
Santhosh Mani, Ph.D., Postdoctoral Basic Science, Cardiology
Eduardo Freitas, M.D., Clinical Fellow, Infectious Diseases
Hesham El-Shewy, Ph.D., Basic Junior Faculty, Endocrinology
Cassandra Salgado, M.D., Clinical Junior Faculty, Infectious Diseases
Vidya Fleetwood, Medical Student, College of Medicine
2009
Jessica Trombetta, Graduate Student, Cardiology
Santhosh K. Mani, Ph.D., Postdoctoral Basic Science, Cardiology
Aisha Thomas, M.D., Clinical Fellow, Infectious Diseases
Chris Parsons, M.D., Basic Junior Faculty, Infectious Diseases
Cassandra Salgado, M.D., M.S.C.R., Clinical Junior Faculty, Division of Infectious Diseases
John Lucas, Medical Student, College of Medicine
MEET OUR 2010 AWARD WINNERS
Denise Kimbrough
Graduate Student
Cardiology
Takamitsu Saigusa, MD
Clinical Fellow
Nephrology
(TIE)
Courtney Haycraft PhD (Neph) &
Patrick Nasarre PhD (Hem/Onc)
Basic Science Junior Faculty
Krupa Desai
Medical Student
Benjamin Neely, PhD
Post-Doc, Basic Sci
Nephrology
Ashley Miller, NP
Clinical Junior Faculty
Hematology/Oncology
(TIE)
Infectious Disease & Rheumatology
Division Participation Award
Poster #1
Urinary Angiotensinogen Predicts Acute Kidney Injury After Cardiac Surgery
Alge, Joseph L.1, M.G. Janech1,2, A.D. Shaw3, L.S. Chawla4, J.A. Tumlin5 and J.M. Arthur1,2.
1
Department of Medicine, Division of Nephrology, Medical University of South Carolina;
Ralph H. Johnson VA Medical Center, Charleston, SC; 3Department of Anesthesiology, Duke
University Medical Center; 4Department of Anesthesiology and Critical Care Medicine and
Division of Nephrology George Washington University; 5Department of Medicine, Division of
Nephrology, University of Tennessee at Memphis
2
Acute kidney injury (AKI) is a common and serious post-operative complication of cardiac
surgery that is associated with an increased risk of several adverse outcomes. The poor
outcomes of these patients are partially attributable to the limitations of the current method of
diagnosis, which is based upon an increase in serum creatinine (sCr). The discovery of novel
biomarkers of AKI could improve patient outcomes by allowing for earlier and more accurate
diagnosis and prognosis. Using a proteomic approach, we have identified novel candidate
biomarkers of AKI. In this study, we validated one of these biomarkers, urinary angiotensinogen
(uAng), in a set of samples that included pre-operative samples, post-operative samples from
patients who did not develop AKI, and patients who developed AKI of increasing severity
(stages I, II, and III). Ten patients developed severe AKI requiring renal replacement therapy
(RRT). Patients with severe AKI had higher levels of uAng compared to the pre-operative
group, and uAng was predictive of the progression of sCr elevation after urine collection (AUC=
0.66, Sensitivity= 74.4%, Specificity= 52.1%). However, it was not a good predictor of AKI,
severe AKI, or the need for RRT. Importantly, however, we found that it was an excellent
predictor of severe AKI (AUC= 0.86, Sensitivity=100%, Specificity= 70.1%), the need for RRT
(AUC= 0.89, Sensitivity= 100%, Specificity= 81.8%), and the future increase of sCr (AUC=
0.74, Sensitivity=100%, Specificity= 64.3%) in the subset of patients who did not undergo
intraoperative cardiopulmonary bypass (CPB). Analysis of paired pre-op and post-op samples
suggested that CPB increased uAng. These results are the first to demonstrate the potential
diagnostic and prognostic utility of uAng in patients at risk of renal injury.
Graduate Student
Poster #2
Association of Willingness to Participate in Research Studies with Payment, Risk,
and Time Among Individuals with Type 2 Diabetes
Arnold Kimberly, Dismuke CE, Strom JL, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
and the Ralph H. Johnson VAMC
There are several factors that influence a patient’s willingness to participate in research
studies including personal values, trust in the healthcare system, and an assessment of
personal benefit (payment and risk). Bentley and Thacker (2004)9 found that monetary
payment had positive effects on respondents’ willingness to participate in research,
regardless of risk, but it did not blind them to the risks involved in the studies. This study
was conducted to discover the effects of payment, risk, and time on the willingness of
patients with type 2 diabetes to participate in research studies. The hypothesis is patients
will be more willing to participate in research studies with higher payment levels and
lower levels of risk and time. A sample of 534 patients with type 2 diabetes was recruited
from the MUSC University Internal Medicine Clinic, the Franklin C. Fetter Health
System, and the Ralph H. Johnson VA Medical Center primary care clinic. To assess
patient willingness to participate in research modules, subjects rated various research
designs that involved different levels of risk, payment, and time. We used the Dickert and
Grady model of payment for research from the study by Bentley and Thacker for this
analysis. There was a negative correlation between risk and willingness with a Pearson
correlation coefficient of -0.42862 and p value of 0.1262, but was not statistically
significant at p≤0.05. There was also a negative correlation between time and willingness
with a Pearson correlation coefficient of -0.52286 and statistically significant p value of
0.0551. There was a positive correlation between payment and willingness with a Pearson
correlation coefficient of 0.48885 and a p value of 0.0761, but was not statistically
significant. The patients involved in this study were concerned with time more than
payment or risk.
Acknowledgements: NIH/NIDDK T35 DK007431-26 (09012151), Center for Health
Disparities Research
Classification: Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Graduate Student
Poster #3
Effects of Fli-1 on T Cell Function in Lupus
Basher, Fahmin (Dept. of Microbiology & Immunology, Dept. of Medicine/Div. of
Rheumatology) Zainab Amani (Dept. of Medicine/Div. of Rheumatology) Marlene Bunni (Dept.
of Medicine/Div. of Rheumatology) Tamara Nowling (Dept. of Medicine/Div. of Rheumatology,
Ralph H. Johnson VA Medical Center)
Lupus is an autoimmune disease characterized by abnormal activation of T and B cells and
consequent production of autoantibodies, inflammation, and deposition of immune complexes in
peripheral organs. Overexpression of the transcription factor Fli-1 in non-autoimmune mice leads
to a lupus-like disease state, while reduction of Fli-1 expression results in decreased T cell
infiltration in the kidney as well as decreased inflammation and increased survival. In this study
we investigated effects of Fli-1 on T cell function in both non-autoimmune (C57BL/6) and
autoimmune (MRL/lpr) mouse models with respect to proliferation and apoptosis after
stimulation with PMA/ionomycin. While a decrease in proliferation was seen in wildtype B6
mice compared to Fli-1+/-, no differences were observed in pre-disease MRL mice, and
proliferation seemed to be driven primarily by CD8+ cytotoxic cells. Fli-1’s known antiapoptotic effects were observed in the B6 mice, with a decrease in early apoptosis in wildtype
mice compared to Fli-1+/-, and a similar trend was seen in the MRL model, with CD4+ cells
exhibiting increased and CD8+ cells decreased early apoptosis. We adoptively transferred T
cells isolated from young wildtype MRL/lpr mice into Fli-1+/- mice, and vice versa and
monitored serum antibodies and proteinuria over 12 weeks. IgG levels in Fli-1+/- mice receiving
wildtype cells, and wildtype mice receiving Fli-1+/- cells exhibited a modest increase but still
significantly lower than wildtype controls, and this trend was also seen in the anti-dsDNA, antiGBM, and proteinuria studies. Conversely, IgM levels did not differ significantly between
wildtype and Fli-1+/- recipients, and transfer of Fli-1 +/- cells to either Fli-1+/- or wildtype
recipients resulted in increased IgA levels. These results indicate that presence of lower levels of
Fli-1 in endogenous or transferred T cells can protect from disease with respect to circulating
antibodies such as IgG but that reduced expression of Fli-1 may limit class switching to IgG
from other subclasses.
Category: graduate student (basic science)
Graduate Student
Poster #4
Lupus Sera from Patients with Interferon Signature Impairs Endothelial Nitric Oxide
Synthase Expression in Human Endothelial Cells
Buie, Joy (Presenting Author/Student)1,2, Jim Oates1,2,3
Department of Microbiology and Immunology, College of Graduate Studies, MUSC Charleston,
SC1 Division of Rheumatology and Immunology2, Ralph H. Johnson VA Medical Center,
Charleston, SC3
Background and Significance: Late stage clinical mortalities in systemic lupus erythematosus
(SLE) are attributed to myocardial infarction and heart disease. Preclinical disease presentation
includes decreased flow mediated dilation (FMD), a surrogate marker of endothelial dysfunction
(ED). Pathways leading to ED converge on the diminished activity of endothelial nitric oxide
synthase (eNOS) and loss of endothelial derived nitric oxide (eNO). Interferon alpha gene
expression is increased in circulating immune cells in lupus patients, and recent studies suggest
that decreased FMD correlates with increased interferon alpha signature gene expression in
circulating endothelial progenitor cells (EPCs), increased EPC apoptosis, and an overall decline
in circulating EPCs, resulting in impaired blood vessel repair. However, interferon alpha’s effect
on endothelial cell (EC) eNOS remains to be unveiled.
Hypothesis: We hypothesized that interferon alpha, present in SLE sera from patients with
interferon signature genes, would cause a reduction in eNOS expression and activation in human
endothelial cells.
Methods: Cultured human ECs and WISH cells (IFNα reporter cells) were preconditioned in
SLE (n=4) and control (n=1) serum. Cells were also treated with IFN alpha at 100 and 1000
international units (IU). Transcript levels of eNOS and IFNα response genes were measured at
6,12, and 24 hrs while protein expression levels were measured at 24 hours by Western blot.
Results: Reverse transcriptase-real time polymerase chain reaction (RT2-PCR) studies showed a
76% reduction in eNOS expression compared to buffer controls and a 20% reduction compared
to cells preconditioned in normal sera. While eNOS protein levels were similar in all sera treated
cells, lupus sera treatment decreased Ser 1177 phospho-eNOS (activated eNOS) protein by 31%
when compared to protein levels in normal control conditioned cells. Lupus sera samples
induced an interferon response gene signature in both the endothelial cells and WISH cells, a cell
line designed to detect the presence of IFNα in serum samples. Thus, we examined the effects of
pure interferon on eNOS gene expression at 12 and 24 hours. For the first time, we showed that
after 24 hours, eNOS is reduced more than 50 fold in cells treated with 100 IU and 1000 IU of
IFN-alpha.
Conclusion: Collectively, these studies indicate that SLE serum causes a reduction in peNOS
protein expression, and eNOS mRNA expression at 24 hrs. These data suggest that interferon
alpha overexpression may be responsible for decreases in eNOS expression and ultimately
endothelial dysfunction in lupus patients.
Type of Research: Basic Science
Email Address of Corresponding Author: [email protected]
Graduate Student
Poster #5
The Role of Estrogen-Related Receptors in Cardiomyocyte Metabolic Adaptation to
Oxidative Stress
Cribben, Kathryn ( [email protected], College of Grad Studies), P.McDermott
(Department of Medicine, VA Medical Center Investigator)
Keywords: cardiomyocyte, metabolism, hypoxia, estrogen-related receptor
Introduction: In the ischemic heart, metabolic adaptation of the cardiomyocyte to
hypoxia is critical to sustain myocardial structure and function. These metabolic
adaptations are dependent on Estrogen-Related Receptors (ERRs), which are members of
the nuclear hormone receptor superfamily of transcription factors. ERRs regulate
expression of genes involved in fatty acid metabolism, oxidative phosphorylation, and
mitochondrial biogenesis. The purpose of these studies is to determine the regulatory
mechanisms governing expression of the alpha, beta and gamma isoforms of ERR in
cardiomyocytes undergoing oxidative stress.
Methods: Adult feline cardiomyocytes in primary culture were electrically stimulated to
contract at 1 Hz under normoxia (21% oxygen), hypoxia (0.5% oxygen), or hypoxia
followed by reoxygenation. Expression of ERR isoforms and target genes was measured
by QRT-PCR. Distribution of mRNA-ribosomal complexes was measured by
fractionation of polysomes on a linear sucrose gradient. SABiosciences QRT-PCR arrays
provided a high throughput tool for prospective target gene identification.
Results: Expression of ERR-alpha mRNA was significantly increased by 3.5-fold over 24
hours of hypoxia compared to normoxic controls. In contrast, ERR-beta mRNA
expression increased 11-fold after 12 hours of hypoxia, and this increase was maintained
over 24 hours. Subsequent reoxygenation for 24 hours caused a partial (25%) reduction in
ERR-alpha expression, but ERR-beta expression returned to baseline levels. Hypoxia also
increased mRNA expression of PGC-1alpha, an ERR co-activator, by16-fold over 24
hours, while reoxygenation reduced expression back to baseline levels by 24 hours.
Conclusions: 1) Hypoxia in cardiomyocytes induced rapid and substantial increases in
ERR-beta and PGC-1alpha expression compared to ERR-alpha expression; 2)
reoxygenation returned expression of ERR-beta and PGC-1alpha to baseline levels; 3)
hypoxia caused a smaller, yet sustained increase in ERR-alpha expression.
Acknowledgements: This research was funded by the NIH Predocotoral Fellowship
Training Grant to Improve Cardiovascular Therapies, and the Merit Review Award of the
Department of Veterans Affairs.
Graduate Student
Poster #6
Seamless Phase II/III Adaptive Dose Finding Design for Longitudinal Data in
Safety/Efficacy Clinical Trials
Ellerbe, Caitlyn N, Biostatistics and Epidemiology, MUSC
Authors: Ellerbe, Caitlyn N, Elm, J., Ramakrishnan, V., Durkalski, V., Biostatistics and
Epidemiology, MUSC
Abstract:
Randomized controlled trials (RCT) remain the gold standard for FDA investigational new drug
or new device certification. Computational advances, have allowed for adaptive trial designs
which modify trial parameters in an effort to increase safety and trial efficiency. Adaptive trials
differ from traditional fixed design trials in that they can pre-specify design features such as
sample size, study population and randomization ratios, which may be modified in response to
the observed data or outside information while the trial is in progress. Although compelling,
clinicians, regulatory bodies and biostatisticians are reticent to implement these designs due to
uncertainties with respect to the validity, implementation, and interpretation of adaptive trials.
Our goal is to propose an adaptive design that takes into account the accruing data and examine
its operating characteristics in terms of type I error and power. In many disease settings
clinicians have lingering questions as to the relationship between efficacy and safety that cannot
be evaluated in a small phase I patient population. Consider a trial in which there are three doses
of interest and a placebo control, as the dose increases efficacy may increase but more adverse
events may also be observed. A seamless phase II/III placebo controlled trial to evaluate the
safety and efficacy of these doses and confirm the benefit of the optimal dose has been proposed.
This design addresses key clinical issues such as: a) most efficacious treatment arm for a
confirmatory phase; b) inclusion of covariates; c) incorporation of earlier surrogate endpoint
information; d) response adaptive randomization; e) early stopping for futility and f) clinical
advice.
Funding:
Net-PD: NINDS U01NS043127, NETT: NINDS U01 NS059041
Email: [email protected]
Scientific Topic: Biostatistics
Graduate Student
Poster #7
Patient acceptance as a barrier to HIV screening in a tertiary care emergency department.
Green, Michael, Shapshak D, Glover N, Navarro B, Houck R, Fesperman C.
Division of Emergency Medicine, Department of Medicine.
Objective: Assess patient acceptance of routine no-cost HIV-screening in an ED setting
Methods: The MUSC Emergency Department is an academic, tertiary care facility with a 40 bed
capacity. From May 2008 to November 2011, MUSC offered routine, non-targeted testing at no
cost for emergency department patients aged 18 to 64. Trained research assistants offered UniGold™ Recombigen® HIV rapid immunoassays to patients during their ED treatment course.
Reasons patients declined testing were documented and categorized. These categories include:
previously tested positive, tested negative within 6 months, not at risk, monogamous, afraid or no
reason.
Results: Of 10985 patients approached, 7543 accepted testing. There were 3442 patients who
declined testing for the following reasons: 175 patients cited “previously positive”; 1618 cited
“recent test”; 336 cited “no risk,”333 cited “married/monogamous”; 60 cited “afraid.” Three
hundred and forty patients provided reasons categorized under “other,” and 589 declined to
provide a reason. The acceptance rate among all–comers was 69%. Among patients without a
prior positive test, the acceptance rate was 85%.
Conclusions: Patient participation is essential for the sustainability of any testing program. An
acceptance rate of 85% suggests ED patients are willing to participate in bedside, rapid HIVscreening offered at no cost. The 31% refusal rate appears inflated because the inclusion of the
16% of patients who previously accepted testing. Only 6% of patients refused testing due to the
perception they were not at risk with less than 1% admitting they were “afraid” of the test result.
Focusing on education regarding HIV risk factors may enhance participation. Lack of patient
acceptance is not a relevant barrier to the success of our ED testing model.
The corresponding author: Dag Shapshak MD ([email protected])
Type of Research: Clinical
Graduate Student
Poster #8
Fli-1 transcription Factor Affects Glomerulonephritis Development by Regulating
Expression of Inflammatory Chemokine in Endothelial Cells in Kidney
Karam, Eva1, Eiji Suzuki1, Sarah Williams2, Xian Zhang1, 2
1
Division of Rheumatology & immunology, Department of Medicine. Med. Univ. of South
Carolina, Charleston, SC, 2Ralph H. Johnson VA Medical Center, Charleston, SC
Expression of Fli-1, a member of the Ets family of transcription factors, is implicated in the
development of glomerulonephritis in murine models of systemic lupus erythematosus (SLE).
Lupus nephritis is a major cause of death in both animal models and human patients, and is
characterized by immune complex formation and inflammatory cell infiltration. Expressions of
monocyte chemotactic protein-1 (MCP-1) and Chemokine (C-C motif) ligand 5 (CCL5) has been
demonstrated to initiate inflammatory cell infiltration in the kidneys of lupus mice. In this study,
we examined the role of Fli-1 on chemokine production and inflammatory cell infiltration in
conjunction with nephritis development in NZM2410 mice, an animal model of SLE. We
generated Fli-1 heterozygous knockout NZM2410 mice (Fli1+/-) and wild-type (WT) littermate
(Fli1+/+) mice. The expression levels of MCP-1 and CCL5 in the kidneys from 18-week-old
mice were analyzed by real-time PCR and it was found that there was a significant reduction in
MCP-1 and CCL5 expression in Fli-1 heterozygous knockout NZM2410 mice (Fli1+/-) when
compared to WT littermate (Fli1+/+). We then examined the expression of MCP-1 in endothelial
cells isolated from the kidneys of both Fli-1+/- and WT controls. We found that there was a
significant reduction in MCP-1 production from endothelial cells isolated from the kidneys of
Fli-1+/- NZM2410 mice compared to those isolated from WT NZM2410 mice kidney. Next, we
studied the production of MCP-1 and CCL5 from endothelial cells transfected with specific Fli-1
siRNA. There was a significant reduction in MCP-1 and CCL5 production from cells transfected
with the specific Fli-1 siRNA when compared to cells transfected with negative control siRNA.
Our data indicates that Fli-1 affects glomerulonephritis development by regulating expression of
inflammatory chemokine MCP-1 and inflammatory cell infiltration in the kidneys. The lower
expression of Fli-1 resulted in decreased expression of MCP-1 in kidney endothelial cells which
significantly reduced infiltration of inflammatory cells, which led to reduced glomerulonephritis
in NZM2410 mice.
This study was supported by National Institutes of Health grants (AR056670 to X.Z.) and
the Medical Research Service, Department of Veterans Affairs (to X. Z.).
Graduate Student
Poster #9
Inhibition Of Histone Deacetylase Activity Represses Matrix Metalloproteinase-9 Induction
by Regulating of Macrophage Secretion of MMPs to Preserving Extracellular Matrix Post
Myocardial Infarction
Kimbrough, Denise, Santhosh K. Mani*, Christine B. Kern*, Benjamin Addy, William T.
Rivers#, Francis G. Spinale#, Rupak Mukherjee# and Donald R. Menick*.
Departments: *Gazes Cardiac Research Institute, Department of Medicine, Division of
Cardiology, #Department of Surgery, Medical University of South Carolina, Charleston, SC
The cardiac extracellular matrix (ECM) consists of a dense network of collagens to which
matrix components such as fibroblast and myocytes attach to maintain cardiac function. Postmyocardial infarction (MI) the ECM undergoes massive remodeling in order to prevent dilation
of the infarct area and maintain cardiac output. This remodeling includes three phases:
inflammation, proliferation/granulation, and mature scar formation. Integral players in this
remodeling are matrix metalloproteinases (MMPs). Post-MI macrophages are a significant
source of MMP production and have been shown to have temporal expression of the two
subtypes (M1 and M2). Differential expressions of macrophage subtypes correlate with the
different phases of ECM remodeling, ECM composition and MMP expression. Increased
expression of MMP-9 and MMP-2 is associated with deleterious effects to the ECM and left
ventricular (LV) dilation following MI. Histone deacetylases (HDACs) are a class of enzymes
that can greatly affect transcriptional regulation of genes during pathological conditions. We
hypothesize that HDACs regulate MMP-2 and -9 in the post-MI heart through mediating
cytokine expression and the M1 and M2 polarization. MI was induced in transgenic mice with
the MMP-9 promoter sequence fused to the Beta-galactosidase (Beta-gal) gene. Twelve hours
prior to MI, mice were administered the HDAC inhibitor trichostatin A (TSA, 2 mg/kg/day) or
vehicle. TSA (n=28) or vehicle treatment (n=23) continued until hearts were harvested 7 days
post-MI. The post-MI change in LV end-diastolic volume was significantly lower in the TSA
treated mice (49±9%) than in mice administered vehicle (69±12%). Similarly, ejection fraction
was also improved in the TSA treated mice (-44±8%) when compared to vehicle (-59±6%).
Beta-gal staining of the post-MI LV was lower in the TSA mice compared to vehicle.
Zymographic levels of MMP-9 were lower with TSA than in vehicle. There is increased
periostin accumulation in the infarct zone compared to remote zone post-MI at day 1 and day 4.
The majority of MMP-9 expression at 7 days post MI is from infiltrating macrophages with some
contribution from resident fibroblasts. TSA treatment of cultured macrophages and isolated
human cardiac fibroblasts repressed MMP-9 induced expression. From these data we conclude
that macrophage secretion of MMPs is an essential component in the promotion of adverse ECM
remodeling post-MI and that HDAC inhibition can attenuate this remodeling and that
macrophage polarization plays an essential role in this attenuation.
Student, Basic science, Email: [email protected]
Graduate Student
Poster #10
Glucosylceramide and lactosylceramide accumulation in lupus nephritis: biomarker or
mediator of disease?
Mather, Andrew R.1, Jennifer Schepp-Berglind2, María José Hernandez-Corbacho2, Jon M.
Donahue2, Ashley J. Snider2,3, Jim C. Oates2,3, and Leah J. Siskind1,2,3
Departments of 1Biochemistry and Molecular Biology and 2Medicine Medical University of
South Carolina, Charleston, SC
3
Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which the immune
system attacks otherwise healthy tissue causing inflammation and damage in various parts of the
body including the kidney. SLE manifests in a variety of ways including the development of
lupus nephritis in roughly 50% of patients. Current therapies have a low success rate along with
infectious and reproductive side effects. Thus, more effective and less toxic therapies for lupus
nephritis are in high demand. Glycosphingolipids are highly abundant in the kidney and play an
important role in a variety autoimmune as well as kidney diseases. However, the role of
glycosphingolipids in lupus nephritis is unknown. We utilized the MRL/lpr lupus nephritis
mouse model to test the hypothesis that the glycosphingolipids glucosylceramide (Glucer) and
lactosylceramide (LacCer) play a role in lupus nephritis. Our data demonstrate accumulation of
both GluCer and LacCer within the kidney cortices of lupus mice via multiple approaches,
including mass spectrometry, immunohistochemistry, and flow cytometry. In addition, these
glycosphingolipids are excreted into the urine prior to the onset of proteinuria. Interestingly, the
expression and activity of neuraminidases are significantly elevated in lupus nephritis mice,
suggesting that ganglioside breakdown is the mechanism by which GluCer/LacCer accumulate.
In addition, humans with lupus nephritis have significantly higher levels of glycosphingolipids in
their urine as compared to those found in normal patients and non-nephritis lupus patients. Thus,
the data suggest that glycosphingolipids may be an important biomarker or even mediator of
lupus nephritis. Specifically, two FDA approved drugs used for the treatment of Gaucher’s
disease and influenza are available that inhibit neuraminidases involved in the metabolism of
these glycosphingolipids showing that results from the above studies could be rapidly translated
to humans for the treatment of lupus nephritis.
This work is supported by the following grants: VA CDA-2 (to LJS, AJS), VA REAP (to LJS,
AJS, JO), COBRE (to LJS, AJS), Alliance for Lupus Research (to JO)
Graduate Student
Poster #11
Effects of Perfluorooctane Sulfonate (PFOS) and Perfluorooctanoic Acid (PFOA) on IL-2
Production in the Human Jurkat T-cell Line
Midgett, Kristin Smith1, Margie Peden-Adams2, Gary S. Gilkeson3,4, Diane L. Kamen3
1
Department of Immunology and Microbiology, Medical University of South Carolina; 2Harry
Reid Center for Environmental Studies, University of Nevada-Las Vegas; 3Division of
Rheumatology and Immunology, MUSC; 4Ralph H. Johnson VAMC, Charleston, SC
The potential human health effects of perfluorinated compounds such as perfluorooctane
sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are becoming an increasing concern in the
United States and worldwide. Both PFOS and PFOA have been shown to alter various immune
functions suggesting that they are immunotoxic. PFOS specifically has been shown in rodent
studies to decrease T-cell IL-2 production, which is characteristic of autoimmune diseases such
as systemic lupus erythematosus (SLE). Along with PFOS, PFOA has been detected in human
blood, but had not previously been investigated for modulation of IL-2 production. The current
study assessed the effects of PFOS and PFOA on IL-2 production in the human Jurkat T-cell
line. Cells, stimulated with PHA/PMA or anti CD-3/anti CD-28, were dosed with 0, 0.05, 0.1,
0.5, 1, 5, 10, 50, 75, or 100 ug/ml of PFOS or 0, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, or 10 ug/ml of
PFOA. Jurkat cells stimulated with PHA/PMA exhibited decreased IL-2 production beginning at
50 ug PFOS/ml. However, cells stimulated with anti-CD3/anti-CD28 exhibited no alteration in
IL-2 production. PFOA exposure in cells stimulated with PHA/PMA resulted in significant
decreases in IL-2 production at 10 ug PFOA/ml, but cells stimulated with anti-CD3/anti-CD28
exhibited no alteration in IL-2 production. Addition of the PPAR-alpha antagonist GW6471 to
PFOS dosed cells stimulated with PHA/PMA resulted in decreases in IL-2 production starting at
50 ug PFOS/ml. However, the addition of GW6471 to PFOA exposed cells stimulated with
PHA/PMA ameliorated the PFOA-induced decrease in IL-2 production. These data suggest that
PFOS affects T-cell IL-2 production via PPAR-alpha-independent mechanisms and that PFOAinduced suppression of IL-2 production may be PPAR-alpha-dependent. Further studies utilizing
cells from SLE patients who have varying blood levels of PFOS and PFOA are underway to
further investigate the role of PFOS and PFOA as environmental triggers of SLE.
This project was supported by the South Carolina Clinical & Translational Research (SCTR)
Institute at the Medical University of South Carolina, NIH/NCRR Grant number UL1 RR029881
and Diane Kamen’s NIH/NIHES 1 R21 ES017934-01 Grant.
Graduate Student
Poster #12
mTORC2-mediated Prosurvival Signaling Requires PKCε in Adult Feline Cardiomyocytes
Pleasant, Dorea L., Phillip Moschella, John McKillop, Sundaravadival Balasubramanian and
Dhandapani Kuppuswamy. Department of Medicine, Division of Cardiology, Medical University
of South Carolina, Charleston SC.
Cardiac hypertrophy occurs in response to stress, such as an increase in hemodynamic overload.
Our laboratory has shown that mammalian target of rapamycin (mTOR) is essential to the
development of various hypertrophic responses, including cardiomyocyte survival. mTOR forms
two independent complexes, mTORC1 and mTORC2, by associating with common and distinct
cellular proteins. Both complexes are sensitive to a pharmacological inhibitor, torin, although
only mTORC1 but not mTORC2 was sensitive to rapamycin inhibition. Since our earlier work
shows that mTORC2 regulates the activation of a prosurvival kinase Akt, we initiated a study to
characterize whether mTORC2 directly mediates Akt activation or whether it requires the
participation of another prosurvival kinase PKCε (epsilon isoform of protein kinase-C). Our
present work reveals that treatment of adult feline cardiomyocytes with insulin results in the
phosphorylation of Akt at S308 and S473 sites for its activation which could be blocked by
pretreatment with torin but not with rapamycin. Furthermore, silencing the expression of a
mTORC2 component, Rictor (rapamycin-insensitive companion of mTOR), with sh-Rictor also
lowers insulin-stimulated Akt activation. These studies demonstrate that insulin-stimulated Akt
phosphorylation in cardiomyocytes is mediated primarily via mTORC2. Next, we explored if
PKCε plays a role in the mTORC2-mediated Akt activation by expressing a dominant negative
isoform of PKCε (DN-PKCε) in cardiomyocytes. DN-PKCε expression was found to
significantly lower insulin-stimulated Akt activation. Furthermore, immunoprecipitation
combined with Western blot analyses revealed that PKCε was part of rictor but not raptor (a
binding partner and component of mTORC1), and phosphorylation of PKCε at the critical S729
site for its activation was found to be blocked by torin. Together, these studies clearly
demonstrate that mTORC2 mediates prosurvival signaling during insulin stimulation in adult
cardiomyocytes where PKCε activation downstream of mTORC2 is critical for the activation of
Akt.
Type of Research: Basic Science
Corresponding Author: [email protected]
Graduate Student
Poster #13
Does Acetylation Regulate miRNA Expression in Myocardial Infarction?
Renaud, Ludivine (PhD student, basic science), Harinath Kasiganesan, Erhe Gao#,
Santhosh K. Mani, Jeffrey A. Jones*, Robert E. Stroud*, Donald R. Menick
Department of Medicine
* Department of Surgery, MUSC, Charleston, SC
# Thomas Jefferson University, PA
Cardiovascular diseases are one of the leading causes of morbidity and mortality in the
world, underlining the need for innovative therapies and diagnosis for heart disease.
MicroRNAs (miRNAs) have been identified as central players in regulating gene
expression. miRNAs are noncoding RNAs that bind to target mRNAs and reduce their
expression. Several recent reports have demonstrated that some miRNAs are aberrantly
expressed in cardiac arrhythmia, hypertrophy, fibrosis, ischemia, vascular atherosclerosis
and heart failure. Histone deacetylase (HDACs) are a class of enzymes that affect the
transcriptional regulation of genes during pathological conditions. Previous studies in our
laboratory demonstrated that 1) class I and class II HDACs play an important role in the
basal expression and upregulation of the sodium calcium exchanger (Ncx1) gene in adult
cardiomyocytes and 2) treatment with HDAC inhibitors trichostatin (TSA) or SAHA
improved ventricular function by suppressing MMP9 gene expression in MI. Both TSA
and SAHA inhibit class I and class IIb HDACs specifically and SAHA is currently FDA
approved for T-cell lymphoma treatment. We hypothesize that SAHA treatment will
ameliorate the shift in expression of some of the miRNA which are misregulated in MI.
Ligation of the left anterior descending (LAD) coronary artery was performed to induce
MI using a novel surgical procedure (Gao et al. 2010) which is less invasive than the
conventional protocol: in less than 2.5min/mouse, the heart is popped out of the chest
through a very small incision between 2 ribs and ligation of the LAD artery is done
before pushing the heart back inside the chest. Mice were divided into 4 treatment
groups: SHAM control, MI-7days, MI-7days+SAHA-day0, MI-7days+SAHA-day1. We
examined the expression level of miRNAs that have been shown previously to be
aberrantly expressed in MI. RT-PCR demonstrated that miR-1, miR-29a, miR-133a, miR208a and miR-486 are decreased and miR-21 is increased by 10 fold 7 days post-MI.
Interestingly, SAHA treatment significantly attenuated the abnormal expression of miR21. miR-21 has been shown to regulate PTEN and indirectly MMP2 expression, and to
contribute to post-MI deleterious pathological remodeling. Our preliminary data confirm
this finding and demonstrate that inhibition of HDACs may provide a novel therapeutic
strategy to attenuate adverse post-MI remodeling.
NIH RO1 HL066223, AHA Grand in Aid 09GRNT2020202
Gao, E., Y. H. Lei, X. Shang, Z. M. Huang, L. Zuo, M. Boucher, Q. Fan, J. K. Chuprun,
X. L. Ma and W. J. Koch (2010). "A Novel and Efficient Model of Coronary Artery
Ligation and Myocardial Infarction in the Mouse / Novelty and Significance." Circulation
Research 107(12): 1445-1453.
Corresponding author: Ludivine Renaud [email protected]
Graduate Student
Poster #14
The Analysis of Acute Stroke Clinical Trials with Responder Analysis Outcomes
Robinson, Kyra M -Division of Biostatistics and Epidemiology, MUSC
Sharon D Yeatts-Division of Biostatistics and Epidemiology, MUSC
Viswanathan Ramakrishnan-Division of Biostatistics and Epidemiology, MUSC
Valerie L Durkalski-Division of Biostatistics and Epidemiology, MUSC
Traditionally in acute stroke clinical trials, the primary outcome has been a dichotomized
modified Rankin scale (mRS). The mRS is a 7-point categorical scale indicating a
patient’s level of disability following a stroke. Standard practice uses a fixed
dichotomization scheme, which dichotomizes ‘success’ as an mRS of 0-1 (or 0-2). This
method fails to address the concern that stroke severity may impact the likelihood of a
successful outcome; subjects with mild baseline stroke severity may achieve the defined
threshold for success more easily than subjects with severe baseline stroke severity 1 . As
a consequence, subjects are not able to contribute equally to the estimation of treatment
effect. Stroke studies are increasingly turning to new methods that make more efficient
use of the available data. These new methods include responder analysis, the global
statistic, and shift analysis 2 . The focus of this study is responder analysis, in which the
definition of success varies according to baseline severity. Through the use of this
sliding dichotomization scheme, responder analysis puts stroke patients on a more level
playing field, producing a more precise insight into the actual effect of investigational
stroke treatments 2 . It is unclear whether or not statistical analyses should adjust for
baseline severity when responder analysis is used, as the outcome already takes into
account baseline severity. In this simulation study, we compare the power and type-I
error rates of adjusted and unadjusted analyses of both a fixed dichotomization scheme
and a sliding dichotomization scheme like that seen in responder analysis. The results of
this study will help delineate the best way to handle such analyses in stroke studies and
will be used to guide analyses for future stroke trials.
This work is funded by the National Institute of Neurological Diseases and Stroke
through grant U01 NS069498-01.
Graduate student poster presentation
Type of research project: Biostatistics
Corresponding author: Kyra M Robinson, [email protected]
1 Murray GD, Barer D, Choi S, Fernandes H, Gregson B, Lees KR, Maas AI, Marmarou A, Mendelow AD, Steyerberg EW, Taylor
GS, Teasdale GM, Weir CJ. Design and analysis of phase III trials with ordered outcome scales: the concept of the sliding
dichotomy. J Neurotrauma. 2005; 22: 511-517.
2 Saver, JL. Novel end point analytic techniques and interpreting shifts across the entire range of outcome scales in acute stroke trials.
Stroke. 2007; 38: 3055-3062.
Graduate Student
Poster #15
Associations between Coping Styles, Diabetes Knowledge, Medication Adherence, and
Self-Care Behaviors in Adults with Type 2 Diabetes
Smalls, Brittany, Walker RJ, Hernandez-Tejada MA, Campbell JA, Davis KS, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
Literature on diabetes and psychological factors show that some actions and thoughts that
compose coping styles relate to compliance with treatment and self-care prescriptions. The
goal of this study is to examine different coping styles and how these are related to diabetes
management in adults with type-2 diabetes. The study had 378 subjects, recruited from the
MUSC Internal Medicine Clinic and Franklin C. Fetter Health Center, who completed the
following measures: 24-item diabetes knowledge questionnaire, Summary of Diabetes SelfCare Scale, COPE-S, and the 8-item emotional-approach coping questionnaire. Our study
population was comprised of 83% Non-Hispanic Blacks, 69% women, 22% 65 years or
older, 68% were not married, 26% had <high school education, 60% unemployed, 39%
uninsured, 47% had a yearly income of <$10,000, and 24% had worsening health status.
Significant correlations were observed between both types of coping: emotional expression
(EE) and emotional processing (EP) (r=0.070, p<0.0001). EE was related to diabetes
knowledge (r=0.18, p<0.001) and EP to foot care (r=0.14, p<0.015). However, both were
related to diet (EE r=0.18, p<0.001; r=0.16, p<0.005); exercise (EE r=0.20, p<0.004; EP
r=0.23, p<0.001); and blood sugar testing (EE r=0.13, p<0.023; EP r=0.15, p<0.008). In the
linear regression model, EP was significantly associated with medication adherence (β 0.17, 95% -0.32, -0.015), diabetes knowledge (β 0.76, 95% 0.29, 1.24), diet (β 0.52, 95%
0.24, 0.81), exercise (β 0.51, 95% 0.19, 0.82), blood sugar testing (β 0.54, 95% 0.16, 0.91),
and foot care (β 0.32, 95% -0.23, 0.67). Contrarily, EE was associated with diet (β 0.38,
95% 0.13, 0.64), exercise (β 0.54, 95% 0.27, 0.82), blood sugar testing (β 0.42, 95% 0.00,
0.76) and foot care (β 0.36, 95% 0.60, 0.66), but was not associated with diabetes
knowledge. In conclusion, coping styles related to emotional processing and emotional
expression was significantly associated with improved diabetes management.
Acknowledgements: NIH T35DK007431, Center for Health Disparities Research
Classification: Graduate Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Graduate Student
Poster #16
SPARC has a Two-Fold Mechanism to Maintain Periodontal Ligament Integrity
Trombetta-eSilva, Jessica 1,2 and Amy D. Bradshaw1,2,3
1
3
Department of Craniofacial Biology, 2Department of Medicine: Division of Cardiology,
Ralph H. Johnson VA
The periodontal ligament (PDL) is a unique tissue that maintains the tooth within the
alveolar bone. PDL is primarily composed of collagen type I, produced by resident
fibroblasts. PDL extracellular matrix (ECM) has a high turnover rate, thus PDL is a prime
tissue to study collagen deposition and remodeling. Collagen binding proteins, such as
SPARC, are critical in collagen secretion and incorporation into the ECM. SPARC is a
matricellular protein with anti-proliferative and counter-adhesive properties. SPARC-null
PDL has significant deficiencies in collagen volume fraction, thickness, and overall
morphology as compared to WT PDL. In a periodontal disease model, lipopolysaccharide
was injected between the first and second molars of WT and SPARC-null mice to induce
local inflammation. In this model, as compared to WT, SPARC-null mice lost a
significant amount of alveolar bone and PDL collagen, despite decreased inflammation.
To address cellular mechanisms of decreased homeostatic collagen content and response
to disease in the absence of SPARC, we cultured PDL fibroblasts and used a novel organ
culture model. Our preliminary results demonstrated, both in vitro and ex vivo, that
SPARC-null PDL fibroblasts had a deficiency in procollagen processing, as indicated by
an accumulation of procollagen in SPARC-null cells and tissue that was not evident in
WT conditions. Furthermore, increases in procollagen were found associated with cell
surfaces in the absence of SPARC. In addition, using similar models we examined the
enzyme transglutaminase, known to catalyze covalent cross-links in the ECM. Utilizing
the organ culture model we established SPARC as a potential transglutaminase inhibitor.
Taken together, these data suggest SPARC is involved in both procollagen processing
and in collagen stabilization via cross-link formation in the PDL.
Presenting Author: Graduate Student
Basic Science Research Project
Corresponding Author: [email protected]
Graduate Student
Poster #17
Association between Fatalism, Medication Adherence and Self-care behaviors in
Adults with Type 2 Diabetes
Walker, Rebekah, Smalls BL, Hernandez-Tejada MA, Campbell JA, Davis KS, Egede
LE MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
Fatalism refers to a complex psychological cycle characterized by perceptions of
hopelessness, meaninglessness, powerlessness, and despair (Powe and Weinrich, 1999;
Egede and Ellis 2009). Few studies have examined the effect of fatalism on health
outcomes. The objective of this study was to examine the association between fatalism
and medication adherence and self-care behaviors in adults with diabetes. Data on 378
subjects with Type 2 diabetes were examined. Fatalism was measured with a 12-item
scale; medication adherence was assessed with the 4-item Morisky scale; diabetes
knowledge was measured with a 24-item diabetes knowledge questionnaire; and self-care
behaviors were assessed with the Summary of Diabetes Self-care Scale. Multiple linear
regression was used to assess the independent effect of fatalism on medication adherence
and self care controlling for covariates. Subject description is as follows: 83% were NonHispanic Blacks, 69% were women, 22% were 65 years or older, 26% had less than high
school education, 60% were unemployed, 61% were insured, 47% had a yearly income
<$10,000, and 24% had worsening health status. Fatalism correlated significantly with
medication adherence (r = 0.24, p<0.001), diet (r=-0.26, p<0.001), exercise (r=-0.20,
p<0.001), blood sugar test (r=-0.19, p<0.001); however there was not significant
association with diabetes knowledge or foot care. In the linear regression model, fatalism
was significantly associated with mediation adherence (β 0.24, 95% CI 0.010, 0.038); diet
(β -0.05, 95% CI -0.077, -0.027), exercise (β -0.04, 95% CI -0.067, -0.011), and blood
sugar test (β -0.05, 95% CI -0.08, -0.013); however, there was not significant association
with knowledge or foot care. In this group, fatalism largely predicted poorer health
behaviors. Thus, fatalism may be an important aspect of patient psychology to consider
when designing interventions, and patients with this personality characteristic or life
outlook may benefit from specific intervention.
Acknowledgements: NIH/NIDDK T35DK007431, Center for Health Disparities Research
Classification: Graduate Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Graduate Student
Poster #18
Effect of Locus of Control on Clinical Outcomes for Diabetes
Ashley Bryan, Hernandez-Tejada MA, Strom JL, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
and the Ralph H. Johnson VAMC
Diabetes, like many chronic diseases, requires important behavioral changes to be
successfully treated. Thus, the impact of cognitive and behavioral traits on glycemic
control is large. Locus of control (LOC), referring generally to how much control one
perceives over one’s health, appears related to positive health outcomes. Specifically, the
internal dimension of LOC (i.e., believing one can actually exert influence on one’s
health outcomes) is most related to outcomes in prior research. The goal of this study was
to establish the association between an individual’s locus of control and glycemic
management. Surveys were collected in three different clinics in the Charleston, SC and
included an 18 question Multi-dimensional Health Locus of Control questionnaire. LOC
scores were categorized as internal, other people, chance, and doctors. 45% of patients
were 50-64 years old, 66% were black, 56% male, 60% were married, 35% completed
High School and 34% had some college, 76% were unemployed, 35% earned less than
$10,000 annually. Analyses were conducted with participant responses for which data
was available for a particular variable (N range: 605 – 683 across variables). Multiple
linear regression indicated that the internal LOC accounted for about 11% of the change
in LDL (beta 0.71, 95% 0.15, 1.26), however no association was noted between LOC and
HbA1c. This lack of association may be due to the length of survey, comprehension of
the instructions, and HbA1c taken from patients’ charts from the last six months. It may
be necessary to include other variables associated with LOC and HbA1c independently,
in order to establish any possible indirect effects of LOC over HbA1c.
Acknowledgements: NIH/NIDDK T35 DK007431-26 (09012151), Center for Health
Disparities Research
Classification: Medical Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Medical Student
Poster #19
Effect Of Trust In Health Care Providers On Multiple Diabetes Outcomes
Bouges Shenikqua, Lynch CP, Strom JL, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
and the Ralph H. Johnson VAMC
Diabetes is the seventh leading cause of death claiming the lives of 25.8 million
Americans. This chronic disease increases the risk of macrovascular and microvascular
complications and heart disease. In order to reduce the number of patients suffering from
this high burden condition, a greater understanding of the obstacles hindering care to
patients with diabetes is needed. Studies have shown a positive relationship between trust
in primary care provider, patient adherence to medication and health related quality of
life in patients with diabetes. In addition, a strong correlation has been shown between
increased patient satisfaction in healthcare services and lowered glycated hemoglobin
levels, better continuity of care and greater trust in the medical system. A sample of 534
patients with type 2 diabetes was recruited from three primary care clinics (an academic
Internal Medicine clinic, a federally qualified health center, and a Veterans Affairs (VA)
primary care clinic). Self-identified type 2 diabetic patients completed a survey about
their personal characteristics, belief systems and preferences, health-related knowledge,
behaviors and attitudes. The predictor variable, trust, was measured by a 17-item
multidimensional trust in health care systems scale (MTHCSS) scored on a 5-point scale
with a minimum score of seventeen and a maximum score of eighty-five. Higher scores
indicate greater trust in the healthcare system. The primary outcome was glycemic
control measured by glycosylated hemoglobin A1C (HbA1c). Mean scores of the trust
index will be compared between older (≥65 years of age) and younger (<65 years of age)
individuals. When examining the mean differences in trust scores, individuals ≥65 years
of age had significantly higher trust scores compared to those younger than 65 year old
(p=0.0030). In addition, age had a significant impact on glycemic control (p=0.0019) and
diastolic blood pressure (p=0.0000). Based on our preliminary results, trust was not a
predictor of glycemic control. Age on the other hand did affect glycemic levels and
diastolic blood pressure. Further studies are needed to determine why trust was not a
predictor of glycemic control in this particular study when current literature shows
different.
Acknowledgements: NIH/NIDDK T35 DK007431-26 (09012151), Center for Health
Disparities Research
Classification: Medical Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Medical Student
Poster #20
Connexin 40 Remodeling in Purkinje Cardiomyocytes Post-Myocardial Infarction
Brown, Satara A. 1, Mary S. Rackley2,3, Brett S. Harris, PhD4, Terrence X. O’Brien, MD2,3
Medical University of South Carolina College of Medicine1, Gazes Cardiac Research Institute,
Division of Cardiology, Medical University of South Carolina2
Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC3, Department of
Regenerative Medicine and Cell Biology, Medical University of South Carolina4
Introduction: Purkinje cardiomyocytes are specialized cardiomyoctes that connect to working
cardiomyocytes to facilitate contraction of the heart muscle. Connexin 40 (Cx40) is the
predominant connexin found in gap junctions of Purkinje cardiomyocytes; however, Cx43 and
Cx45 are predominant in working cardiomyocytes. In working cardiomyocytes following
myocardial infarction (MI), Cx43 remodeling occurs, which is indicated by lateralization of
Cx43 and ensuing arrhythmias. We hypothesize that in murine Purkinje cardiomyocytes, MI
will cause disorganization of Cx40 expression at gap junctions.
Methods: A Cx40EGFP/+ transgenic mouse model post-surgical ligation of the left anterior
descending artery was utilized to conduct this study. EGFP, enhanced green fluorescence
protein, allowed identification of Purkinje cardiomyocytes. Antibodies to detect pan-cadherin
and Cx40 were used in immunofluorescence staining of tissues. Immunofluorescence and
confocal microscopy were employed to image gap junctions and intercalated disks in EGFP
areas. Differences in Cx40 expression, cadherin expression, and colocalization of Cx40 and
cadherin in control mice and mice that have experienced MI were quantified.
Results: Cx40 remodeling was indicated by decreased Cx40 expression, decreased cadherin
expression, and decreased colocalization of Cx40 and cadherin in the Purkinje cell areas. Cx40
expression decreased by 56%, cadherin expression decreased by 69%, and colocalization
decreased by 24%. This indicated that gap junctions were deficient and relocated from their
normal locations at intercalated disks following MI.
Conclusion: These results parallel changes that have been detected with Cx43 expression in
working cardiomyocytes. Alterations in Cx40 in Purkinje cells may be responsible for lifethreatening arrhythmias that can occur post-MI. These findings in the mouse model can be used
to develop a treatment for post-MI arrhythmias in humans in the future.
Medical Student
Poster #21
Inhibiting Effect of Albumin on Biofilm Formation in Titanium Implants In vivo
Desai, Shivam, College of Medicine Year 2
Basic Science
Mentor: Qian Kang ([email protected]), Department of Orthopaedic Surgery
Bacterial infection is an extremely serious complication after orthopaedic surgeries namely
because of the biofilm mode of growth of the infecting bacteria. Postoperative infections often
require removing the implant altogether so more preventative measures are needed to inhibit
bacterial adhesion. This study aimed to evaluate whether titanium surfaces coated with crosslinked albumin could reduce bacterial biofilm in vivo. Titanium discs were coated with bovine
serum albumin cross-linked with carbodiimide. The discs were placed subcutaneously into 8 rats
and challenged with S. aureus. 7 days after the infection, the discs were retrieved and evaluated
using confocal fluorescent microscopy and dilution plate enumeration. The results show that the
albumin coating disrupted and prevented strong bacterial biofilm formation. The discs covered
with albumin displayed 80% fewer colony forming units. These results imply that implants
coated with cross-liked albumin coating may offer viable prophylaxis to reduce infection in any
implantation surgery.
Medical Student
Poster #22
Multiple Cardiovascular Risk Factor Control (MCRFC) Across Sites of Care in
Type 2 Diabetes
DeWeerth, Jacob, Dismuke CE, Strom JL, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
and the Ralph H. Johnson VAMC
Background: Diabetes affects 8.3% of the US population. Glycemia (HbA1c), Lowdensity Lipoprotein (LDL) cholesterol and blood pressure (BP) control are the main
cardiovascular risk factor targets for clinicians in managing diabetes. There is little
evidence regarding the association of facility type with diabetes outcomes. We examined
the association of facility type with single and a multiple measure of control of
cardiovascular risk factors (MCRFC).
Methods: 534 individuals with type 2 diabetes were recruited from a private hospital
affiliated clinic (MUSC), a Federally Qualified Health Center (FQHC) and a VA facility.
We created MCRFC which took the value of 1 if all three factors under control. We
performed chi2 to examine socio-economic, separate risk factors and MCRFC by facility,
We estimated the independent association of facility type with each risk factor and
MCRFC, adjusting for covariates in logistic regression.
Results: At FHQC, individuals were predominantly Black (84.83%), female (65.56%),
50-64 (52.81%), unmarried (70.06%), high-school graduates (43.75%), unemployed
(72.30%), and uninsured (45.76%) with less than $10,000 income (54.34%). At VA,
individuals were predominantly Black (51.88%), male (97.51%), 50-64 (46.47%),
married (52.08%), some college (47.48%), unemployed (79.17%), government insured
(75.00%), had $35,000 plus income. At MUSC, individuals were predominantly Black
(65.13%), female (66.41%), 65 plus (42.15%), unmarried (59,5%), equally less than high
school (30.23%) and high school (30.23%) educated, unemployed (75.38%), government
insured (74.71%), had $35,000 plus income. In unadjusted analysis, at FQHC, 38.89%
had BP, 51.63% LDL, 10.43% MCRFC control. At VA, 57.74% had BP, 74.15% LDL,
19.17% MCRFC control. At MUSC, 37.35% had BP, 64.37%, 7.34% MCRFC control.
After adjustment, MUSC associated with 57% lower MCRFC (OR 0.428, 95% CI
0.187:0.978), male with 277% higher MCRFC, Black with 44% lower MCRFC.
Conclusion: After adjusting for socio-economic factors, VA facilities are associated with
better MCRFC in individuals with diabetes.
Acknowledgements: NIH/NIDDK T35 DK007431-26 (09012151), Center for Health
Disparities Research
Classification: Medical Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Medical Student
Poster #23
Effect of Spirituality on Multiple Diabetes Outcomes
Ezenekwe, Chisom, Hernandez-Tejada, MA, Strom JL, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
and the Ralph H. Johnson VAMC
Health care and disease management researchers have again turned attention to the
connection between religiosity/spirituality (R/S) and health. One way R/S may moderate
health outcomes is through increasing the likelihood of positive health behaviors in
chronic diseases that are affected by behavior such as Type 2 diabetes (T2DM).
However, the topic of increased pro-health behaviors directly or indirectly resulting from
R/S and revealed by indicators for glycemic control remains unexamined. The present
study identified patient glycemic control by optimal biomarker values for LDL
cholesterol, hemoglobin A1C (HbA1C), body-mass index (BMI), pulse, and systolic and
diastolic blood pressure. A sample of 683 participants with T2DM was recruited from the
MUSC University Internal Medicine Clinic, VA Medical Center, and Fetter Health
Center. A 6-item Daily Spiritual Experiences Scale was used. Indicators of glycemic
control were extracted from subjects’ medical records. 45% of patients were 50-64 years
old, the majority of the participants (56%) were male, 66% were black, 60% were
married, 35% completed High School and 34% had some college, 76% were
unemployed, 35% earned less than $10,000 annually and 68% received public healthcare.
Linear regression predicted the possible relationship between spirituality and glycemic
control. R/S correlates with Diastolic Blood Pressure (beta = 0.25, 95% 0.11, 0.40), in the
adjusted model, indicating higher spirituality was associated with lower Diastolic blood
pressure. There were no relationships between R/S and other indicators of glycemic
control. Future research should focus on which specific practices across faiths are
responsible for decreasing diastolic blood pressure, which then might be appropriate
targets of a treatment regimen for patients with T2DM.
Acknowledgements: NIH/NIDDK T35 DK007431-26 (09012151), Center for Health
Disparities Research
Classification: Medical Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Medical Student
Poster #24
Effect Of Delayed Discounting On Multiple Diabetes Outcomes In Adults With
Diabetes
Fox, Adam, Dismuke CE, Strom JL, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
and the Ralph H. Johnson VAMC
Background: Diabetes affects 8.3% of the US population. Glycemia (HbA1c), Lowdensity Lipoprotein (LDL) cholesterol and blood pressure (BP) control are the main
cardiovascular risk factor targets for clinicians in managing diabetes. . Delayed
discounting (DD) is a measure of an individual’s impulsivity based on willingness to
forgo benefits today to receive a higher amount in the future. It is being increasingly
considered as a barrier to patient adherence. We examined the association of DD rates
with BP, HbA1c and LDL. Methods 534 individuals with type 2 diabetes were recruited
from MUSC a private hospital affiliated clinic, VA and the Franklin C. Fetter Federally
Qualified Health Center (FQHC). We used the 1996 Kirby model of delayed discount
rate to estimate an individual’s level of impulsivity on a scale of 1-9 with 1 representing
the lowest impulsivity and 9 representing the highest impulsivity levels. We estimated
Pearson correlations of DD and impulsivity with BP, HbA1c and LDL. We estimated
independent association of DD with each diabetes outcome adjusting for covariates.
Results: Our sample was predominantly Black (65.63%), 50-64 (44.85%), male
(56.37%), unmarried (59.50%), unemployed (76.18%), government insured (66.52%),
less than $10,000 income (35.37%) and better or same health status as previous 12
months (71.99%). Unadjusted correlation showed no association between DD,
impulsivity and diabetes outcomes. Adjusted analyses showed that each additional point
in DD rate was associated with 17.89 lower systolic (95% CI -33.73:-2.05) BP. In same
model, Black was associated with 9.67 higher systolic BP relative to White, private
insurance 7.07 lower, and government insurance 5.72 lower, relative to uninsured. VA
was associated with 7.88 lower, and MUSC 5.76 lower systolic BP relative to FQHC.
Conclusion: In adjusted models, DD rate is associated with lower systolic BP. DD rates
may have implications for clinical management of BP in individuals with diabetes.
Acknowledgements: NIH/NIDDK T35 DK007431-26 (09012151), Center for Health
Disparities Research
Classification: Medical Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Medical Student
Poster #25
P21-Activated Kinases (PAKs) as Potential Targets of HIV Infection
Hayes, Lauren1; Serguei Spitsin, PhD2; John Meshki, PhD2; Florin Tuluc, MD, PhD2; and Steven D
Douglas, MD2,3
1
College of Medicine, Medical University of South Carolina, Charleston, SC, United States; 2Division of
Allergy and Immunology, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA,
United States; and 3Department of Pediatrics, University of Pennsylvania Medical School, Philadelphia,
PA, United States.
Background: Human Immunodeficiency Virus (HIV) is a virus that is transmitted through sexual contact
and exposure to blood products, and leads to the development of AIDS. HIV/AIDS has caused
devastating loss of life and is a widespread public health concern; there are intensive efforts toward
creating treatments in the wake of new resistant HIV strains. The goal of this project was to examine the
prospective HIV inhibitor, IPA3. HIV inhibitors act in several different mechanisms, and different classes
of drugs are often combined as a part of highly active antiretroviral therapy (HAART). IPA3 functions by
inhibiting a group of enzymes found in human cells, p21-activated kinases (PAKs). PAKs are involved
with various cell functions, including proliferation and motility, and they are also involved with HIV
infection of the cell. PAKs associate with Nef, an HIV protein, and this interaction leads to increased viral
replication. By inhibiting PAKs, IPA should theoretically reduce HIV infection.
Objective: To examine the efficiency of IPA3 as an HIV inhibitor.
Design/Methods: Monocyte-derived macrophages (MDMs) and peripheral blood mononuclear cells
(PBMCs) were first exposed to various concentrations of IPA3. Cells were then infected with HIV. For
four of the patient samples, PBMCs were exposed to the IIIB strain of HIV, while one patient sample had
PBMCs that were exposed to the BaL strain. All four of the patient MDM samples were exposed to the
BaL strain of the virus. After a set incubation time, cells were collected and lysed. RNA was isolated and
converted to cDNA, and real-time PCR was performed in order to quantify the presence of mRNA copies
of the HIV gag gene.
Results:
HIV infectivity (GAPDH normalized GAG copies) as percentage of control
PBMC
MDM
IIIB Strain
BaL Strain
BaL Strain
Control
100.00
100.00
100.00
IPA3 1µm
91.56
57.28
53.99±18.36*
IPA3 2µm
143.67
37.15
--IPA3 3µm
116.01
--37.33±15.83*
IPA3 5µm
89.59
20.58
11.07±2.89*
IPA3 10µm
72.64
9.10
17.39±18.98
Results are presented as average ±SD, (*) P<0.05 versus non-treated control
Conclusions: IPA3 showed statistically significant inhibition (P<0.05) of HIV when MDMs were
infected with the BaL strain. Though IPA3 did not show statistically significant inhibition of either strain
of HIV in PBMCs, there was some moderate inhibition of the BaL strain in PBMCs. In conclusion, PAKs
are potential drug targets for the inhibition of HIV replication, and PAK inhibitors such as IPA3 deserve
further study.
Type of research project: basic
E‐mail address of the corresponding author: [email protected] Medical Student
Poster #26
Bleeding in Autosomal Dominant Polycystic Kidney Disease
Iyer, Arun, MUSC, Department of Medicine, Division of Nephrology, Medical Student
[email protected]
Mentors: P. Darwin Bell, Ph.D., Rachel Sturdivant, M.D., Ruth Campbell, M.D., Division of
Nephrology
Abstract:
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disease characterized by
multiple bilateral cystic kidneys. The precise etiology is unknown but is related to the genes
pkd1 and pkd2. Recent observations from murine model studies have noted that PKD mice
display profuse bleeding in comparison to non-PKD mice. In our study, we examined the
coagulation characteristics of PKD and non-PKD mice and human subjects. Hemostatic profiles,
as measured by standard bleeding times (prothrombin time, PT, and activated partial
thromboplastin time, aPTT) and rotational thromboelastometry (ROTEM). Additionally, the
patient model was controlled by basic measures of kidney function, estimated glomerular
filtration rate (eGFR), to avoid patients in kidney failure. Comparison of these groups yielded
results that were not statistically different due to a small sample size (n=6, mice and n=9,
human); however, possible correlation is evident warranting further investigation. Additional
studies are ongoing. The problem will continue to be investigated to determine if conclusion is
accurate. Assay studies will likely be completed to determine if there are any specific factor and
metabolic deficiencies.
Medical Student
Poster #27
Epidermal growth factor-induced activation of Na+/H+ exchanger in orpk cilia (+)
and orpk cilia (-) renal cells from a mouse model of polycystic kidney disease
involves different signaling mechanisms.
Joyner, Alisha1, Tanjina Akter2, Mary G. Blanton3, Maria N. Garnovskaya3 and Sonya
D. Coaxum3. College of Medicine1, Rheumatology and Immunology2, Nephrology3,
Medical University of South Carolina, Charleston, SC.
Epidermal growth factor (EGF) receptor has been implicated in the pathogenesis of
polycystic kidney disease (PKD). We explored the effects of EGF in orpk cilia (-)
collecting duct cell line, derived from a mouse model of PKD, and in control, orpk cilia
(+) cell line, to determine signaling pathways activated by EGF. We measured changes
in extracellular pH as a reflection of the Na+/H+ exchange (NHE) with a Cytosensor
microphysiometer. Exposure to 10 ng/ml of EGF caused ≥20% increase in NHE activity
in orpk cilia (+) cells and ≥30% increase in NHE activity in orpk cilia (-) cells.
Stimulation of proton efflux by EGF was blocked in the presence of 5-(N-methyl-Nisobutyl) amilioride in orpk cilia (+) and cilia (-) cells; however, the effect was much
greater in orpk cilia (-) cells suggesting that NHE-1 and/or NHE-2 are involved in EGFinduced signaling in these cells. Immunoprecipitation experiments showed that EGF
induced complex formation between NHE-1 and CaM in both cell lines. However, EGF
induced complex formation between Jak2 and CaM only in orpk cilia (-) cells but not in
orpk cilia (+) cells. These results suggest that EGF induces NHE-1 activity in orpk cilia
(-) cells by the following pathway: EGFÆ EGFRÆ Jak2 activation Æ CaM binding to
NHE-1Æ conformational change of NHE-1Æ activation of NHE-1. A separate pathway
exists for orpk cilia (+) cells: EGFÆ EGFRÆ CaM binding to NHE-1 (independent of
Jak2) Æ conformational change of NHE-1Æ NHE-1 activation.
Medical Student
Poster #28
The Role of Tissue Transglutaminase 2 in the Modulation of Polymorphonuclear
Leukocyte Function
Lebel, David P., Meghan K. Anderson, Titus A. Reaves
COM 2nd Year student, Department of Regenerative Medicine and Cell Biology
Polymorphnuclear leukocyte (PMN) migration toward the lumenal surface is a major
inflammatory event involving mucosal surfaces. In particular, inflammatory bowel disease which
collectively includes Crohn’s Disease and Ulcerative Colitis, presents as a series of inflammatory
conditions that involves dysregulated PMN transmigration across the intestinal epithelium.
While the etiology is unknown, patients’ symptoms are more pronounced during such migration.
Tissue Transglutaminase (TGM) 2 is an enzyme that catalyzes calcium-dependent crosslinks of
amino groups and has been implicated in a variety of cellular functions that include; GTPase
activity (affects PMN adhesion), cell growth and wound healing. Interestingly, antibodies to
TGM 2 are present in patients with Celiac Disease (inflammation localized to the small intestine)
and a majority of Crohn’s Disease patients also have Celiac Disease. Despite these observations,
the role of TGM 2 in PMN activity has not been widely explored. Using immunofluorescence,
we determined that TGM 2 has both an extracellular and intracellular deposition in PMN.
Treatment of PMN with an inhibitor of TGM 2 appears to promote translocation of the
leukocyte-specific integrin CD11b to the surface of PMN. Cellular adhesion studies show that
antibodies to TGM 2 can inhibit PMN attachment to fibrinogen (ligand for CD11b) by nearly
50%. This result suggests that TGM 2 may have a role in CD11b-mediated activities. Transwell
migration experiments also show that TGM 2 can inhibit fMLP-directed migration more than
50%. Bacterial formylated peptides (fMLP) promote PMN migration toward such peptides. The
fMLP receptor is a G-protein coupled (7TM spanning) receptor that regulates the PMN response
through an up-regulation of adhesion and migration (PMN) receptors. Using Flow Cytometry
experiments, we determined that TGM 2 affects adhesion and migration by modulating the
PMN-fMLP receptor. These data highlight TGM 2 as a potential target molecule in the treatment
of mucosal inflammation that involves aberrant PMN transmigration.
Email: [email protected]
Medical Student
Poster #29
Glycemic Control In VA Clinical Sites Compared To Non VA Sites Among Adults
With Type 2 Diabetes
Lumpkin, Jeanne, Dismuke CE, Strom JL, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
and the Ralph H. Johnson VAMC
Background: Diabetes affects 8.3% of the US population. Glycemia (HbA1c) is the main
outcome target for clinicians in managing diabetes. There is little evidence regarding the
association of facility type with HbA1c levels. We examined the association of facility
type with HbA1c level in a population of adults with type 2 diabetes.
Methods: 534 individuals with type 2 diabetes were recruited from a private hospital
affiliated clinic (MUSC), a Federally Qualified Health Center (FQHC) and a VA facility.
We performed chi2 tests to examine socio-economic characteristics by facility. We
examined the unadjusted association of HbA1c level with facility type, using one-way
ANOVA and Bonferroni tests .We estimated the independent association of facility type
with HbA1c levels using linear regression and adjusting for covariates.
Results: At FHQC, individuals were predominantly Black (84.83%), female (65.56%),
50-64 (52.81%), unmarried (70.06%), high-school graduates (43.75%), unemployed
(72.30%), and uninsured (45.76%) with less than $10,000 income (54.34%). At VA,
individuals were predominantly Black (51.88%), male (97.51%), 50-64 (46.47%),
married (52.08%), some college (47.48%), unemployed (79.17%), government insured
(75.00%), had $35,000 plus income. At MUSC, individuals were predominantly Black
(65.13%), female (66.41%), 65 plus (42.15%), unmarried (59,5%), equally less than high
school (30.23%) and high school (30.23%) educated, unemployed (75.38%), government
insured (74.71%), had $35,000 plus income. In unadjusted analysis, VA was associated
with 0.799 lower HbA1c and MUSC with 0.767 lower HbA1c relative to the FQHC.
After adjusting for all covariates, VA was associated with 0.519 lower HbA1c (95% CI 1.023:-0.016), MUSC was associated with 0.505 lower HbA1c (95% CI -0.935:-0.075)
relative to the FQHC. Age 65 and older was associated with 0.657 lower HbA1c (95% CI
-1.139:-0.174), government insured with 0.491 lower HbA1c (95% CI -0.955:-0.028).
Conclusion: After adjusting for socio-economic factors, VA and private facility was
associated with lower HbA1c levels relative to FQHC.
Acknowledgements: NIH/NIDDK T35 DK007431-26 (09012151), Center for Health
Disparities Research
Classification: Medical Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Medical Student
Poster #30
INCREASED RENAL INVOLVEMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS
(SLE) PATIENTS WITH CHILDHOOD DISEASE ONSET
Meyer, Anna Katrina 1, Elizabeth McKinney2, James C. Oates1, Gary S. Gilkeson1, Diane L. Kamen1
INSTITUTIONS (ALL): 1. Department of Medicine, Division of Rheumatology and Immunology, Medical
University of South Carolina, Charleston, SC, United States. 2. School of Medicine, University of Virginia,
Charlottesville, VA, United States.
ABSTRACT BODY:
Purpose of Study: The purpose of this study is to investigate the influence of age of SLE disease onset in
the development of renal disease.
Methods Used: We investigated the incidence of renal disease in SLE patients enrolled in our Lupus Clinic
Database and compared patients with childhood SLE disease onset ( 18 years of age). The analysis also
included dialysis, renal transplantation, and death.
Proportions between groups were compared using Pearson’s Chi Square or Fisher’s Exact as appropriate. A
p-value of <0.05 was considered to be statistically significant.
Summary of Results: Table 1 shows demographic, renal, and outcome data of the study patients, 18.8% of
whom had childhood onset SLE (cSLE). The mean age of SLE onset was 29.8 +/- 13.1 years. We found a
statistically significant increase in incidence of renal disease in cSLE compared to adulthood onset SLE
(aSLE) patients (p<0.01). When comparing mortality rates, we found a statistically significant increase in
the number of deaths among cSLE compared to aSLE patients (p<0.04) with age of death at 25.4 +/- 5.0
years in cSLE and 47.4 +/- 7.7 years in aSLE (p<0.01). Although the values did not reach statistical
significance, a higher proportion of cSLE patients compared to aSLE required dialysis and had renal
transplant.
Conclusions: There is strong evidence that childhood onset SLE tends to be more severe than SLE
occurring during adulthood. Data from our center concur with several studies and suggests that SLE
patients whose initial disease onset occurred before adulthood are more likely to develop renal
abnormalities and have more severe disease outcomes, including death.
Total Patients
N=319
Age of SLE onset +/- SD in years
cSLE
n=60
aSLE
n=256
29.8 +/- 13.1 13.6 +/- 3.8 33.6 +/- 11.5
P-value
(cSLE vs. aSLE)
<0.01
SLE disease duration +/- SD in years
6.7 +/- 7.4
9.6 +/- 9.3
6.0 +/- 6.7
0.01
Renal disease (%)
177 (55.5)
45 (75.0)
132 (51.0)
<0.01
Females (%)
292 (91.5)
55 (91.7)
237 (91.5)
NS
African American (%)
257 (80.6)
49 (81.7)
208 (80.3)
NS
Caucasians (%)
52 (16.3)
8 (13.3)
44 (17.0)
NS
Dialysis (%)
29 (9.1)
9 (15.0)
20 (7.7)
NS
Renal transplant (%)
14 (4.4)
4 (6.7)
10 (3.9)
NS
Deceased (%)
12 (3.8)
5 (8.3)
7 (2.7)
0.04
Medical Student
Poster #31
High Prevalence of Vitamin D Deficiency in Adult with Inflammatory Bowel Disease at the
Medical University of South Carolina
Patel, Ankit1, Diane Kamen2, Lawrence Comerford3
College of Medicine, Medical University of South Carolina (MUSC).
Division of Rheumatology, MUSC.
Division of Gastroenterology, MUSC.
Introduction: Vitamin D deficiency is a common occurrence in patients suffering from
inflammatory bowel disease (IBD). Although vitamin D has long been known to be essential for
bone health and mineralization, recent studies have proposed that vitamin D plays an antiinflammatory role and may play a part in the pathogenesis of Crohn’s disease and ulcerative
colitis. The aim of our study was to look at the prevalence of vitamin D deficiency in patients
with IBD and determine if there are any predictors that strongly correlate with vitamin
deficiency.
Methods: Using the Enterprise Data Warehouse at MUSC, de-identified data on 490 patients 18
years or older, since 2006, who had a diagnosis code of either “regional enteritis” (Crohn’s) or
“ulcerative colitis unspecified AND a total 25-hydroxyvitamin D (25D) lab value were studied.
The season (summer, winter, spring, fall) that the initial 25D lab was drawn was used, in addition
to age, sex, and race. Because all information was de-identified, IRB approval was not needed.
Stata v11 was used to perform t-tests comparing mean 25D levels and logistic regression models
comparing deficient to sufficient patients, with p-values of <0.05 considered significant.
Results: Of the 490 patients, 19.8% were African American and 78.0% Caucasian. 67.0% had a
diagnosis code of Crohn’s, 19.8% with ulcerative colitis, plus 13.2% who had both codes listed.
25D was significantly lower in African Americans ( n=97, mean= 20.4 +/- 12.9 ng/mL) than
Caucasians (n=382, mean=32.0 +/- 12.8 ng/mL, p=0.00). Those with a diagnostic code of
Crohn’s also had significantly lower 25D levels (n=330, mean =28.3 +/- 13.8 ng/mL) than
ulcerative colitis (n=97, mean=31.9 +/- 13.7 ng/mL, p=0.02). Those with 25D levels in the
summer had a mean value of 30.5 +/- 13.7 ng/mL & winter 27.4 +/- 12.1. Using a cutoff value
of 30ng/mL for 25D, logistical regression analysis showed that race, diagnostic code of Crohn’s,
and season are all significant predictors for 25D deficiency. Furthermore, with a lower cutoff of
20 ng/mL, analysis shows that race and diagnostic code are significant predictors.
Conclusion: Vitamin D deficiency is highly prevalent among IBD patients. Race, season and
type of IBD are significant predictors of vitamin D insufficiency (25D < 30ng/ml), with African
Americans with Crohn's being at the highest risk. This exploratory analysis utilizing the MUSC
Clinical Data Warehouse provides support for pursuing a prospective study investigating the role
of vitamin D deficiency in IBD.
Medical Student
Poster #32
Ethnic Differences in Control of Multiple Diabetes Risk Outcomes
Reid, Jameka, Lynch CP, Strom JL, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
and the Ralph H. Johnson VAMC
The leading cause of death in diabetes is cardiovascular disease (CVD), which is even
higher among ethnic minorities. Hypertension and hyperlipidemia are each independent
risk factors for CVD. With poor glycemic control, these risk factors have greater adverse
consequences in minority groups. Thus, ethnic differences in control of multiple diabetes
risk factor outcomes were examined. A cross-sectional study was performed among 524
people recruited from three clinics: MUSC primary care, Veterans Affairs primary care,
and Fetter, a federally qualified health center. Data on the primary outcome, multiple risk
factor control, were obtained from medical records; poor control defined as glycosylated
hemoglobin, HbA1c ≥7%, blood pressure (BP) ≥130/80mmHg, and low-density
lipoprotein (LDL) cholesterol ≥100mg/dL. The independent effect of ethnicity on risk
factor control was analyzed with a multiple regression using STATA v11. Results
showed significantly fewer elderly (≥65 years) black participants (32.2%) than whites
(53.5%). Other ethnic differences showed more blacks than whites were female (52.1%
versus 27.5%), unmarried (66.1% versus 48.2%), not high school graduates (29.2%
versus 13.5%), had no insurance (21.5% versus 11.0%), and had annual income <$10,000
(44.5% versus 16.8%). Blacks had significantly worse BP (61.2% versus 42.5%) and
composite risk factor (90.0% versus 82.3%) control than whites (p<0.001 for both). After
adjusting for demographics, logistic regression showed blacks had 55% lower odds (odds
ratio, OR 0.45, 95% CI 0.30-0.67) of good BP control and 43% lower odds (OR 0.57,
95%CI 0.33-0.98) of good composite control than whites. The odds of poorer BP control
were also shown among VA (OR 2.02) and Fetter participants (OR 1.66) compared to
MUSC. Black participants had poorer control of multiple diabetes risk factor outcomes
than whites. Findings suggest that ethnic minorities likely need more supportive efforts
and culturally sensitive approaches to management of diabetes risk to reduce disparities
in care.
Acknowledgements: NIH/NIDDK T35 DK007431-26 (09012151), Center for Health
Disparities Research
Classification: Medical Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Medical Student
Poster #33
Absence of Estrogen Receptor Alpha Reduces the Number and Function of
Plasmacytoid Dendritic Cells in Lupus Prone Mice
Scott, Jennifer1, Melissa Cunningham2,3, Osama Naga2, Gary Gilkeson2 ,3
1
College of Graduate Studies, Department of Microbiology & Immunology. Med. Univ.
of South Carolina, Charleston, SC 2Division of Rheumatology & immunology,
Department of Medicine. Med. Univ. of South Carolina, Charleston, SC 3Ralph H.
Johnson VA Medical Center, Charleston, SC
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that
affects women at a 9:1 ratio compared to men. As a result of this female predominance,
the role of estrogen and its receptors are under investigation. Previous work in our
laboratory shows that estrogen receptor alpha (ERa) deficient lupus-prone mice have
significantly increased survival and less renal disease compared to wild type lupus prone
mice. The improvement occurs despite similar levels of renal immune complex
deposition and autoantibody production in ERa deficient and wild type lupus prone mice.
Since autoantibody production and immune complex deposition remain intact in ERa
deficient lupus prone mice, we hypothesize that ERa deficiency improves SLE by
reducing the innate immune system’s ability to respond to this immune activation. To
study the innate immune response this research focuses the role of the ERa in the
plasmacytoid dendritic cell (pDC). pDCs are the body’s major producers of type I
interferon, a key cytokine in the innate defense against viruses. In addition to type I
interferon’s role in host defense, its serum levels are elevated in SLE and it can cause the
dissolution of tolerance when given to healthy individuals. Our findings show a decrease
in pDC levels in ERa deficient lupus prone mice compared to wild type lupus prone mice.
pDCs account for 60% of total bone marrow derived dendritic cells in wild type lupus
prone mice, but only 35% in the ERa deficient lupus prone mice. Additionally, the pDCs
from ERα deficient lupus prone mice produce decreased levels of type I IFN compared to
wild type lupus prone mice. Given these findings, the next step will be determining the
mechanism by which ERα deficiency reduces plasmacytoid dendritic cell number and
decreases type I interferon production.
Type of Research: Basic Science
Affiliation: Rheumatology
E-mail: [email protected]
Medical Student
Project #34
Unanticipated Effects of Adenosine Agonists on Microtubule Density
Simmons, Flora, College of Medicine; Grace Wallenborn, Division of Cardiolgy, Department of
Medicine; George Cooper IV, Division of Cardiology, Department of Medicine
Increased microtubule density is one factor in the impairment of contractility and growth in
pathological hypertrophy. This increase in microtubule density is caused by MAP4, a
microtubule associated protein, decoration along microtubules. This, in turn, hyperstabilizes
microtubules, impairing the heart’s ability to compensate with contraction or growth. There is a
pathway developed that leads to MAP4 decoration of microtubules, beginning with
catecholamine induced activation of Pak1. Adenosine is an endogenous nucleoside that has antiadrenergic effects in the heart. Adenosine has recently been showed to decrease the
catecholamine induced increase in microtubule density. This research looked at the three
receptor agonists of adenosine, A1, A2A, and A3 to find which one is responsible for the
cardioprotective effects, ie, decreasing ∆-tubulin and pPak1. Isolated feline cardiomyocytes
were treated with isoproterenol, A1, A2A, and A3 for courses of 1, 4, 24, and 48 hours. It was
found that A1 agonist in the presence of β-adrenergic stimulation provided cardioprotection by
decreasing ∆-tubulin and pPak1 after 4 hours. A1 agonist treatment on control cells actually
behaved in a cardiotoxic manner, increasing ∆-tubulin and pPak1. A2A and A3 did not decrease
∆-tubulin or pPak1 by very much, leading us to believe that the three receptors act synergistically
to provide cardioprotection.
Affiliation: Medical Student
Type of Project: Basic Science research
E-Mail: [email protected]
Medical Student
Poster #35
Imbalance in Histone Acetyl Transferase and Histone Deacetylase Activity During
Hypertrophy
Smith, Christopher, Mona S. Li, Olga Chernysh, Elizabeth S. Inks*, James C. Chou*,
Santhosh K. Mani and Donald R. Menick.
Gazes Cardiac Research Institute, Department of Medicine, Division of Cardiology,
*Department of Pharmaceutical and Biomedical Sciences, MUSC, South Carolina.
Abstract:
The high rate of morbidity in patients with diastolic heart failure, along with the 62
million people in the US annually diagnosed with some form of cardiovascular disease
emphasizes the need for alternative means of therapy to treat heart failure. Previous work
has demonstrated that inhibition of histone deacetylase (HDAC) activity has protective
properties and significantly decreases symptoms associated with pressure-overload
induced hypertrophy. This suggests that the natural equilibrium at which histone acetyl
transferase (HAT) and HDAC enzymes are maintained in healthy heart tissue could be
shifted in diseased myocardium. However, no one has measured HAT or HDAC
activities in the normal or hypertrophic heart. We hypothesize that the normal balance of
enzymatic HAT/HDAC activity is disrupted under pathological hypertrophic conditions.
To investigate, feline myocardium were subjected to Pulmonary Artery Banding (PAB)
to cause pressure overload induced hypertrophy for periods of 2 weeks, 4 weeks, and 8
weeks, and then examined for HAT activity to support previous findings of HDAC
activity. Results indicated a decrease in HAT activity after 2 weeks and even more
pronounced decrease in the 4th week of pressure overload. HAT activity was still
significantly decreased after 8 weeks of pressure overload, in comparison to the nonbanded feline myocardium. HAT and HDAC activity in isolated adult cardiomyocytes
and cardiac fibroblast were much lower than what is seen in other cell types. These
results indicate that there is a disruption in the normal balance of HAT/HDAC activity in
pathological hypertrophy. Inhibition of HAT/HDAC enzyme activity may be a potential
therapeutic target for the treatment of heart failure.
Type of Project: Basic Science
E-mail: [email protected]
Medical Student
Poster #36
Predictors of Adequate Health Literacy In a Diverse Primary Care Sample with
Type 2 Diabetes
Teuber, Julie, Bains SS, Strom JL, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
and the Ralph H. Johnson VAMC
Background: Diabetes disproportionately affects minorities and populations with lower
levels of education and socioeconomic status. Among diabetics, inadequate health
literacy is common and has been associated with poor disease knowledge and selfmanagement. The objective of our study was to determine the sociodemographic
predictors of health literacy in a minority diabetic population.
Methods: 674 type 2 diabetes patients were recruited from three medicine clinics. A
validated survey and screener was used to assess sociodemographic characteristics and
health literacy. Health literacy status was dichotomized into inadequate and adequate
health literacy. Health literacy status was compared by demographics using chi-squared
statistics. Logistic regression models were used determine independent predictors of
health literacy.
Results: 66% of the sample was African American, 39% were 65+ years, 24% had less
than a high school education, and 75% percent of our sample had adequate health
literacy. There were significant differences in health literacy by demographic
characteristics. Among those with adequate literacy, it was higher among white race
(Whites 80%, Blacks 72%; p<0.02), married status (78% married, 71% unmarried;
p<0.05), higher education (92% college +, 60% < high school; p<0.001), those employed
(89% employed, 70% unemployed; p<0.001), those insured (83% private insurance, 77%
noninsured; p=0.02), and higher income (92% > $35,000, 64%<$10,000; p<0.001). In the
logistic regression model, independent correlates of adequate health literacy were higher
education (p=0.02), being employed (p=0.006), and higher income (p<0.001).
Hispanic/other race was associated with inadequate health literacy (p0.03).
Conclusions: In our sample, health literacy status varied by sociodemographic
characteristics. Independent predictors of adequate health literacy included higher
educational status, being employed, and higher income. Further research should be
implemented to identify the mechanism by which these sociodemographic characteristics
relate to health literacy in this population. Also, further studies should identify strategies
to increase health literacy in minority groups at risk.
Acknowledgements: NIH/NIDDK T35 DK007431-26 (09012151), Center for Health
Disparities Research
Classification: Medical Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Medical Student
Poster #37
Does Electrical Conduction Delay Progress with Time, Therefore, Increasing the Need for
Resynchronization?
Tuten, Neill, Medical Student, Robert Leman, MD, John Sturdivant, MD, Frank Cuoco, MD and
J. Marcus Wharton, MD. Medical University of South Carolina, Charleston, SC
Abstract:
Introduction: The magnitude and response rate with cardiac resynchronization therapy (CRT) is
dependent on QRS duration. Accordingly, temporal changes in QRS duration may affect CRT
eligibility or response. To assess this possibility, we evaluated serial ECGs at a large Universitybased hospital.
Methods: We conducted a review of ECGs showing sinus rhythm and QRS prolongation over a
6-year period. They were grouped into LBBB, RBBB, or IVCD by standard criteria. Patients
with at least 2 ECG separated by > 12 months were analyzed. QRS measurements were
determined by a computerized ECG system.
Results: The database consisted of 6537 ECGs with LBBB, RBBB, or IVCD over a period of six
years. There were 75 patients with LBBB, 117 patients with RBBB, and 51 patients with IVCD
having serial measurements. Fourteen of the 75 patients with LBBB had a QRS width less than
130ms, with an average QRS change of -0.57ms (SD 12.2) over an average period of 38 months
and an average baseline QRS of 124.3ms (SD 6.6). Forty-one of 117 patients with RBBB had a
QRS width less than 130ms, with an average QRS change of 6.15ms (SD12.7) over an average
period of 36 months and a baseline QRS of 120.3ms (SD 10.4). All patients with IVCD had a
baseline QRS width less than 130ms (116.1ms SD 6.5, which changed 1.61ms SD 11.8 over an
average time of 25 months).
Conclusions: QRS duration changes little over a 3 year time period; therefore, it is unlikely that
more progressive QRS prolongation will impact CRT eligibility or response.
Author Disclosure Information: N. Tuten: None. R. Leman: None. J. Sturdivant: None. F.
Cuoco: None. J. Wharton: None.
Medical Student
Poster #38
Gender Differences in Composite Control of Cardiovascular Risk Factors
Winchester, Rhonda, Lynch CP, Strom JL, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
and the Ralph H. Johnson VAMC
Women with diabetes are at greater risk than men of developing cardiovascular disease
(CVD) and worse outcomes. CVD risk factors are also less well-controlled in women
than men. However, gender differences in composite control of these risk factors in
diabetes are less clear; therefore, this study sought to understand this relationship. Data
were collected from participants with type 2 diabetes at 3 primary care settings (MUSC
University Internal Medicine, Franklin C. Fetter Family Health Center, Inc., a Federally
Qualified Health Center, and the Ralph H. Johnson VAMC primary care clinic).
Participants completed surveys to gather demographic data (personal characteristics,
socioeconomic status, and self-rated health). Data for the outcome, composite risk factor
control (glycosylated hemoglobin, HbA1c; blood pressure, BP; and low-density
lipoprotein-cholesterol, LDL-C), were obtained from medical records. STATA v11 was
used to analyze demographic differences by gender with chi-square tests and the
independent effect of gender on composite control (odds ratio, OR, with 95% confidence
interval, CI) with multiple regression. Of 534 participants, 56.3% were male (41.4%
white, 55.8% black, 2.9% other) and 43.7% female (20.3% white, 78.4% black, 1.3%
other). Significant gender differences showed that, compared to males, more females
were <50 years old (12.3% versus 22.2%), not married (47.9% versus 74.4%), had less
than high school education (18.2% versus 31.4%), and lower income (23.5% versus
50.3%). A higher proportion of males than females had good BP (≥130/80mmHg), LDLC (<100mg/dL), and composite control (all p<0.001). In multivariate analyses adjusted
for demographic variables, males had an OR of 1.70 (95%CI 1.17, 2.48) for good LDL
control, OR 1.66 (95%CI 1.16-2.38) for good BP control, and OR 3.14 (95%CI 1.705.79) for good composite control than females. Findings demonstrate poorer composite
risk factor control among women than men. This suggests that management of CVD risk
in women with diabetes is inadequate. Therefore, more aggressive efforts should target
women in attaining early risk factor control.
Acknowledgements: NIH/NIDDK T35 DK007431-26 (09012151), Center for Health
Disparities Research
Classification: Medical Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Medical Student
Poster #39
Prevalence and Predictors of Sleep Disorders in an Adult Sample with Type 2
Diabetes
Yazdy, G, Bains SS, Strom JL, Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics
and the Ralph H. Johnson VAMC
Objective: To determine the overall prevalence and sociodemographic predictors of sleep
disorders in a diabetic population. Methods: Validated surveys were distributed at three
clinics in Charleston, South Carolina. Data was obtained regarding sociodemographic
factors and sleep disorders. 683 patients were recruited over a 10-week period. Sleep
disorder questions assessed quality of sleep/rest. Logistic regression models were used to
assess sociodemographic predictors of sleep disorders.
Results: In our sample, 66% were white race, 85% were 50 years old or older, 56% were
male, 60% were unmarried, 58% had < high school education, 76% were unemployed,
18% were uninsured, 35% had <$10,000 income, and 72% reported their health status as
either better or the same as last year. Among the sleep disorders, 41% reported sleeping <
7 hours daily, 64% reported snoring, 65% reported unintentionally nodding off for at
least 1 day a month, and 10% reported unintentionally nodding off while driving at least
1 day a month. In our logistic regression models, less than 7 hours sleep was less likely
among those with poor health status (p<0.001) and participants at the VA site (p=0.006).
Unintentionally nodding off was associated with black race (p=0.004) and unintentionally
nodding off while driving was less likely among black (p=0.001) and Hispanic/other race
(p=0.03) . No sociodemographic variables were significantly associated with snoring.
Conclusions: OSA risk factors are prevalent in this population of patients with diabetes.
The relationship between sociodemographic characteristics and varying sleep disorders
need to be investigated to establish a possible mechanism by which they are linked.
Acknowledgements: NIH/NIDDK T35 DK007431-26 (09012151), Center for Health
Disparities Research
Classification: Medical Student
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Medical Student
Poster # 40
Using proteomics analysis to identify novel proteins in marrow niche microenvironment
that contribute to the enhanced donor cell engraftment with plerixafor treatment.
An, Ningfei1, Alison Bland2, John Lazarchick3, Zihai Li1,4, Andrew Kraft1, John Arthur2, and Yubin Kang1
1
Division of Hematology-oncology, 2Division of Nephrology, Department of Medicine, 3Department of
Pathology and Laboratory Medicine, 4Department of Microbiology and Immunology, Medical University of
South Carolina, Charleston, South Carolina
Enhancing donor cell recovery is a very important goal in hematopoietic stem cell transplantation (HCT).
Hematopoietic stem cell (HSC) reconstitution is regulated by marrow niche microenvironment that
consists of cellular and non-cellular elements including cytokines, chemokines and many other soluble
factors. We recently found that post transplant administration of plerixafor (a specific and reversible
CXCR4 antagonist) selectively enhanced donor cell engraftment and promoted recovery of all donor cell
lineages in a congeneic mouse transplant model (Kang et al, 2010, PLoS One 5, e11316). We
hypothesized that plerixafor enhances donor cell reconstitution in part by modulating the levels and
constitution of soluble factors in niche microenvironment. METHODS AND RESULTS: To test this
hypothesis, we transplanted lethally irradiated C57Bl/6 mice with sorted c-Kit+ Lin- Sca-1+ HSCs and then
injected s.c. PBS or plerixafor (5 mg/kg) every other day beginning at day +2 post transplant. At day +7
post transplant, the mice were sacrificed. Tibias and femurs were flushed with PBS and marrow
supernatants collected. We found that the marrow supernatants from PBS treated- transplant mice
inhibited bone marrow cell (BMC) colony forming units (CFUs). In contrast, the marrow supernatants
from plerixafor treated- transplant mice significantly increased BMC CFUs. Plerixafor per se did not
affect CFUs. We next used a multiplexed, mass spectrometry-based, quantitative isobaric tagging
proteomics approach to compare the protein expression in marrow supernatant of PBS treated- transplant
mice and that from plerixafor-treated transplant mice. We identified a total of 289 proteins, 3 of them
only present in the marrow supernatants of PBS treated- transplant mice. Twenty-three proteins were
increased (>2 fold) and 7 decreased in plerixafor treated- transplant mice. We then performed additional
studies to validate our proteomics results. We focused on thioredoxin, one of the 23 proteins that
increased in the marrow supernatant of plerixafor treated- transplant mice. Thioredoxin is a small
oxidoreductase protein important in preserving tissue redox homeostasis, metabolic functions, and
cellular integrity. We found that thioredoxin mRNA expression in BMCs was up-regulated in plerixafor
treated- transplant mice. Furthermore, we found that thioredoxin increased BMC CFUs, enhanced the
recovery of platelet counts in sublethally irradiated mice, and protected against radiation-related death.
CONCLUSION: Our studies demonstrated that factors in the marrow niche microenvironment play a
critical role in hematopoiesis. Measuring changes in proteins in marrow niche microenvironment will not
only allow us to understand the mechanisms of action of plerixafor, but also provide clue on potential
novel targets that can be used to further enhance hematopoiesis.
First Author: Ningfei An, postdoctal,
Type of research: basic science
Corresponding Author: Yubin Kang
Emial: [email protected]
Postdoctoral Basic Science
Poster #41
Role of p38/Akt Signaling Pathway in the Regulation of Sodium/Calcium Exchanger
Expression in Adult Cardiomyocytes
Chernysh, Olga, Santhosh K. Mani and Donald R. Menick
Department of Medicine, Division of Cardiology, Medical University of South Carolina,
Charleston, SC
Introduction: The sodium/calcium exchanger (NCX1) is regulated at the transcriptional
level in cardiac hypertrophy and heart failure. Upregulation of NCX1 affects
sarcoplasmic reticulum calcium loading and directly contributes to contractile
dysfunction of failing myocardium. In animal models, it has been demonstrated that
pharmacological inhibition of NCX1 may be beneficial in heart failure and during
ischemia/reperfusion. However, most studies have focused only on the acute effects of
NCX1 inhibitors on calcium homeostasis, and there is little information available on the
potential risks and benefits of chronic therapeutic inhibition of NCX1. Previous work
from our laboratory has shown that prolonged treatment with NCX1 inhibitor, KB-R7943
results in the upregulation of Ncx1 gene expression in both isolated adult cardiomyocytes
and intact mouse hearts. This upregulation is mediated via the activation of p38 and
formation of a NCX1-p38 complex. However, the signaling pathway leading to the
increase in Ncx1 gene expression remains to be elucidated.
Hypothesis: NCX1, whose activity is acutely sensitive to cytosolic calcium, sodium and
membrane potential, can also regulate its own expression in an activity-dependent
manner as part of a macromolecular signaling complex.
Results: To identify potential downstream targets of p38, we treated isolated adult feline
cardiomyocytes with KB-R7943 in the presence of p38 inhibitor, SB203580, which
resulted in the inhibition of Akt kinase activation. Co-immunoprecipitation studies also
showed that Akt was in complex with NCX1.
Conclusion: Our results suggest that p38/Akt pathway plays a role in regulating Ncx1
gene expression in response to pharmacological inhibition of the exchanger.
Type of Project: Basic Science
E-mail: [email protected]
Postdoctoral Basic Science
Poster #42
Specific targeting of virus-infected cells through inhibition of sphingolipid biosynthesis
Dai, Lu 1,2, Zhiqiang Qin1,2, Charles D. Smith3 and Chris Parsons1,2
Affiliations: Departments of Medicine1, Craniofacial Biology2, and Pharmaceutical &
Biomedical Sciences3, Hollings Cancer Center, Medical University of South Carolina, 86
Jonathan Lucas St., Charleston, SC 29425
Abstract: Generation of sphingosine-1-phosphate (S1P), through the enzymatic activity of
sphingosine kinase isoforms 1 and 2 (SK1 and SK2), facilitates signal transduction associated
with cell proliferation and survival. Furthermore, targeting of SK2 reduces cancer progression in
animal models. Roles for SK and S1P in viral cancer pathogenesis have, however, not been
explored. The Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of
Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), tumors most often encountered
in the setting of HIV/AIDS and organ transplantation. The most common therapeutic approach
for these tumors—conventional cytotoxic chemotherapy—is limited by its lack of efficacy and
toxicities that compound those incurred by antiretroviral and immunosuppressive agents. We
used a novel compound preferentially targeting SK2 (ABC294640) to determine whether SK2
regulates cellular pathogenesis following de novo KSHV infection of primary human endothelial
cells (EC) and for patient-derived, KSHV-infected PEL cells. We found that targeting SK2
induced caspases-mediated apoptosis more readily for KSHV-infected EC and PEL cells relative
to their respective KSHV-negative counterparts. Moreover, we identified two possible
mechanisms for this effect: 1) preferential accumulation of pro-apoptotic ceramide species in
KSHV-infected cells during SK2 inhibition; and 2) induction of KSHV “lytic” genes associated
with programmed cell death. Exploring potential mechanisms for these endpoints, we found that
SK2 inhibition selectively suppresses expression of specific KSHV-encoded microRNAs
(miRNAs) which activate anti-apoptotic signaling and which suppress KSHV lytic gene
expression. Subsequent experiments revealed that SK2 inhibition suppressed KSHV-induced
phosphorylation of signaling intermediates associated with cell survival, and ectopic expression
of specific KSHV miRNAs during SK2 inhibition partially restored activation of these
intermediates, reduced KSHV lytic gene expression, and restored viability for infected cells.
Finally, using an established murine model for PEL, we found that ABC294640 significantly
prolonged disease-free survival if given shortly after tumor initiation and dramatically reversed
disease progression if given following establishment of PEL tumors in the model. Collectively,
these data demonstrate a role for SK2 and S1P in the selective regulation of anti-apoptotic KSHV
miRNAs and suggest that targeting SK2 offers a viable therapeutic strategy for KSHV-associated
malignancies.
Category: Postdoctoral Scholar (Lu Dai), Basic Science
E-mail: [email protected]
Postdoctoral Basic Science
Poster #43
Global DNA Methylation and DNA Hydroxymethylation in Systemic Lupus Erythematosus
(SLE) within the Gullah African American Population
French, Kristen L.1,2, Anna K. Meyer1,3, Gary S. Gilkeson1, and Diane L. Kamen1
1
Division of Rheumatology and Immunology, Department of Medicine
2
Corresponding author ([email protected]), Postdoctoral Fellow, Basic Science
3
Medical Student, College of Medicine
This epigenetic project is based in both clinical and basic sciences, with translational
implications.
SLE disproportionately affects females and African Americans, yet occurrence of SLE has not
been satisfactorily explained by genetic, hormonal or socioeconomic factors. This has led to
growing interest in epigenetic modifications such as DNA methylation, which has been shown to
be decreased below normal levels (hypomethylation) in SLE patients. Interestingly, the
demethylating agent 5-azacytidine is known to cause a reversible lupus-like syndrome in both
humans and animal models. In addition, some normally silenced, methylation sensitive genes
related to autoimmunity are found to be overexpressed in SLE patients. However, DNA
methylation studies in SLE have not differentiated between the two DNA nucleic acids 5methylcytosine (5-meC) and 5-hydroxymethylcytosine (5-hmC). While 5-meC modifications
silence gene expression, 5-hmC appears to promote conditions which lead to gene expression,
similar to hypomethylation. We hypothesized that patients diagnosed with SLE would exhibit
global decreases in 5-meC and global increases in 5-hmC in peripheral blood mononuclear cells
(PBMCs) compared to controls. By focusing on the Gullah African American population, we
hoped to limit genetic and environmental variability, due to the historical geographical isolation
and low genetic admixture (with non-African descendents) of this population. Additionally, we
hypothesized that levels of 5-meC and/or 5-hmC would correlate with biomarkers of immune
dysregulation and autoimmunity in both patients and controls. ELISA-like assays with
antibodies specific for 5-meC or 5-hmC were utilized in this study. Our preliminary results
indicate that there is no significant difference in 5-meC or 5-hmC levels in the PBMCs between
patients (n=45) and controls (n=45) or between controls who are positive (n=11) or negative
(n=33) for antinuclear antibodies (ANA). We did observe a significant difference between
females (n=80) and males (n=10) with females having lower levels of 5-meC (p<0.01) and 5hmC (p<0.05) compared to males. Levels of 5-meC and 5-hmC showed a moderate positive
correlation to each other (r=0.56, p<0.001), contrary to our prediction of a negative correlation.
The finding of no difference in 5-meC or 5-hmC levels between patients and controls may
indicate that Gullah AAs have similar sensitivities to influences on DNA methylation or have
had similar exposures due to their historical geographic isolation. The gender difference
observed is intriguing and may be partially explained by the wider variability in 5-meC and 5hmC levels seen in males. Further analysis of more specific clinical biomarkers is currently
underway.
Support: SCTR Grant #1206 (NIH/NCRR Grant Number UL1RR029882); Training Grant in
Inflammatory and Fibrosing Diseases (NIAMS T32 AR050958-07); and Environmental
Determinants of Autoimmunity (NIH/NIEHS R21 ES017934).
Postdoctoral Basic Science
Poster #44
Acquired Defects of Lupus Prone Mice-derived Mesenchymal Stem Cells Lead to Poor
Effects of Autologous Transplantation in NZB/NZW F1 mice.
Gu,Fei1,2, Ivan Molano1, Lin Yung Sun2 and Gary Gilkeson1,3. 1Division of Rheumatology &
Immunology, Department of Medicine. Medical University of South Carolina, Charleston, SC ,
2
Division of Rheumatology & Immunology, Drum Tower Hospital, Nanjing, China, 3Ralph H.
Johnson VA Medical Center, Charleston, SC.
Objectives: Lupus is a systemic autoimmune disease characterized by the production of
autoantibodies and end organ damage from immune complex deposition. Mesenchymal stem
cells (MSC) possess immunomodulatory properties and also participate in tissue repair. Defects
in MSC function are reported in cells derived from lupus prone mice and lupus patients. Thus, a
key question in the use of MSC in lupus is whether MSC from lupus donors are intrinsically
defective and thus not suitable for autologous transplantation.
Methods: NZB/NZW F1 mice were treated with a single intravenous injection of 1×106
C57BL/6J (B6) MSC (B6-MSC, allogeneic/normal MSC, n=8), young NZB/NZW F1 MSC
(YBW-MSC, autologous/pre-lupus MSC, n=8), old NZB/NZW F1 MSC (OBW-MSC,
autologous/post-lupus MSC, n=8), B6 fibroblasts (FB, n=7), or phosphate buffered saline (PBS,
n=7) at 24 to 26 weeks of age after onset of disease. We monitored proteinuria and serum anti-ds
DNA antibody levels every two weeks. All mice were sacrificed at 8 weeks after treatment.
Splenocytes were stained with CD3,CD4 and CD19 to identify T cells and B cells, respectively.
Kidney pathological slides were stained with haematoxylin and eosin (H&E) and scored in a
blinded fashion. The average intensity of glomerular immune complex deposition in five
independent fields of one kidney section per animal was quantitated.
Results: The mice in all three MSC transplantated groups got 100% survival at 8 weeks after
treatment. All three sources of MSC led to less proteinuria and significant differences between
the three MSC transplantation groups and PBS group were observed at 8 weeks after treatment.
However, neither source of MSC impacted serum anti-dsDNA antibody levels though there was
a trend towards lower levels in B6-MSC group. We found the spleens weight in B6-MSC and
YBW-MSC group were significantly less than those in the other three groups. All three sources
of MSC-treated animals had marked reduced C3 deposits in glomeruli compared to controls.
However, only B6-MSC and YBW-MSC, but not OBW-MSC led to statistically decreased
intensity of glomerular IgG depositon. All three sources of MSC significantly decreased the
occurrence of renal vasculitis and necrosis versus the controls. B6-MSC and YBW-MSC
improved overall renal pathology significantly and B6-MSC also ameliorated interstitial
inflammation in kidneys. In addition, B6-MSC and YBW-MSC significantly reduced the
absolute number of spleen CD4+ T cells and CD19+ B cells. We also found all three sources of
MSC suppress T-cell proliferation in vitro potently but OBW-MSC did not work as well as B6MSC and YBW-MSC.
Conclusion: These results indicate MSC transplantation after onset of disease does impact lupuslike disease in NZB/NZW F1 mice through mechanisms including suppression of T-cell and Bcell proliferation and suggest that allogeneic sources of MSC may be preferred to autologous
sources, but the functional defects of lupus-MSC are not intrinsic, but acquired.
Type of Project: basic science
Postdoctoral Basic Science
Poster #45
Effect of Perceived Control on Quality of Life in Indigent Adults with Type 2
Diabetes
Hernandez-Tejada Melba, Strom JL, Lynch CP, & Egede LE
MUSC Department of Medicine, Division of General Internal Medicine and Geriatrics &
Ralph H. Johnson VAMC
Patients with type 2 diabetes mellitus (T2DM) report higher quality of life(QOL) when
adequate glycemic control is achieved. However, it is uncertain whether control per se, or
perception of control is most predictive of increased quality of life. To address this, we
evaluated perceived control of diabetes and QOL in 188 patients from a low income clinic
located at an academic medical center. QOL was assessed with the Medical Outcomes SF12. We computed physical and mental component scores. Perceived control was measured
with a 15-item Perceived Control Questionnaire. Correlational analyses indicated a
positive relationship between perceived control and both physical and mental QOL
(r=0.53 and r=0.34 p<0.001, respectively). Linear regression analyses, in which related
factors were controlled, supported this finding, with the first model accounting for 29.1%
of the variance, and when controlling for demographics and comorbidity, 33.8% of the
variance in the final model. Thus, increasing perceived control, perhaps by a combination
of education and skills building (i.e., self-efficacy), may result in higher perceived QOL
for patients with T2DM.
Acknowledgements: Agency for Health Care Research and Quality 5K08HS11418,
Center for Health Disparities Research
Classification: Post Doctoral Fellow
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Postdoctoral Basic Science
Poster #46
TLR4 Activation Triggers a Robust Inflammatory Response and Interaction with
Mononuclear Cells by Microvascular Endothelial Cells
Lu, Zhongyang, Yanchun Li, Junfei Jin, Xiaoming Zhang, Maria F. Lopes-Virella, Yan Huang
Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine
Although coronary artery disease is a macrovascular disease, microvessels are developed inside
atherosclerotic plaques and contribute to plaque inflammation and intraplaque hemorrhage. As
the major cells in vessels, both macrovascular endothelial cells (MAC ECs) and microvascular
endothelial cells (MIC ECs) contribute to atherosclerosis. However, the responsiveness of these
cells to the activation of toll-like receptor (TLR)4, an innate immune receptor, has not been well
characterized and compared. In this study, we showed that TLR4 activation by
lipopolysaccharide (LPS) stimulated a much higher expression of inflammatory genes including
cytokines, chemokines, growth factors and adhesion molecules in MIC ECs when compared to
those in MAC ECs. Furthermore, TLR4 activation in MIC ECs, but not MAC ECs, led to an
interaction with U937 mononuclear cells through MIC EC-released IL-6 to upregulate matrix
metalloproteinase (MMP)-1 expression in U937 cells. To explore the mechanisms underlying
the different responses to TLR4 activation by MIC and MAC ECs, we found that MIC ECs had
higher expression levels of TLR4, MD-2 and CD14, and higher TLR4-mediated NFKB
transcriptional activity than MAC ECs. Taken together, this study showed that TLR4 activation
triggers a robust inflammatory response in MIC ECs. Given the essential role of inflammatory
cytokines and MMPs in plaque destabilization in advanced atherosclerotic lesions, our study
indicates that MIC ECs may contribute to plaque vulnerability through a TLR4-dependent
mechanism.
Dr. Zhongyang Lu, Postdoctoral Research Fellow
Type of Research: Basic Science
Corresponding author: Dr. Yan Huang (email: [email protected])
Postdoctoral Basic Science
Poster #47
Proteomic analysis of cerebral spinal fluid reveals candidate biomarkers of domoic acid
toxicosis in California sea lions
Neely, Benjamin A.1, Jennifer Soper2, Frances M. D. Gulland2, John M. Arthur1,3, Michael G.
Janech1,3
1
Department of Medicine, Division of Nephrology, Medical University of South Carolina,
Charleston, SC
2
The Marine Mammal Center, Sausalito, CA
3
Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC
Domoic acid toxicosis (DAT) is a major cause of California sea lion (Zalophus californianus)
strandings along the west coast of the United States. Domoic acid is a potent neurotoxin
produced by some marine diatoms, which causes hippocampal atrophy and necrosis as a result of
excessive stimulation of AMPA-kainate and NMDA receptors, and is rapidly cleared from the
body. DAT is classified as acute or chronic, with the former recovering over time and the latter
progressing to status epilepticus. Currently markers of DAT are limited and inconclusive;
therefore by developing markers of DAT, diagnosis and treatment could be greatly facilitated.
For this reason we evaluated whether protein differences exist in the cerebral spinal fluid (CSF)
that could be utilized as markers of DAT. CSF samples from 11 sea lions [3 without DAT, 2
diagnosed with acute-DAT and 6 with chronic-DAT] were acquired from The Marine Mammal
Center and proteins were digested with trypsin for analysis by tandem mass spectrometry. Data
were searched using Mascot against a mammalian database, with identifications supported by
Scaffold. We identified 182 experiment-wide proteins with a protein false discovery rate of
<0.1%. Relative protein abundance was estimated for comparison by spectral counts across all
samples and differences were detected using a Wilcoxon rank-sum test. Six proteins were
significantly different (p<0.05) between non-DAT and DAT animals, five of which were higher
in animals with DAT. Interestingly, Dickkopf-3 and Gelsolin were elevated in sea lions with
DAT. Both of these proteins have been implicated in the progression of Alzheimer’s disease,
suggesting that DAT and Alzheimer’s may share common features. Future studies to qualify
these proteins as markers of DAT are ongoing.
Postdoctoral Basic Science
Poster #48
Diabetes accelerates cystogenesis and results in glomerular and tubular damage in a mouse
model of polycystic kidney disease
Sas, Kelli M.1 and P. Darwin Bell1,2.
1
Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC;
2
Ralph H. Johnson VA Medical Center, Charleston, SC.
The rate of progression in polycystic kidney disease (PKD) is highly variable and poorly
understood. It is believed that additional, non-genetic factors such as environmental influences
and pathophysiological conditions can influence the rate of cyst formation and disease
progression. Diabetes (hyperglycemia) results in structural and functional hypertrophy in the
kidney. We have previously found that renal hypertrophy accelerates cystogenesis. The goal of
this study was to determine if the presence of diabetes would modify the time course and degree
of renal cyst formation in a mouse model of PKD in which cilia are depleted. To examine the
role of diabetes on cyst formation, we utilized a conditional floxed allele for the ift88/Tg737
gene to produce cilia (+) or cilia (-) adult mice. Mice were administered streptozotocin at 50
mg/kg for 5 days to induce diabetes. Blood glucose concentrations were elevated but not
significantly different between groups. After 6 weeks, mice underwent MRI to determine cystic
burden and kidneys were removed after 6 weeks or 3 months for histological analysis and
electron microscopy. MRI and histological analyses identified accelerated cystogenesis mainly in
the glomeruli and collecting ducts of diabetic cilia (-) mice. Additionally, diabetic cilia (-) mice
exhibited abnormalities in non-cystic regions with signs of tubular stress and glomerular disease,
as evidenced by primitive renal tubules, mesangial cell expansion, and fusion of glomerular foot
processes. These abnormalities did not occur in cilia (+) mice. There was also a marked
increase in lymphocytic infiltration and enhanced AKT, mTOR, Wnt, and EMT signaling in
kidneys from the diabetic cilia (-) mice. Diabetes may be a significant risk factor for accelerated
cyst formation and renal failure in PKD, and cilia may be reno-protective in diabetes.
*Kelli M. Sas is a post-doc in basic science research.
Corresponding author email: [email protected].
Postdoctoral Basic Science
Poster #49
Association between Spirituality and Depression in Adults with Type 2 Diabetes
Strom, Joni, Lynch CP, Hernandez-Tejada MA, & Egede LE
Department of Medicine, Division of General Internal Medicine and Geriatrics & Ralph H.
Johnson VAMC
Purpose: Comorbid depression complicates glycemic control in patients with diabetes.
Potentially protective factors have received little attention. This study examines the
association between spirituality and depression among patients with type 2 diabetes.
Methods: This prospective study included 201 adult participants with diabetes from an
indigent clinic of an academic medical center. Participants completed validated surveys on
spirituality and depression. The Daily Spiritual Experience Scale (DSES) measured a
person’s perception of the transcendent (God, the divine) in daily life. The Center for
Epidemiologic Studies-Depression scale assessed depression. Linear regression analyses
examined the association of spirituality as the predictor with depression as the outcome,
adjusted for confounding variables.
Results: Greater spirituality was reported among females, non-Hispanic blacks (NHB),
those with lower educational levels, and those with lower income. The unadjusted
regression model showed greater spirituality was associated with less depression. This
association was mildly diminished but still significant in the final model. Depression scores
also increased (greater depression risk) with females and those who were unemployed but
decreased with older age and NHB race/ethnicity.
Conclusions: Treatment of depression symptoms may be facilitated by incorporating the
spiritual values and beliefs of patients with diabetes. Therefore, faith-based diabetes
education is likely to improve self-care behaviors and glycemic control.
Acknowledgements: Agency for Health Care Research and Quality 5K08HS11418, Center
for Health Disparities Research
Classification: Post Doctoral Fellow
Type of Research Project: Clinical Science
Email Address of Corresponding Author: [email protected]
Postdoctoral Basic Science
Poster #50
IRS-1/2 Mediated Regulation of Hepatic OGT and OGA Expression
Sundararaj, Kamala1&2, Abdelmohsen M Alqalam2, Katherine A Robinson2, Maria G Buse2,
Lauren E Ball1.
1
Pharmacology, 2Medicine/Endocrinology, Medical University of South Carolina, Charleston,
SC
To investigate the role of hepatic insulin signaling in the postprandial regulation of O-GlcNAc
transferase (OGT) and OGlcNAcase (OGA) expression, C57BL/6 male mice with a conditional
knock out of IRS-1/2 in liver (LKO) were fed a chow or high fat diet (HFD) for 16 weeks and
then either fasted for 18 hrs or fasted and refed ad libitum for 4 hrs. In control animals that were
fasted or refed, qRT-PCR revealed a postprandial increase in OGT expression (146% ± 12.8,
n=5) and a reduction in OGA transcript levels (65.7% ± 6.1, n=5). High fat feeding attenuated
both the postprandial rise in hepatic OGT expression (123% ± 5.0, n=5) and the suppression of
OGA expression (77.2% ± 4.6, n=5). In LKO mice in the refed state, OGT mRNA expression
was reduced by 68% ± 1.5 (n=6) after 16 weeks HFD as compared to animals fed a chow diet.
Furthermore with 16 weeks HFD, an elevation in the expression of OGA was observed in hepatic
(170% ± 7.5) and adipose (316.5% ± 21.6, n=6) tissue as compared to chow diet. These studies
reveal that the postprandial changes in hepatic expression of OGA and OGT are regulated, in
part, by IRS-1/2 mediated insulin signaling in vivo and that the suppression of OGA expression
in fat fed animals is lost in the absence of hepatic IRS-1/2. Supported by T32 HL07260 and
RO1DK002001.
Postdoctoral Basic Science
Poster #51
Site specific phosphorylation of cardiac MAP4 reduces MAP4-microtubule binding and
prevents deleterious effects of left ventricular pressure overload.
Wallenborn, J. Grace1, Kasiganesan H1, Baicu C1, Harris BS2, Cheng GM1, Menick DR1,
Cooper G1.
1
Department of Medicine, Division of Cardiology
2
Department of Regenerative Medicine and Cell Biology
In severe pressure overload-induced cardiac hypertrophy, a dense microtubule network is formed
in cardiomyocytes which is one cause of contractile dysfunction. This densification is the result
of transcriptional upregulation of MAP4, the major cardiac microtubule binding and stabilizing
protein, as well as increased MAP4-microtubule affinity. This increased affinity is driven by
site-specific dephosphorylation of MAP4 at several serine residues, including serine 924, located
in the microtubule binding domain of MAP4. Adenoviral mediated overexpression of mutant
MAP4 mimicking constitutive phosphorylation at serine 924 leads to decreased microtubule
network density. We hypothesized that in vivo, constitutive phosphorylation of cardiomyocyte
MAP4 at serine 924 would ameliorate pressure overload-induced contractile dysfunction. To
address this, site directed mutagenesis of MAP4 cDNA was used to switch serine 924 to aspartic
acid (MAP4-S924D). This cDNA was cloned into the α-myosin heavy chain promoter, and used
to create a new transgenic mouse with cardiac restricted overexpression of MAP4-S924D. Left
ventricular pressure overload (LVPO) was produced by transverse aortic constriction in male and
female mice, 10-12 weeks old. Following 4 weeks of LVPO, LV structure and contractile
function was characterized via echocardiography. Cardiomyocytes were isolated, and contractile
function was measured in terms of sarcomere mechanics. In wild type mice, LVPO induced an
increase in LV mass (128mg to 269mg), decrease in ejection fraction (50% to 19%), and
decrease in fractional shortening (25% to 9%). Much lesser changes were seen in banded
transgenic mice; LV mass was only marginally increased (112mg to 130mg), ejection fraction
only decreased 51% to 46%, and fractional shortening from 26% to 23%. Isolated
cardiomyocytes from WT mice had shorter resting sarcomere length, extent of shortening,
shortening and relaxation velocity compared to transgenic mice. Overall, our results suggest that
constitutive phosphorylation of serine 924 of cardiomyocyte MAP4 leads to a less deleterious
response to pressure overload.
Postdoc, Basic Sciences
Corresponding author email: [email protected]
Postdoctoral Basic Science
Poster #52
Growth factor plus preemptive plerixafor successfully mobilizes hematopoietic stem cells
(HSC) in all multiple myeloma patients despite prior lenalidomide exposure.
Abbas, MD, Jonathan A., Kristine McDonald, MD, Cindy Kramer, Kathy Hogan, Colleen
Butcher, Amanda Littleton, Katie Shoptaw, YUbin Kang, MD, Robert K. Stuart, MD, Luciano J.
Costa, MD/PhD
Division of Hematology/Oncology, Department of Medicine
OBJECTIVE. Lenalidomide, a component of several modern induction regimens in multiple
myeloma (MM), is associated with suboptimal autologous hematopoietic stem cell (AHSC)
mobilization. Cyclophosphamide plus filgrastim mobilization at least partially overcomes the
negative impact of lenalidomide but leads to higher cost and toxicity. We hypothesized that
growth factor plus preemptive plerixafor is a safe and highly efficient strategy for initial AHSC
mobilization in MM despite prior exposure to lenalidomide.
METHODS. We retrospectively reviewed patient characteristics and mobilization outcomes of
89 consecutive MM patients undergoing first mobilization with filgrastim or pegfilgrastim +/preemptive plerixafor using a previously validated algorithm based on day 4 peripheral blood
CD34+ cell count (PB-CD34+) and mobilization target. Mobilization outcomes were analyzed
for three distinct groups according to the extent of prior exposure to lenalidomide: no prior
exposure (group A, N=40), 1 to 4 cycles (group B, N=30) and > 4 cycles (group C, N=19).
RESULTS. Median age was 57.5 years and similar across groups. Multivariate analysis with PBCD34+ as the dependent variable yielded only age, number of prior cycles of lenalidomide and
mobilization with pegfilgrastim as significantly associated with PB-CD34+. Only 45% of
patients in A required plerixafor vs. 63% in B and 84% in C ,P=0.01. The median yield of
CD34+ collected was 8.1 x 10^6 CD34+/kg in A, 7.4 x 10^6 CD34+/kg in B and 7 x 10^6
CD34+/kg in C. A higher proportion of patients in A (100%) met the mobilization target (6 x
10^6 CD34+/kg for most patients) than in B (90%) or C (79%), P=0.008. All patients collect at
least 2 x 10^6 CD34+/kg. HSC collection was completed after a median of 1.5 daily apheresis
sessions in A and B and 2 in C. The estimated cost of mobilization and collection was similar
between A (median US$ 22,280) and B (US$ 22,280), but substantially higher in C (US$
35,020).
CONCLUSION. Steady state growth factor mobilization with a validated algorithm for
preemptive use of plerixafor is an adequate upfront mobilization strategy for MM patients
regardless of prior exposure to lenalidomide, negating the need for chemotherapy mobilization.
Project Type: Clinical Research Project
Lead Author Contact Information: [email protected]
Clinical Fellow
Poster #53
REVISITED IMPACT OF HUMAN LEUKOCYTE ANTIGEN-DR MATCH IN KIDNEY
TRANSPLANT RECIPIENTS
Ahmed, Vaqar1 (Fellow Clinical Nephrology), Maria Francesca Egidi1,
Bethany Jacobs Wolf2
1.
Transplant Nephrology, 2. Division of Biostatistics & Epidemiology. Medical University of
South Carolina.
BODY:
Purpose of Study: HLA-DR has been associated with poor long-term graft function. However,
the impact of HLA-DR remains unclear under new immunosuppressive agents. We analyze graft
outcomes in kidney transplant recipients with 1 and/or 2 HLA-DR mismatches compared to 0
HLA-DR mismatches.
Methods Used: We reviewed 555 patients who received kidney transplants between January
2005 and June 2008. Kaplan-Meier survival analyses were used to examine associations between
graft failure and different variables using a log-rank test to test for differences between groups.
We developed a Cox regression model to determine graft survival by HLA-DR status adjusted
for demographic and clinical characteristics. A two-tailed P value <0.05 was considered to be
statistically significant.
Summary of Results: Graft survival was lower in HLA-DR 2MM relative to HLA-DR 0MM
(p=0.025). Subjects who received IL-2 antibody induction had significantly increased hazard of
graft failure with 2 HLA-DR MM relative to those with 0 HLA-DR MM (95% CI for the hazard
ratio (HR) 1.38-24.6, p=0.016). However, 0 HLA-DR MM was not associated with increased
graft survival compared to 2 HLA-DR MM in patients who received induction with ALA
(p=0.646). There was no significant effect of either CYA or FK on graft failure (p=0.295).
However there was significantly increased hazard of graft failure for 2 HLA-DR mismatches
relative to 0 mismatches (p=0.041) in both groups.
Conclusions: Despite strong immunosuppression, HLA-DR mismatch has an adverse impact on
long-term graft survival particularly in subjects who receive IL-2 induction. We conclude from
this data that patients with HLA-DR mismatch may benefit from ALA induction.
Type of research: Clinical
Email address: [email protected]
Clinical Fellow
Poster #54
The Impact of Lobar Perfusion on Exercise Response to Endobronchial Valve Therapy in
Advanced Pulmonary Emphysema
Argula, Rahul G *, Charlie Strange*, Viswanathan Ramakrishnan+
* Division of Pulmonary & Critical Care Medicine, + Division of Epidemiology & Biostatistics
Medical University of South Carolina, Charleston, South Carolina
Background: Advanced heterogeneous pulmonary emphysema with hyperinflation impacts
exercise tolerance in COPD. We evaluated whether baseline perfusion to the target lobe of
patients receiving Zephyr® endobronchial valves (EBV) was associated with an improvement in
6 minute walk test distance (6MWTD).
Methods: We performed a retrospective analysis on the treatment group of the VENT trial (N
Engl J Med 2010; 363:1233) to evaluate the impact of baseline perfusion, measured by 99mTcMAA perfusion scintigraphy, on six-month improvement in 6MWTD. A mixed model analysis
(SAS, Cary, NC) was performed for the treatment outcome adjusting for other variables such as
age, fissure integrity, BMI, gender, heterogeneity score, destruction score, and lobar exclusion.
Results: Of the 220 patients who received EBV therapy, 193 had complete perfusion
scintigraphy data available. Dichotomized at the median, 99 had a low baseline target lobe
perfusion and 94 had high target lobe perfusion. Among EBV patients with complete lobar
exclusion at follow-up, a low baseline target lobe perfusion was associated with a significant
improvement in 6MWTD when compared to a high baseline target lobe perfusion (30.24 Vs.
3.72 meters, p = 0.03). This effect persisted after controlling for target lobe destruction and
heterogeneity scores. Correlations between the target lobe perfusion, destruction score and
ipsilateral heterogeneity were small (R2 = 0.15 and 0.13 respectively, p<0.0001). The mixed
model analysis also suggested interactions with gender.
Conclusions: Patients having heterogeneous emphysema with a low baseline target lobe
perfusion benefit from EBV therapy, with limited impact from the degree of target lobe
destruction and heterogeneity. This effect is attenuated if the valves are not occlusive.
Characterization of baseline perfusion may enhance clinical results of emphysema patients
undergoing EBV therapy
Author designation: Clinical fellow, Division of Pulmonary & Critical Care Medicine, MUSC.
E-mail: [email protected]
Type of research: Clinical
Clinical Fellow
Poster #55
Endoscopic Resection of Duodenal Bulb Carcinoids:
A Comparison of Rates of Complete Resection among the Suck-and-Ligate,
Inject-and-Snare, and Snare-Alone Techniques
Baltz MD, Joseph 1, Jim Madory DO2, Joseph Romagnuolo MD, MSc1, Robert Hawes MD1, and Brenda
Hoffman MD1
1
MUSC Department of Medicine, Division of Gastroenterology & Hepatology, Charleston, SC
2
MUSC Department of Pathology and Laboratory Medicine, Charleston, SC
Purpose: Endoscopic mucosal resection (EMR) is typically reserved for mucosal lesions, but mixed
mucosal/submucosal tumors such as carcinoids are resectable without special techniques like submucosal
dissection. The suck-and-ligate technique is used mostly in the esophagus and stomach rather than the
duodenum for fear of perforation risk. The purpose of this study is to evaluate the adequacy of resection
and complications of different endoscopic resection techniques of carcinoid tumors in the duodenal bulb.
Methods: The medical records of patients in whom carcinoid tumors were endoscopically resected from
the duodenal bulb from the year 2000 to 2010 were retrospectively reviewed. Patient demographics,
endoscopic ultrasound (EUS) evaluation, type of resection technique, adequacy of resection (from
pathology reports), specimen sizes, and complications were recorded. The Paris Classification was
determined by photographs or by description of the lesions. Resection techniques included suck-andligate, inject-and-snare, and snare-alone. Statistical comparisons of proportions were performed using
Fisher exact test.
Results: A total of 30 consecutive cases of endoscopic resection were included. Please see the table below
for complete results and analysis. 3 of 13 lesions in which the suck-and-ligate technique was used had
positive margins. 4 lesions were Paris class IIa (flat, elevated lesions). 7 of 11 lesions in which the injectand-snare technique was used had positive margins. 1 lesion was Paris class IIa. 4 of 6 lesions in which
the snare was used alone had positive margins. 1 lesion was Paris class IIa. No complication was noted in
any patient. The average specimen size was similar among the three groups. The differences among the
three techniques in their rate of positive margins did not reach statistical significance.
Total Procedures
Positive Margins (%)
Specimen Avg. Size (range)
Number of IIa Lesions (%)
Fisher exact (p Value) margin negative
Fisher exact (p Value) Paris class
Suck-and-Ligate
13
3 (23%)
7.5mm
(3-13mm)
4 (31%)
-------
Inject-and-Snare
11
7 (64%)
7.8mm
(5-12mm)
1 (9%)
p = 0.095
p = 0.37
Snare Alone
6
4 (67%)
7.2mm
(4-13mm)
17 (%)
p = 0.13
p = 1.0
Conclusions: EMR is an effective way to remove mixed mucosal/submucosal lesions, such as carcinoid
tumors, in the duodenal bulb with a high rate of negative margins. The suck-and-ligate technique is as
safe as and had a non-significant trend towards a higher percentage of complete resection than either of
the other techniques. There is likely selection bias as certain morphologies may preferentially have been
removed by one technique vs. another. It is not clear whether positive margins described by pathology
were due to simple extension of lesion margin to the cautery line versus truly due to residual tissue
incompletely resected as follow up data is not available at this time.
Clinical Fellow
Poster #56
The Impact of Adult CF Programs on Adult Achievement
Barto MD, Tara Lynn, 1, Patrick A. Flume, MD 1.
1
Division of Pulmonary and Critical Care Medicine, Medical University of South
Carolina, Charleston, SC, USA.
Introduction: CF patients are living longer and there is a growing adult population. We
have established adult programs to provide age-appropriate care to this growing
population. Transition programs are recommended to prepare patients not only for the
movement from pediatric to adult health care but also to provide tools necessary for adult
development. We would anticipate with implementation of these programs there would
be a subsequent increase in achievement of adult milestones.
Methods: We analyzed the CFF Patient Registry (CFFPR) comparing patients aged 2530 years in 1999 and 2008. In 2000, the CFF mandated there be adult care programs at
each CF center, therefore patients were analyzed prior to and after this mandate. We
evaluated clinical parameters as well as adult milestone achievement (i.e. education,
employment, and marital status).
Results: There were differences between the two groups (1999 vs. 2008, respectively) in
employment status with a decrease in those working full-time (51% vs. 45%) and an
increase in those characterized as disabled (14% vs. 22%). There were no differences in
the milestones of education (completion of college; 40% vs. 41%) and married status
(48% vs. 49%). Overall health had improved in all groups, with better lung function and
nutritional status, including in those patients characterized as disabled (Table).
Discussion: Clinical outcomes of adult CF patients have improved over the last decade.
Despite the implementation of adult programs, there is no evidence of improved adult
milestone achievement, and there has been an increase in the number of patients
characterized as disabled. Patients characterized as disabled have also realized
improvement in overall health, possibly because they are better able to attend to their
health care needs. However, we should consider that the lack of an increase in milestone
achievement may be because transition programs have not fully matured and require
further development.
Table: Comparison of 25-30 year-olds characterized in the CFFPR as disabled.
1999
2008
p value
Disabled (%)
FEV1 (median % predicted)
BMI (%<20)
College graduate (%)
Married (%)
Parent (%)
Clinical Fellow
14.3
31.6
53.9
17.4
43.6
0
22.1
44.5
37.7
18.4
43.7
2.67
<0.0001
<0.0001
<0.0001
NS
NS
NS
Poster #57
The Colon Had an “Air” About It: A Case of Symptomatic Pneumatosis Intestinalis
Brunson MD, Brian, Andrew Hardie, MD, David Lewin, MD, Shaoli Sun, MD, Lawrence Comerford,
MD
Medical University of South Carolina, Charleston, SC
Purpose: We present a case of pneumatosis intestinalis (PI) responsive to treatment with antibiotics and
an elemental diet
Case: An 87 year-old retired pathologist presented with a change in bowel habits, specifically alternating
diarrhea and constipation, of 4 months duration. More recently, he experienced explosive non-bloody
diarrhea with up to seven episodes daily, and a significant amount of bloating and flatus that at times was
uncontrollable in social settings. He denied any upper GI symptoms or constitutional symptom s such as
weight loss or fever. On physical exam, he appeared well and younger than his stated age. Lab work and
stool studies were unremarkable other than a mildly elevated sedimentation rate. Celiac serology was
negative. Due to his advanced age, he was treated conservatively and sequentially with a trial of a lactosefree diet, a 2 week course of rifaximin, probiotics, over-the-counter beano, cholestyramine and pancreatic
enzymes with no improvement.
After the failure of empiric therapies, EGD with duodenal biopsies was performed and was unremarkable.
A colonoscopy, however, showed multiple areas of mucosal edema and polypoid appearing lesions in the
transverse, descending colon, and sigmoid colon. Ischemia was considered due to reported intermittent
hypotension, however, biopsies of the involved colon showed submucosal giant cell reaction suggestive
of pneumatosis coli. CT enterography confirmed extensive left-sided colonic pneumatosis . He was then
placed on a course of metronidazole. After two weeks with only minimal improvement, he was started on
an elemental diet in combination with metronidazole, and his symptoms markedly improved. Repeat CT
scan and colonoscopy (repeated for removal of a large adenomatous polyp) a few months later confirmed
resolution of the pneumatosis.
Discussion:
• PI is a rare condition marked by gas-filled cysts in the wall of the small or large bowel
• The true incidence is unknown since most patients are asymptomatic
• The course is variable and is largely determined by the underlying etiology
• It is often a benign and incidental finding, but can cause non-specific bowel symptoms
• In some cases (but not our case), PI may reflect a life-threatening abdominal catastrophe
• The pathogenesis is unclear and probably multifactorial, due to mechanical, biochemical, or
bacterial causes
• The presence of portal venous gas or bowel obstruction is associated with the need for surgery
• Once an intra-abdominal catastrophe has been excluded, a variety of treatment options have been
recommended based on a number of small case series
• Treatment options include long term antibiotics, elemental diet, high-flow oxygen, hyperbaric
oxygen, or endoscopic cyst puncture or surgical therapy
Conclusion: Pneumatosis intestinalis can cause gastrointestinal symptoms such as bloating and diarrhea
and should be considered in patients who fail conservative treatment. Elemental diets and antibiotics may
prove helpful in relieving symptoms presumably by altering the colonic gas producing microflora.
Clinical Fellow
Poster #58
Phase I Trial of the HDAC Inhibitor LBH589 in Combination with Sorafenib in Patients
with Renal Cell Carcinoma, Non Small Cell Lung Cancer and Soft Tissue Sarcomas.
Butler MD, Charles M1*, Lydia T Laboccetta MD2*, Alan Brisendine3*, Thomas E. Keane
MD3*, and Harry A. Drabkin, MD3*
1
Division of Hematology/Oncology, Medical University of South Carolina, Charleston, SC; 2
Division of Urology, Medical University of South Carolina, Charleston, SC; 3Medical
University of South Carolina, Charleston, SC.
Introduction: LBH589 is a novel histone deacetylase inhibitor (HDACi) that induces apoptosis
of tumor cells. In renal cell carcinoma (RCC) and NSCLC cell lines, the combination of
sorafenib and HDACi was found to have synergistic inhibition, which correlated with the
induction of an ER stress response. In this phase I study, we evaluated the combination of
LBH589 and sorafenib in previously treated patients with RCC (9pts), soft tissue sarcomas (1pt),
and non-squamous-non small-cell lung cancers (6pts). The trial was designed to determine the
safety profile and maximum tolerated dose of LBH589 and sorafenib when administered
concurrently.
Methods: Patients were dosed with either i.v. (Days 1,8, and 15) or oral LBH 589 (three times
per week, continuously) every twenty eight days in combination with standard daily dose
sorafenib (400 mg bid). The dose escalation was based on a “3+3” algorithmic design.
Results: Sixteen patients, median age 57 years, have been treated. Dose limiting toxicities were
observed with grade 4 thrombocytopenia in two patients at the oral dose of 25 mg. There were no
other grade 4 events. Grade 3 events included fatigue (2 pts), hypophosphatemia (2 pts),
hypertension (1 pts), anemia (1 pt), rash (1 pt) and hand-foot erythroderma (1 pt). Common
toxicities for the combination were fatigue (81%), weight loss (62%), loss of appetite (56%),
diarrhea (56%), rash (50%), thrombocytopenia (31%), and hand-foot erythroderma (25%).
There was 1 partial response in a patient with lung cancer (31 weeks). Stable disease was noted
in seven patients with RCC (78+, 48, 47, 31, 21, 17, and 10+ weeks). Seven patients had
progressive disease.
Conclusions: The administration of oral LBH589 at a dose of 20 mg appears to be well
tolerated. Prolonged stable disease was observed in patients previously treated with sorafenib
alone, sunitinib and axitinib.
Clinical Fellow
Poster #59
OUTCOMES OF PATIENTS WITH END STAGE LIVER DISEASE AND ACUTE
KIDNEY INJURY REQUIRING DIALYSIS AT DISCHARGE
Clark, Stephen D., David G. Koch, Roberto Pisoni, Ruth C. Campbell
Department of Medicine, Divisions of Nephrology and Gastroenterology
Medical University of South Carolina, Charleston, SC
Acute Kidney Injury (AKI) is a common complication in patients with End Stage Liver
Disease (ESLD). There is little data on the survival of ESLD patients with prolonged AKI who
require dialysis after discharge. To determine the overall survival and potential for successful
liver transplantation (LT) in this population, we retrospectively reviewed outcomes for adult (age
> 18 yrs) ESLD patients with AKI who required dialysis at discharge at our institution over the
past five years.
Using ICD-9 codes and chart review, we identified patients with ESLD who developed AKI
who were dialysis dependent at discharge. Patients who received a LT during the index
hospitalization or who were on dialysis prior to the index admission were excluded. Twenty-one
patients met the criteria for analysis. The median age was 54 (29-71) years. Sixty-two percent
were male and 81% were Caucasian. The most common causes of ESLD were alcoholic
cirrhosis (43%) and Hepatitis C (19%). The most common causes of AKI were hepatorenal
syndrome (48%) and acute tubular necrosis (29%). Two patients were lost to follow-up and
were not able to be included in the outcomes analysis. One patient regained renal function and
stopped dialysis. Thirteen patients (68%) died with a median survival time of 45 (7-110) days.
Seven patients were listed for LT either prior to or after discharge and 4/7 were transplanted (one
liver and three liver-kidney) with a median time to transplant of 63 (30-210) days. Two patients
died on the waiting list and one is still alive undergoing dialysis.
In conclusion, dialysis for patients with ESLD and AKI after discharge may provide a bridge to
LT. However, without LT, the outcome for these patients is very poor due to high mortality.
Primary Author: Stephen Clark, MD
Affiliation: Fellow, Division of Nephrology
E-mail: [email protected]
Clinical Fellow
Poster #60
Does Timing/Delay of ERCP Affect Outcomes in Patients with Cholangitis?
Craft M.D., Brandon, Fellow-Division of Gastroenterology/Hepatology
AUTHORS: Brandon M. Craft1 , Peter Cotton1, Rob Hawes1, Christopher Lawrence1, Mark
Payne1, Joseph Romagnuolo1
INSTITUTIONS (ALL): 1Department of Gastroenterology, Medical University of South
Carolina, Charleston, SC, United States.
Purpose: Cholangitis can be a life-threatening problem. However, many patients defervesce
quickly on antibiotics, are easily resuscitated, and appear to tolerate waiting for ERCP days later,
at the same or different/tertiary institution. Some institutions have a policy of urgent/same-day or
within-24h ERCP, while others are more conservative, esp. on weekends when routine support
may be absent, and in sicker patients allowing for complete resuscitation first. We tend towards
the latter, but few published data support one approach over another.
Methods: We retrospective reviewed patients admitted/transferred to our facility with
cholangitis, documented from a billing database, or with cholangitis as the indication/outcome of
an ERCP in the Endoworks database. We included patients with clinical cholangitis: fevers,
elevated white blood cell count, and evidence of biliary obstruction (biochemical/imaging). Our
focus was straightforward causes of cholangitis (common duct stone, occluded stent, or
extrahepatic stricture) more consistently helped with ERCP; we excluded surgically altered
anatomy, sclerosing cholangitis, and intrahepatic stones. Delay from time of presentation to
ERCP was stratified into 4 groups: 0d delay, 1-2d, 2-5 days, or > 5 days.
Results: 60 patients met inclusion criteria, with a mean age of 61, and 60% were male. 43% had
stones, and 28% had occluded stents. All patients were managed with IV fluid resuscitation and
antibiotics awaiting ERCP, with a spectrum of regimens. 31% were inpatient transfers, and 69%
presented after hours. The average time from presentation of symptoms to ERCP was 2.57 d
(range 0-17). 47 patients had fever, with 43 (81%) defervescing with antibiotics; 1 death
occurred (1%), 6 (11%) patients were managed via an intensive care unit. 2 (3.8%) ERCPs were
unsuccessful, and required PTC. 5 (9.4%) required repeat ERCP during their admission, and 4
(7%) adverse events occurred after ERCP, including 1 post-ERCP bleed, and 1 pneumonia.
In all the cohort groups, if the patients had organ failure pre-procedurally it was noted on
presentation, and no patient developed organ dysfunction while waiting on their procedure. Only
2 patients, one each from the earliest groups, developed organ failure post-procedurally.
There did not appear to be a significant difference regarding clinical outcomes including death
(only death was in early group from withdrawal of care for cancer patient), organ failure (12%
for earliest, 20% for latest groups; p=0.7), or length of hospital stay (5-6 days) in patients
undergoing ERCP for relief of obstruction at day 0, 1-2d, 2-5 days, or > 5 days
Conclusion: In patients with ascending cholangitis, there does not appear to be a striking
difference in outcomes between conservative management with antibiotics and intravenous fluids
pending a delayed, semi-elective inpatient ERCP, versus earlier/urgent ERCP. Review of a larger
cohort is ongoing
Clinical Fellow
Poster #61
Virologic Efficacy of Antiretroviral Regimens Containing Abacavir + Tenofovir
Deol, Dilraj; Church, L.W. Preston; Salgado, Cassandra D.
Division of Infectious Diseases, Department of Medicine.
BACKGROUND:
Abacavir (ABC)and tenofovir (TDF)are well tolerated and allow for once-daily dosing. Previous
studies of ABC+TDF+3TC as a once daily triple nucleoside regimen were stopped prematurely
because of high rates of virologic failure (VF). A number of reasons have been suggested to
explain this, with the strongest evidence pointing to a low genetic barrier to resistance, leading to
selection of drug resistance mutations. Consequently, some providers have been reluctant to
combine these agents. Inclusion of an additional active antiretroviral agent from another class
might be a successful strategy to achieve and maintain viral suppression (VS) in treatment
experienced patients (pts) while offering convenient once daily dosing.
METHODS:
Records were reviewed on 468 HIV infected pts seen at the Ralph H. Johnson VAMC between
2000 and 2010. Pts on regimens of concurrent ABC and TDF were identified. HIV viral load,
CD4 count, HIV genotype (if available) and medication refill history obtained throughout the
course of therapy were recorded. VF was defined as failure to achieve HIV RNA<50 copies/ml
or rebound in viral load defined by two consecutive measurements of >50 copies/ml.
Nonadherence was defined as a medication possession ratio <.9.
RESULTS:
37 pts were identified on regimens containing ABC+TDF and additional antiretrovirals not in the
NRTI class. 20 (54%) maintained VS (HIV RNA <50) for a median of 28 months (range 2-62).
17 (46%) pts experienced VF. 11 of these 17 pts never achieved full VS and 6 experienced viral
rebound after a median of 19.5 months. 13 patients failing therapy were identified as
nonadherent . Therapy was switched among 8 pts and 4 developed complete VS while the other
4 continued to have detectable virus attributed to failure to adhere to the new regimen as well.
10 genotypes post VF detected new K65R and new K70R in 1 and 2 pts, respectively.
CONCLUSIONS:
Despite advances in antiretroviral therapy, options for once daily regimens are limited,
particularly for pts that acquire the M184V mutation. Our observational study suggests that over
50% of pts assigned to a regimen of concurrent ABC and TDF achieved full VS when an active
agent from another class was utilized and adherence was maintained. Medication nonadherence
appeared to be the major reason for treatment failure
Affiliation: Fellow Infectious Diseases-PGY 5.
Type of Research Project: Clinical; Retrospective Observational Antiretroviral Therapy Study.
Email ID: [email protected]
Clinical Fellow
Poster #62
Prevalence and Causes of Unexpandable Lung Over a Ten Year Period
DiVietro, Matthew, Huggins JT, Doelken P, Gurung P, Kaiser L, Sahn SA, Medical University
of South Carolina, Charleston
Introduction: The development of an unexpandable lung is attributed to either visceral pleural
restriction, chronic atelectasis, or endobronchial disease. Visceral pleural restriction due to active
inflammation/infection or malignancy is defined as lung entrapment. Trapped lung is defined as
visceral pleural restriction with the development of a fibrous pleural membrane in the absence of
active inflammation/infection or malignancy. The diagnosis of an unexpandable lung is made by
elevated pleural space elastance using manometry during thoracentesis.
Methods: We identified 113 (39%) patients with unexpandable lung from a consecutive series of
291 patients with pleural effusion undergoing therapeutic thoracentesis with manometry from
2002 to 2011 at the Medical University of South Carolina. Clinical history, pleural manometry,
and pleural fluid analysis were reviewed.
Results:
Trapped Lung n=60
Post Cardiac Surgery
15 (25.0%)
Resolved Parapneumonic
12 (20.0%)
Repeated Thoracentesis
11 (18.3%)
Uremic Pleuritis
7 (11.6%)
Unknown
7 (11.6%)
Radiation Fibrosis
6 (10.0%)
Amyloidosis
1 (1.6%)
Hemothorax
1 (1.6%)
Lung Entrapment n=50
Malignant
21 (42%)
Parapneumonic
12 (24%)
Paramalignant
9 (18%)
Hemothorax
2 (4%)
Tuberculosis
1 (2%)
Idiopathic Fibrosing Pleuritis 1 (2%)
Rheumatoid Pleurisy
1 (2%)
Post Cardiac Surgery
1 (2%)
Prolonged Chest Tube
1 (2%)
Unknown
1 (2%)
* 3 additional cases attributed to chronic atelectasis
Clinical Implications The presence of an unexpandable lung defined by abnormal pleural space
elastance is a common finding in patients presenting with pleural effusions. Most common cause
trapped lung related to prior cardiac surgery, followed by remote parapneumonic, and then
multiple thoracentesis. Greater than 60% of cases of lung entrapment are directly or indirectly
related to underlying cancer.
Clinical Fellow
Poster #63
CYSTATIN C BASED EQUATIONS AS MARKERS OF RENAL FUNCTION IN
AFRICAN AMERICAN LIVING KIDNEY DONOR
Sunil Kumar Jain1, Amy H Wahlquist1, Paul J Nietert1, John M Arthur1, Milos N Budisavljevic1
ABSTRACT BODY:
Purpose of Study: There are no data on serum creatinine (sCr) or Cystatin C (CysC) based
equations that estimate glomerular filtration rate (GFR) in African American (AA) kidney donors.
Since AA have an increased incidence of diabetes and hypertension, these donors may be at
increased risk of kidney disease. Better methods are needed to follow renal function in these
kidney donors over time.
Our goals were to determine in AA kidney donors whether CysC is a better estimator of GFR than
sCr and to determine which estimated GFR (eGFR) equation performs the best.
Methods Used: Data were obtained from 33 AA who donated a kidney 5-21 years ago. GFR was
measured (mGFR) by 125 I Iothalamate clearance. CysC was measured by particle enhanced
turbidimetric assay. sCr was measured by enzymatic colorimetric assay calibrated to an isotope
dilution mass spectrometry traceable method. Equations used for eGFR are listed in Table 1.
Pearson correlation coefficients were calculated to determine which of the equation most highly
correlates with mGFR.
Summary of Results: The mean mGFR was 76.18 ml/min/1.73 m2. Pearson correlations between
mGFR and eGFR from CysC and sCr based equations ranged from 0.51 - 0.81 (Table 1), all were
statistically significant (p<0.01). Correlations were higher for the equations that used CysC
compared to those that used sCr. Highest correlation was seen in CKD epi equation using both sCr
and CysC.
Conclusions: The use of the CKD epi estimating equation for GFR which uses both sCr and CysC
provides an best correlation with mGFR and can be used to estimate the changes in renal function
in AA kidney donors.
Variables
GFR ml/min (mean)
SD
Pearson Correlation p value
mGFR
76.18
13.11
CysC Based eGFR, CKD unadjusted
77.36
17.54
0.7365
<0.0001
CysC Based eGFR, CKD adjusted
78.65
16.79
0.7851
<0.0001
Creatinine based eGFR, MDRD2
84.84
15.95
0.6683
<0.0001
Creatinine based eGFR, AASK
87.73
16.09
0.6754
<0.0001
Creatinine based eGFR, CG
107.87
35.21
0.5084
0.0025
Creatinine based eGFR, Nankivell
123.06
15.05
0.5756
0.0005
CysC & Creatinine based eGFR, CKD Epi
80.87
15.66
0.8067
<0.0001
Clinical Fellow
Poster #64
The Peroxidase Peroxiredoxin1 (Prdx1) promotes DNA double strand
through Rad51
Jeter, M.D., Ashley A.
Hematology/Oncology Fellow
Medical University of South Carolina
Many in vitro studies have supported the hypothesis that reactive oxygen species (ROS),
such as H2O2, play a role in carcinogenesis by inducing DNA damage, lipid peroxidation,
and protein structural and functional modifications. Ionizing radiation (IR) damages
DNA mainly through ROS generated by the decomposition of water to its elements and
H2O2. H2O2 is an important regulator of cell signaling through oxidation of low pKa
catalytic cysteines in protein tyrosine phosphatases. Mice lacking Prdx1 die prematurely
from cancer and hemolytic anemia and Prdx1-deficient cells have higher amounts of
H2O2, IR-induced double strand breaks (DSBs) and reduced DNA repair activity. Here
we demonstrate for the first time that Prdx1 promotes DNA repair dually by regulating
Rad51 indirectly through Akt/Chk1 signaling and directly through protecting Rad51 from
oxidation-induced inactivation. When compared to Prdx1 wild type cells, IR induces Akt
activity and cytoplasmic retention of Chk1 to a higher extent in Prdx1 null cells, which in
turn leads to a reduction of nuclear Brca2 and Rad51 loci formation and reduced DNA
repair. Furthermore, Prdx1 binds directly to Rad51 protecting it from oxidation-induced
inactivation and promoting its DNA repair activity. Using alkylation methods, we
identified a Rad51 cysteine residues prone to oxidation and crucial for its activity. This
cysteine when mutated to serine decreases Rad51 activity and sensitizes cells to PARP
inhibition. Taken together, we provide the first mechanistic evidence that IR-induced
ROS cause DNA damage by inhibiting its repair enzymes. At the same time we provide
exciting novel evidence that Prdx1 plays an essential role in DNA repair.
Clinical Fellow
Poster #65
URINARY BIOMARKERS IN PREDICTING PATEINT OUTCOME AND RENAL
RECOVERY IN EARLY ACUTE KIDNEY INJURY
Karakala, Nithin1, John M Arthur1, Nishant Bhensdadia1
1
Nephrology, Medical University of South Carolina, Charleston, SC, United States.
ABSTRACT BODY:
Purpose of Study: Acute Kidney Injury (AKI) is commonly seen in critically ill patients and is
associated with increased mortality. Elevation of Cr, and decreased urine output cannot predict
patient outcome and renal recovery in medical intensive care unit (MICU) patients early in AKI.
We studied urine biomarkers concentrations for predicting renal recovery and outcome in ICU
patients.
Methods Used: Urine samples were collected from any patient who had AKI; Cr >0.3 mg/dl
from baseline with in the first 24 hours of the initial diagnosis of AKI. Urine biomarker
concentrations were measured using ELISA assays.
Summary of Results: 31 patients were included in this study, 6 needed CRRT, 12 died in the
hospital and 14 had renal recovery or survived without needing CRRT. The mean urine NGAL
concentration in patients who had a combined outcome of CRRT and death in the hospital was
835±146 ng/dl compared to 119±49ng/dl in patient who had renal recovery or did not need renal
replacement therapy (p<0.001). A NGAL value of ≥282.4 ng/ml had a sensitivity 72.2%,
specificity 92%; AUC 0.801 for predicating CRRT or mortality in these patients. Other urine
biomarkers (cystatin C, HGF and IL18) concentrations did not correlate with the clinical
outcomes.
Conclusions: Urine NGAL concentration appears to be very useful in predicting outcomes in
ICU patients on the day of initial diagnosis of AKI.
Clinical Fellow
Poster #66
Progression of Pleural Fluid Acidosis and Inflammation in Acute vs. Chronic Hemothorax
Kummerfeldt, Carlos1, DiVietro M1, Nestor J1, Huggins JT2 , Sahn SA2
1
Pulmonary Fellows and 2 Faculty, Department of Medicine, Division of Pulmonary and Critical Care
Medicine, Medical University of South Carolina
Introduction: Hemothorax is defined as pleural fluid/serum hematocrit (HCT) ratio > 50%. The pleural
fluid findings in acute hemothorax are clearly defined in the literature, but findings in chronic hemothorax
are not as well established.
Methods: We identified 6 cases of hemothorax by clinical history, radiographic imaging and pleural fluid
analysis from a database of 1133 cases undergoing thoracentesis from 2002 to 2010 at the Medical
University of South Carolina.
Results: Table. Six cases of hemothorax.
The protein is given as g/dL with the pleural fluid to serum ratio in parenthesis; LDH is lactate
dehydrogenase given as IU/L, RBC is red blood cell count given as cells/mm3, P HCT is the pleural fluid
hematocrit in percentage, S HCT is the serum hematocrit in percentage, and ANC is absolute neutrophil
count given as cells/mm3. Microbiology and pathology was negative in all cases.
Clinical Implications: The development of inflammation correlates to the duration of blood in the pleural
space. In chronic hemothorax (greater than one week), the pleural fluid analysis resembles a sterile
empyema showing a low pH, elevated lactate dehydrogenase, and significantly elevated absolute
neutrophil counts. We hypothesize that the following mechanisms may explain these pleural fluid
findings in a chronic hemothorax. First, impaired clearance of carbon dioxide and lactate due to
development of a fibrinous membrane and secondly a diminished erythrocyte Duffy antigen in old, lysed
red blood cells both lead to impaired chemokine scavenging allowing for uncontrolled neutrophil
recruitment.
Research: clinical
Clinical Fellow
Poster #67
De Novo Establishment of a Transradial Percutaneous Coronary Intervention Training
Program for Cardiology Fellows: Safety and Efficacy
Leonardi, MD, Robert A.*, Jacob C. Townsend, MD, David D. Bonnema, MD, Thomas M.
Todoran, MD, MSc, Christopher D. Nielsen, MD, Eric R. Powers, MD, and Daniel H. Steinberg,
MD
Medical University of South Carolina Department of Medicine, Division of Cardiology
*Fellow in Cardiovascular Medicine (email: [email protected])
Background
Radial arterial access for percutaneous coronary intervention (PCI) offers advantages over
femoral arterial access, but cardiology fellowship training programs in the United States continue
to produce cardiologists with little or no transradial (TR) training. The safety and effectiveness
with which TR training programs can be established in academic centers is not established.
Methods
In July of 2009, a programmatic preference for TR catheterization was established in a training
program for both general and interventional cardiology fellows. PCI-related data for the 20082009 (Y1) and 2009-2010 (Y2) academic years were prospectively collected and retrospectively
analyzed. Baseline patient characteristics, procedural characteristics, and outcomes were
compared across years (Y2 vs. Y1) and arterial access sites (radial vs. femoral).
Results
Of 1366 PCIs performed over both years, 193 of 673 (28.7%) in Y2 vs. 1 of 693 (0.1%) in Y1
were performed transradially. The TR PCIs in Y2 were performed by 13 different cardiology
fellows and 9 different attending cardiologists, none of whom were routinely performing
transradial PCI previously. Patients treated in Y2 vs. Y1 were more likely to have a history of
diabetes (43 vs. 37%, p=0.04) or hypertension (92 vs. 84%, p<0.001). Patients undergoing TR
vs. transfemoral (TF) PCI were heavier (91.1 vs. 86.7 kg, p=0.01) and had lower serum
creatinine levels (1.1 vs. 1.4 mg/dL, p=0.01). Patients treated in Y2 vs. Y1 and patients treated
with TR vs. TF PCI were less likely to be treated with glycoprotein 2b/3a inhibitors (2 vs. 15%
in Y2 vs. Y1, p<0.001; 0.5 vs. 10% in TR vs. TF, p=0.002), required more fluoroscopy time
(18.6 vs. 17.2 m in Y2 vs. Y1, p=0.05; 20.4 vs. 17.5 m in TR vs. TF, p=0.01) but similar contrast
volumes, and were similar in terms of procedural duration, length of stay, and rates of procedural
failure and pre-discharge mortality. Combined bleeding and vascular complication rates were
lower in Y2 vs. Y1 (0.7 vs. 2.0%, p=0.05).
Conclusions
A TR PCI training program was safely and effectively established de novo at an academic
medical center, significantly reducing the combined incidence of PCI-related bleeding and
vascular complications in its first year. Given the advantages of radial arterial access for
coronary arteriography and PCI, formal TR training should be an integral part of every
cardiology fellowship training program.
Clinical Fellow
Poster #68
Biopsies of the nodules GAVE us the diagnosis
Marsteller, William 1, MD, David Lewin2, MD, Adrian Reuben1, MBBS
1
Department of Medicine, Division of Gastroenterology and Hepatology
2
Department of Pathology
Purpose: To describe an underappreciated endoscopic appearance of a common disorder, gastric
antral vascular ectasia (GAVE).
Case Presentations: We describe the cases of 3 patients who have a nodular form of GAVE.
Our first patient is a 51 year old man with a history of cirrhosis due to non-alcoholic
steatohepatitis who underwent evaluation with esophagogastroduodenoscopy (EGD) for iron
deficiency anemia and was found to have multiple medium-sized antral nodules and mild linear
antral erythema. The nodules were biopsied and the histopathology showed GAVE. Our second
patient is a 61 year old woman with a history of cirrhosis due to non-alcoholic steatohepatitis
who underwent evaluation with EGD for esophageal variceal surveillance and was found to have
small esophageal varices, portal hypertensive gastropathy, and many antral nodules. The
nodules were biopsied and the pathology showed GAVE. Of interest, she did not have any
endoscopic evidence of GAVE other than the antral nodules. Our third patient is a 58 year old
man with alcoholic cirrhosis who underwent EGD for iron-deficiency anemia and melena that
showed antral nodules and punctate antral erythema in crops. Biopsies of the nodules showed
GAVE.
Discussion: GAVE is a well-established cause of iron deficiency anemia and rarely of overt
upper GI bleeding. It is normally idiopathic, but can be associated with cirrhosis. It is defined
histopathologically by vascular ectasias, spindle cell proliferation, thrombosis in venules and
fibrohyalinosis. There are 2 classic endoscopic appearances of GAVE. The first is longitudinal
red stripes in the antrum radiating proximally from the pylorus, which has been termed the
“watermelon stomach”. The second is a punctate form that lacks the red stripes and is the more
common form seen in association with cirrhosis. Nodular GAVE is a third phenotype of this
disorder which is far less well-known and could easily be dismissed as a fundic gland or
hyperplastic polyp, based only on the endoscopic appearance. Thus, taking biopsies of antral
nodules is required to make the diagnosis.
Conclusion: Nodular GAVE is a third endoscopic variant of GAVE, which can only reliably be
differentiated from other gastric nodules/polyps through biopsy.
Corresponding author: William Marsteller, GI fellow ([email protected])
Type of project: Clinical
Clinical Fellow
Poster #69
The Prevalence of Lung Entrapment in Malignant Pleural Effusions: Does the pleural fluid
analysis and chest radiograph predict the presence of abnormal pleural space elastance?
Nestor MD, Jennings (fellow), John T. Huggins, MD (faculty), Steven Sahn, MD (faculty),
Matthew DiVietro, MD (fellow), Carlos Kummerfeldt, MD (fellow)
Pulmonary and Critical Care Medicine
Abstract:
Background: The frequency of abnormal pleural space elastance (PEL) in malignant pleural
effusions (MPE) is unknown. Pleurodesis outcomes have been correlated to increase pleural
space elastance (PEL) with the first 500 mL of fluid removed in one prior study.
Methods and Measurements: We reviewed pleural manometry, pre- and post-procedural CXRs
and identified 138 consecutive patients diagnosed with a MPE at the Medical University of
South Carolina between January 2001 and January 2010. Of the 138 patients, 56 underwent
therapeutic thoracentesis with pleural manometry, 59 underwent therapeutic thoracentesis
without pleural manometry, and 23 underwent a diagnostic thoracentesis only. Pleural
manometry was performed using both an over-damped, water manometer and an electronic
acquisition system.
Results: Abnormal PEL was identified in 33 of 56 (58.9%) patients. Twenty-five of 34 (73.5%)
patients with PEL demonstrated a biphasic P/V curve, while 8 of 34 (26%) demonstrated a
monophasic P/V curve with increase PEL. We found no statistical significant differences with
regards to age, race, gender, tumor origin, tumor cell type, volume of pleural fluid drained, and
pre- and post-procedural CXRs between the manometry and non-manometry groups. Similarly,
no statistical significant difference was noted on the pre- and post-procedural CXRs between
those with normal versus abnormal PEL. Volume loss or a post-procedural pneumothorax was
uncommon in those with abnormal PEL.
Conclusions: Abnormalities of lung expansion are more common than previously appreciated.
This finding may have clinical implications by providing a physiologic explanation for the
variability in pleurodesis success rates in MPE.
Type of Research: Clinical
E-mail Address of Corresponding Author: [email protected]
Clinical Fellow
Poster #70
Combination of Bortezomib, Cyclophosphamide and Dexamethasone in Patients
with Newly Dignosed Multiple Myeloma and Impaired Renal Function: Fast
Improvement in Creatinine Clearance and Outcome Similar to Patients with
Preserved Renal Function
Ortiz-Cruz, MD, Karen,*1 Jonathan Abbas, MD1 Charles Butler, MD1Yubin Kang, MD1 Robert
K. Stuart, MD1 Luciano J. Costa, MD PhD1
1
Division of Hematology and Oncology, Department of Medicine, MUSC
* Fellow, Division of Hematology and Oncology, presenting author.
Background: Near a third of patients with multiple myeloma present with renal impairment (RI).
These patients have worse outcome than their counterparts with preserved renal function (PRF).
We hypothesized that prompt treatment with a combination of bortezomib, cyclophosphamide
and dexamethasone without dose adjustment for renal dysfunction will lead to fast disease
response and reversal of renal dysfunction in RI patients and to outcomes similar to PRF patients.
Methods: Retrospective analysis of consecutive patients with newly diagnosed symptomatic MM
treated with induction therapy consisting of bortezomib 1.3 mg/m2 intravenously on days
1,4,8,11,22,25,29 and 32 , cyclophosphamide 300 mg/m2 intravenously on days 1,8, 22 and 29
and dexamethasone 40 mg PO on days 1,8,15,22,29 and 35 of each 6-week cycle (VCD).
Treatment was started promptly once diagnosis was completed and not adjusted or modified for
renal function or age. Patients were treated for up to 4 cycles followed, in eligible patients, by
autologous hematopoietic stem cell transplantation with melphalan 200mg/m2. Patients reaching
day 100 post transplantation or not eligible for transplantation received lenalidomide
maintenance. Creatinine clearance (CrCl) was calculated at the diagnosis (once dehydration and
hypercalcemia were corrected) and frequently throughout therapy utilizing the Cockcroft-Gault
equation. None of the patients underwent plasma exchange for treatment of cast nephropathy.
Results: Twenty-eight patients have received at least 2 cycles of VCD and are evaluable for
response. Eleven patients had RI defined as CrCl<50 ml/min (median 22 ml/h, range 8-44
ml/min) and 17 patients had PRF defined as GFR ≥ 50ml/min (median 104, range 50.2->120).
Median age was 67 years in RI (range 48-71) and 60 years in PRF (range 30-80). Patients with RI
were more likely to have light chain disease (45.4% vs. 5.8%) and international scoring system
stage 3 (90.9% vs. 11.7%). High-risk chromosome abnormalities were detected by florescence in
situ hybridization in 4/9 patients with RI and 6/15 patients with PRF. After a median follow up of
25 weeks, 100% of patients with RI and 88.2% of patients with PRF have reached at least a
partial response (PR, P=0.24). Very good partial response (VGPR) has been reached in 72.7%
and 35.3% (P=0.053) and complete responses (CR) in 36.3% and 16.6% (P=0.3) of patients in RI
and PRF respectively. Responses were fast with median time to response (≥PR) of 6.4 weeks in
RI and 8 weeks in PRF (Figure, panel a). All but one patient in RI had improvement in CrCl
(Figure, panel b) with median CrCl for the group increasing from 22 to 55 ml/h. Grade 3 and 4
cytopenias were uncommon during induction but dose reductions of bortezomib were frequent
due mostly to neuropathy. Four patients had at least one episode of hospitalization during the
induction phase (2 with RI and 2 with PRF) and 2 patients (both with PRF) have discontinued
therapy due to toxicity. There have been no progressions in either arm, although the follow up is
short.
Conclusion: Modern, triplet induction therapy with VCD is feasible in newly diagnosed MM
patients with RI, leads to rapid reversal of renal dysfunction and response rates comparable to
patients with PRF. Longer follow up is necessary to determine if the negative impact of RI in
survival can be overcome with this approach.
Clinical Fellow
Poster #71
Distal Baseline Impedance (DBI) Is A Specific Diagnostic Marker For Achalasia
Person MD, Erik, Erick Singh MD, & Donald Castell MD
MUSC Internal Medicine / Gastroenterology
Purpose: During esopheageal manometry, reduced distal baseline impedance (DBI) is
believed to indicate fluid retention in the distal esophagus. Patients with achalasia are
well known often to have a very low DBI due to inability to clear esophageal contents.
The sensitivity and specificity of this marker has not been evaluated. This study tests the
hypothesis that low DBI on impedance-manometry testing can accurately identify
achalasia as a sole marker of disease.
Methods: A retrospective analysis of 189 individuals who underwent esophageal function
testing was performed and analyzed for DBI values using Sandhill BioView Analysis
Software. These patients were divided into four groups; 50 healthy volunteers, 50 with a
diagnosis of achalasia, 50 consecutive patients with various chief complaints, and 50
patients with a chief complaint of dysphagia. The software “MedCalc” was utilized to
calculate three receiver operating characteristic (ROC) curves to quantify the sensitivity
and specificity of a range of DBI values in predicting the diagnosis of achalasia. In
addition, the mean, median, mode, and confidence intervals of each data set were
calculated.
Results: The achalasia vs. healthy volunteers ROC curve demonstrated that DBI <=949
ohms carries 82% sensitivity and 90% specificity for the diagnosis of achalasia. The
achalasia vs. consecutive patients group demonstrated that DBI <=718 ohms carries 72%
sensitivity and 88% specificity for achalasia. DBI <=561 ohms carries a 60% sensitivity
but 96% specificity for achalasia. The achalasia vs. dysphagia patients curve
demonstrated that DBI <=561 ohms carries 59% sensitivity but 90% specificity for
achalasia. DBI means were significantly lower in achalasia group as compared to other 3
groups.
Conclusion: Reduced distal baseline impedance has low sensitivity but high specificity
as a single measurement to predict achalasia. The high specificity of reduced DBI may be
useful clinically to help characterize achalasia in patients with uncertain diagnoses.
Type of Research Project: Clinical retrospective analysis
Corresponding author: Erik Person, MUSC Internal Medicine Resident
Clinical Fellow
Poster #72
Lessons Learned from High Resolution Manometry - Inter-Observer Variability in
Esophageal Body Measurements Amongst New Physician Users
Rife, Christopher, Erick Singh, Steven Clayton, Peter Naas, Paul Nietert, & Donald Castell
BACKGROUND: Esophageal high resolution manometry (HRM) has been heralded as an
advance due to the ability to easily observe esophageal motility via the pressure topography plot.
The topographic plot allows visual distinction between areas of rapidly conducted contractions
and compartmentalized intraesophageal pressurization. Little is known about the inter-observer
variability which physicians new to this technology may encounter.
AIM: To evaluate inter-observer variability amongst new physician users with background
training in esophageal motility on measures of esophageal body function via HRM.
METHODS: Three resident or fellow level physicians each interpreted 10 liquid swallows of 20
esophageal HRM studies using the BioVIEW Analysis Suite (Sandhill Scientific, Inc.). Studies
evaluated were from patients referred for evaluation of dysphagia but found to have normal
esophageal manometry. Prior to study onset, the physicians received an orientation session
structured by Sandhill Scientific, Inc, and also reviewed several recent publications regarding
HRM. Each physician independently recorded pressurization front velocity (PFV) and distal
contractile integral (DCI) for a total of 200 liquid swallows.
STATISTICS: Inter-observer agreements for PFV and DCI were assessed by intraclass
correlation (ICC) values. Linear correlations between measurements by two readers were
assessed using linear regression modeling techniques. RESULTS - PFV and DCI values of up to
200 data points (10 liquid swallows of 20 patients) were analyzed for the three physicians. Three
readers results for both PFV and DCI showed good to excellent correlation between readers, and
was strongest for measures of DCI (ICC=0.99). PFV results showed good correlation (ICC=0.88),
but with wider variability. Further correlation was performed with two readers who evaluated all
200 swallows to apply additional statistical measures. Comparison between readers 1 and 2
revealed excellent correlation with respect to DCI (r=0.95, p<0.001) and good correlation with
PFV (r=0.61, p<0.001).
CONCLUSIONS: HRM is an exciting new tool to assess esophageal body contractility. With an
initial structured orientation session, good to excellent agreement for PFV and DCI measurements
can be obtained from new physician users. PFV measures exhibit greater inter-observer
variability possibly due to the phenomenon of intraesophageal pressurization.
Multiple Observer Esophageal Body Contractile Measures and Correlation
( ) denotes 95% confidence interval
Clinical Fellow
Poster #73
Under-Reporting of Cardiopulmonary Incidents and Events During Endoscopy
Utilizing Anesthesia Administered Mixed-Propofol Sedation
Roberts MD, Jason, Peter Cotton MD, Robert Hawes MD,
Christopher Lawrence MD, Mark Payne MD, Joseph Romagnuolo MD
Division of Gastroenterology and Hepatology
Background: Incidents and adverse events (AE) during endoscopy have been recently defined in
an effort to standardize their reporting and allow for comparisons between studies. Endoscopic
retrograde cholangiopancreatography (ERCP) is known to have the highest rate of overall
incidents and AE among endoscopic procedures. Cardiopulmonary events are among the lowest
reported AEs, but are among the highest cause of mortality; cardiopulmonary “incidents” (no
clear clinically significant outcome or new intervention) are even less reliably reported.
Endoscopists may be less aware of periprocedure changes to cardiopulmonary parameters when
anesthesia administers/monitors sedation and not report them as incidents or AE, due to the
anesthesia’s comfort level with vasopressors, IV antihypertensives, etc.
AIM: To determine the rate of significant hemodynamic changes requiring intervention by the
anesthesiologist but are not reported as cardiopulmonary incidents or AE by the endoscopist.
Methods: 125 consecutive patients underwent ERCP from November-December 2010. At our
center, all ERCP sedation is administered by an anesthesiologist using mixed-propofol. Patients
are generally nonintubated and are positioned prone. Endoscopy reports and anesthesia sedation
notes were reviewed to collect patient demographics, American Society of Anesthesiologists
score (ASA), dosage of propofol, fentanyl, and midazolam, as well as the use of vasopressors or
intravenous antihypertensives. Planned intubation was distinguished from cases that converted
to intubation.
Results: 101 patient charts had complete data and were included in analysis. The mean patient
age was 52 (14-91) and 64 were female; 5% were ASA-1, 49% ASA-2, 45% ASA-3, and 2%
ASA-4. There were 14 cases with planned intubation (2 ASA-2, 10 ASA-3, 2 ASA-4) and 4
required conversion to intubation for hypoxia (3 ASA-2, 1 ASA-3). The mean anesthetic doses
used for propofol, fentanyl, and midazolam were 79.0mg (0-400mg), 91.6mcg (0-300mcg), and
2.2mg (0-5mg) respectively. Vasopressors (phenylephrine) were used in 17 cases (6 ASA1-2 vs
11 ASA 3-4, p=0.08) with a mean dose of 432.9mcg (80-1280mcg). None of the hemodynamic
changes requiring vasopressors resulted in AEs however 30 day data are still being collected.
Pressor use was not recorded in any endoscopy reports.
Conclusion: The low rate of cardiopulmonary incidents and AE reported in the literature may be
the ‘tip of the iceburg’ in anesthesia-administered cases, due to under-reporting of vasopressor
use for hemodynamic changes occurring during endoscopy. Although these would be classified
as incidents, delayed AE occurring within 30 days are still being collected; pressor use without
an anesthesiology team sedating would likely have been coded differently and affects
comparative safety analyses.
Clinical Fellow
Poster #74
Complications of Atrial Fibrillation Ablation in Patients Anticoagulated with Dabigatran
Compared to Warfarin
Rowley, Christopher P., Natalie S. Bradford, Michael L. Bernard, Peter C. Netzler, Darren S.
Sidney, William W. Brabham, Frank Cuoco, J. Lacy Sturdivant, Robert B. Leman, Michael R.
Gold, J. Marcus Wharton
Division of Cardiology, Department of Medicine. Medical University of South Carolina
Introduction: In order to decrease the risk of thromboembolic complications, patients (pts) with
atrial fibrillation (AF) who are undergoing ablation are anticoagulated with either warfarin or
more recently dabigatran. However, tests to monitor compliance with dabigatran are not readily
available as they are with warfarin. The present study evaluates efficacy and safety of dabigatran
compared to warfarin prior to AF ablation.
Methods: We retrospectively evaluated 282 pts undergoing AF ablation who were
anticoagulated with either dabigatran (113 pts) or warfarin with enoxaparin bridging (169 pts)
before and after AF ablation. Efficacy endpoints were stroke, TIA, or peripheral embolus at the
time of or within 30 days of ablation. Safety endpoints were major life threatening vascular
complications (e.g. RP bleed) and non-life threatening vascular or bleeding complications (e.g.
AV fistula, pseudoaneurysm, bleeding requiring transfusion of blood products, and hematoma
requiring further diagnostic evaluation or intervention at the time of or within 30 days of
ablation.
Results: The mean age (63 ± 10 years old) and CHADS2 score (1.3 ± 1) were similar between
groups. Dabigatran pts received their last dose the day before AF ablation and typically restarted
the day following ablation. Warfarin pts received enoxaparin the day before AF ablation and
typically resumed warfarin the day after with bridging enoxaparin until INR >1.8. The primary
efficacy endpoint occurred in 2 (1.7%) dabigatran and 2 (1.2%) warfarin patients (RR 1.49, 95%
CI 0.21 to 10.41, p=0.69). There was one stroke and one TIA in the dabigatran group and one
stroke and one PE in the warfarin group. There was 1 major life threatening vascular
complication (RP bleed) in the warfarin group and none in the dabigatran group. Non-life
threatening vascular complications occurred in 5 (4.4%) dabigatran and 33 (19.5%) warfarin
patients (RR 0.26, 95% CI 0.10 to 0.65, p=0.004).
Conclusion: Pts undergoing AF ablation who are anticoagulated with dabigatran have
significantly fewer complications compared to patients receiving warfarin with enoxaparin
bridging without an increased risk of stroke. Thus dabigatran is the preferred anticoagulation
strategy prior to AF ablation.
Corresponding author: Christopher Rowley, MD., Fellow in cardiovascular disease
Email: [email protected]
Abstract Category: Clinical science
Clinical Fellow
Poster #75
Impact of Contrast-Induced Acute Kidney Injury on Progression to End-Stage Renal
Disease Among Subjects with Preexisting Advanced Chronic Kidney Disease
Salazar, M.D., Maria Nieva 1, Christopher D. Nielsen, M.D.2, Juan Carlos Q. Velez, M.D.3
Fellow, Division of Nephrology; 2Faculty, Division of Cardiology; 3Faculty, Division of
Nephrology
1
Growing evidence indicates that acute kidney injury (AKI) may cause new-onset end-stage renal
disease (ESRD). However, the impact of contrast-induced AKI (CI-AKI) on long-term renal
survival remains unknown. We hypothesized that CI-AKI is an underreported cause of
progression of chronic kidney disease (CKD) to ESRD or death, and that standard preventive
measures are not consistently implemented. Thus, we conducted a retrospective review of
patients who underwent contrast-enhanced cardiac catheterization over the last 2 years. Since the
risk of CI-AKI is proportional to the severity of preexisting CKD, we included subjects with
estimated glomerular filtration rate (eGFR) < 45ml/min pre-procedure. CI-AKI was defined as ≥
25% increase in sCr within 48-96 hours post-procedure. CKD Progression was defined as
decrease in eGFR ≥10ml/min within 3-12 months post-procedure. Of 98 subjects identified, 53
were excluded because of unavailable sCr after 48 hours post-procedure. The incidence of CIAKI was 24% (11/45). Among them, 2/11(18%) reached ESRD, 3/11 (27%) had CKD
Progression and 1/11 (9%) died. The composite endpoint of CKD Progression, ESRD or death,
after CI-AKI, was reached by 13.3% (6/45) of the subjects, occurring more often in those who
developed CI-AKI compared to those who did not developed CI-AKI [55% (6/11) vs. 9% (2/22);
p=0.0037] Among those with CKD stage 3B (eGFR 30-45ml/min), 6/22 (27%) developed CIAKI: none developed ESRD, 3/6 (50%) had CKD Progression and 1/6 (16%) died; whereas
among those with CKD stage 4 or lower (eGFR ≤ 30ml/min), 5/23 (21%) developed CI-AKI: 2/5
(40%) progressed to ESRD but none died. Isotonic volume expansion with saline and/or
bicarbonate was given to 64% (7/11) of the patients who developed CI-AKI. Moreover, such
intervention was only implemented in 40% (2/6) of those who reached the composite endpoint,
whereas 83% (5/6) of them received N-acetyl-cysteine, a drug with marginal benefit. Cognizant
of the limitations of our study, we conclude that CI-AKI may have an ominous long-term impact
in subjects with advanced CKD. There appears to be room for improvement on the systematic
implementation of preventive measures and post-procedural testing.
E-mail: [email protected]
Clinical Fellow Category
Clinical Fellow
Poster #76
Are Protocol Biopsies Useful for Predicting Renal Transplant Recipient Outcomes?
Shahira MD, Eram, Elizabeth Chua, MD M Aurora Posadas, MD, Beje Thomas, MD, M Francesca Egidi, MD.
Transplant Nephrology, Medical University of South Carolina, Charleston, South Carolina, United States.
Background: Data is conflicting regarding the utility of protocol biopsies (PB) to identify subclinical rejections and
prevent graft dysfunction. Our center began doing PB at 4-8 wks after kidney transplant (KTX). The aim of this
study was to analyze the predictive and clinical value of PB.
Methods: Cross-sectional analysis of KTX recipients who underwent PB from 2009-10. PB was read by
pathologists based on Banff criteria. Patients received ATG or anti-IL-2 receptor induction followed by FK, MMF,
and steroids. Treatment of PB was left to the discretion of the physician. Groups were divided based on PB: normal,
abnormal (ATN or arteriolar Hyalinosis AH), or borderline rejection. One PB showed mild acute rejection and was
included in the borderline group.
Results: 120 patients had PBs that were analyzed. Baseline demographics between the 3 groups were similar [table
1]. Of the 44 patients with abnormal biopsy, 22 had borderline rejection,17 of whom did not receive anti-rejection
treatment. None of these patients went on to develop acute rejection. 18% of the PBs demonstrated abnormal results
with ATN/AH. The serum creatinine (SCr) in this group were significantly higher early post-KTX (1 and 6 months),
but equilibrated long-term (12-24 months).
Table 1- Baseline Characteristics
Table 2 - FK and SCr Level
Conclusions: PB showed a relatively high rate of borderline rejection, supporting the usefulness of PB in identifying
and treating borderline rejection. However, we also showed that patients with borderline rejection did not go on to
have subsequent rejection and continued to have stable renal function. Some also showed ATN/AH, which
correlated with significantly higher SCr. Our data reveal that PBs may be useful in recognizing patients that would
benefit from modification of CNIs to prevent or minimize chronic toxicities.
Clinical Fellow
Poster #77
Natural History of Hepatocellular Cancer in Setting of Liver Transplantation at a
Single Transplant Institution and Evaluation of Pre-operative Investigation and
Post-Operative Surveillance for Recurrent Hepatocellular Cancer
Simpson, Heather, Adrian Reuben, David Lewin
Department of Internal Medicine - Division of Gastroenterology
Background: Hepatocellular cancer is the third leading cause of cancer related deaths in
the world. Liver transplantation has become a leading treatment for hepatocellular
cancer, although not every patient is a candidate for liver transplant. We reviewed a large
number of patients referred to the Medical University of South Carolina for liver
transplantation that were found to have hepatocellular cancer. This study evaluates the
natural history of hepatocelluar cancer by monitoring patient outcomes including the
following: survival, recurrent hepatocellular cancer, yield of hepatocellular cancer
surveillance studies post-transplant, and utility of diagnostic lab tests and imaging for
hepatocellular cancer in pre-transplanted patients.
Methods: We conducted a restrospective analysis of 162 patients referred to the Medical
University of South Carolina for liver transplantation prior to May 30, 2009. Patients
included in the study had to be at least one year out from their initial transplantation
evaluation. Data reviewed included laboratory tests, radiologic imaging, pathology
specimens, history from clinic notes, demographics of the patient population, and
etiology of liver disease. All patients were de-identified and information was placed into
a de-identifed database.
Results: 93 patients were known to have hepatocellular cancer at the initial transplant
evaluation based on confirmatory imaging or biopsies of the tumor, while 45 patients
were found to have hepatocellular cancer during the transplant evaluation process. In
addition, 24 patients were found to have hepatocellular cancer in their explanted liver
specimens that were previously not thought to have hepatocellular cancer during their
transplant evaluation.
Conclusion: Liver transplantation is an effective and novel treatment for patients with
hepatocellular cancer in patients with a limited number of tumors that are of a small size.
However, the preoperative evaluation does not always accurately identify the prevalence
of hepatocellular cancer in patients with cirrhosis. Extensive follow up labwork and
imaging in transplanted patients rarely reveals recurrent hepatocellular cancer.
Email: [email protected]
Clinical Fellow
Poster #78
Relevance of Renal glucosuria in proteinuric glomerular diseases
Talwar, Manish1; Nietert, Paul2, Self Sally3, Velez, Juan Carlos Q1
Institution: 1Division of Nephrology, Dept. of Medicine 2Division of Epidemiology and
Biostatistics, Dept. of Medicine. 3Department of Pathology
Dipstick glucosuria is occasionally observed in non-diabetic proteinuric glomerular
diseases, even in the absence of hyperglycemia. However, its frequency and potential
association with disease severity is unknown. We searched for pathology reports of adult
patients who underwent percutaneous kidney biopsy at MUSC between 1998 and 2011,
indicated for proteinuria. Accordingly, we included reports with a diagnosis of focal
segmental glomerulosclerosis, membranous glomerulopathy, minimal change disease,
membranous lupus nephritis, amyloidosis, light chain deposition disease and HIVassociated nephropathy, all proteinuric glomerulopathies. Since proliferative glomerular
diseases are typically nephritic in nature, they were not included in our study. Subjects
with diabetes or those taking tubulo-toxic medications were also excluded. Demographics
and laboratory values were collected, including serum creatinine, estimated glomerular
filtration rate (eGFR) and urine protein-to-creatinine ratio (UPCR). Glomerular and
tubulointerstitial chronicity indices were extracted from pathology reports. We identified
147 patients who met our selection criteria. Among them, 13 patients were found to have
renal glucosuria. Our analysis revealed that patients who presented with dipstick
glucosuria were characterized by a higher serum creatinine, lower eGFR and higher
UPCR at the time of the kidney biopsy, compared to those without glucosuria [3.93 +/3.48 vs. 1.83 +/- 1.72, p=0.0001; 28.69 +/- 18.08 vs. 65.51 +/- 38.41, p=0.0002; 9.17 +/5.09 vs 5.46 +/- 5.52 p= 0.010 respectively]. Histopathological scores were not
significantly different between groups. In addition, presence of glucosuria did not help
discriminate among diseases. Our study is limited by its retrospective nature. Quantitative
urine glucose is not routinely obtained; therefore, it was not available to us. We conclude
that renal glucosuria is a feature of more advanced forms of proteinuric glomerular
diseases as evidenced by its correlation with worse kidney function and heavier
proteinuria. We speculate that it may represent a marker of tubular damage or impairment
of glucose tubular handling.
Type of Project: Clinical Fellow
Corresponding author: Talwar, Manish ([email protected])
Clinical Fellow
Poster #79
Inhaled Tobramycin Timing Alters Intravenous Tobramycin Concentrations
Stenbit MD, PhD, Antine E. Wendy M. Bullington, PharmD, Julie L. Heh, Pharm D, and
Patrick A. Flume, MD
Department of Medicine, Division of Pulmonary and Critical Care
Department of Clinical Pharmacy Services
Aerosolized tobramycin inhalation solution (TIS) may be absorbed and result in measurable
serum levels. This could affect calculation of pharmacokinetic (PK) parameters and dosing if TIS
is used concurrently with intravenous (IV) tobramycin for treatment of a pulmonary exacerbation.
Computer PK modeling predicts that TIS given in the latter portion of the IV dosing interval
would result in increased tobramycin trough levels in some patients. We wanted to assess the
significance of timing of TIS on IV tobramycin trough levels in the clinical setting.
Adult CF patients infected with P aeruginosa admitted to the hospital for treatment of a
pulmonary exacerbation were eligible for the study. IV tobramycin was dosed every 12 hours
based on previous PK measures for a planned tobramycin trough <1mcg/ml. Tobramycin levels
were drawn approximately 2 and 9 hours after an IV dose. The following day, tobramycin levels
were again drawn at 2 and 9 hours, but TIS was given 5-9 hours after the IV dose.
Sixteen patients have participated thus far. All tolerated the IV tobramycin and TIS without any
adverse effects. Seven patients had a clinically significant change in the tobramycin trough level
and 3 of those patients had an increase in their trough level >2mcg/ml. Seven patients had a
doubling of their trough. Eight patients had a reduced elimination rate constant after TIS
administration, which may be misinterpreted by the medical team as a perceived decreased in
clearance of IV tobramycin. The creatinine remained stable throughout the treatment in all
patients.
Conclusion: Trough tobramycin levels were significantly influenced in some (44%) of CF
patients following aerosolized TIS when given in the latter part of the IV dosing interval,
consistent with significant absorption of inhaled drug in some patients. This study does not
address the efficacy or safety of TIS when given concomitantly with IV tobramycin. However,
these findings suggest that timing of the inhaled dose should be considered when interpreting PK
measures of IV drug dosing.
This project was supported by a generous grant from the Novartis Pharmaceuticals Corporation.
Clinical Junior Faculty
Poster #80
The Impact Of a Health Information Exchange on the Management of Patients in an
Urban Academic Emergency Department: An Observational Study and Cost-Benefit
Analysis
Carr, Christine, Krywko, DM, Saef, SH, Medical University of South Carolina, Charleston, SC
Abstract:
Background: Health Information Exchanges are systems designed to electronically move clinical
information among disparate health care information systems while preserving the integrity of the
information being exchanged. An HIE was recently made available to clinicians in the Emergency
Departments (EDs) of the four major hospitals in greater Charleston, SC. We conducted a pilot study to
evaluate the impact of this HIE on the management of ED patients at the academic medical center and
trauma center for the region.
Objectives: Characterize how access to an HIE modified the care of patients presenting to an urban
academic medical center and trauma center. Perform a cost-benefit analysis based on the data obtained.
Methods: The study site was the ED at an urban level I trauma and tertiary care center at a southeastern
academic medical center. The study design was prospective, observational using a voluntary, anonymous
survey administered to ED clinicians asking how access to an HIE influenced their decisions regarding
patient management. Survey items addressed whether information from the HIE avoided the use of
resources. Items used branching logic to ascertain the specific types of services being avoided including
laboratory and radiologic testing, consultations, prescription of medications, performance of procedures,
and arrangements for hospital admission. Additional items asked how the HIE affected the overall
quality of care and length-of-stay. The survey was automated using a survey construction tool (REDCap
Survey Software © 2010 Vanderbilt University) which also collated and summarized the results. A cost
analysis was performed using actual dollar values multiplied by the numbers and types of services
avoided.
Results: One hundred thirty-eight surveys were completed of which 105 were for patients who had
information available in the HIE. Within this group the following services were avoided [number of
studies (% of those who had information in the HIE)]: Laboratory/Microbiology: 32 (30.5%); Radiology
studies: 50 (47.6%); Consultations 20 (19%); Prescriptions: 13 (12.4%); Procedures: 1
(0.95%), Admission: 12 (11.4%). Changes in management other than avoidance of a service were made
for 34 (35%). Ninety-one (86.7%) of participants stated that the quality of care delivered to their patients
had been improved. Eighty five (81%) reported that valuable time was saved with a mean time saved of 2
hours. Cost savings during the 4 month study period were as follows: Laboratory: $462.85; Radiology:
$163,893.00; Consultations: $5,250.00; Admissions: $120,000.00; Grand Total: $286,605.85.
Conclusions: Observational data provided by ED clinicians in a urban academic medical center showed
a noteworthy reduction in resource use as a result of having access to an HIE involving the 4 major
hospitals in the area. Total cost savings during the 4 month study period based on resource avoidance
was $286,605.85 with the principal contributions coming from avoided radiologic studies ($160,893.00)
and admissions ($120,000.00). The pilot data obtained from this study justifies further investigation
regarding the ability of an HIE to affect management of patients who come to Emergency Departments in
our region. Limitations include the observational nature of the study, selection bias, and the Hawthorne
effect.
Clinical Junior Faculty
Poster #81
Tandem autologous transplantation vs. autologous plus reduced intensity conditioning
(RIC) allogeneic transplantation in the management of newly diagnosed multiple myeloma:
meta-analysis of prospective trials with biological randomization.
Costa, MD, PhD, Luciano J. 1*, Kent E Armeson, MS 2, Elizabeth G. Hill, PhD 2
1
Division of Hematology and Oncology, Department of Medicine, MUSC
Division of Biostatistics and Epidemiology, Department of Medicine, MUSC
*Presenting author
2
Introduction:
Autologous transplantation has a defined role in the upfront treatment of multiple myeloma
(MM) but nearly all patients will eventually relapse. Allogeneic transplantation carries the
benefit of graft versus myeloma (GVM) effect but also high risk of treatment related mortality
(TRM). Trials randomizing patients with newly diagnosed MM to tandem autologous (TA) or
the combination of autologous + RIC allogeneic transplantation (AR) based on the availability of
an HLA-matched donor have yielded heterogeneous results. We performed a meta-analysis of all
reported trials comparing TA with AR transplantation in newly diagnosed MM to summarize the
available evidence supporting the upfront use AR in multiple myeloma.
Methods:
We utilized a comprehensive search strategy to identify all trials meeting the following entry
criteria: prospective trial, inclusion only of newly diagnosed patients (typically after
conventional induction therapy), subjects undergoing similar induction therapy and first
autologous transplantation in both arms, assignment to RIC allogeneic transplantation or a
second autologous transplantation based exclusively on the availability or not of a HLA matched
donor, use of RIC and report of at least overall survival (OS) and/or progression-free survival
(PFS) as endpoint. OS analyzed per intention to treat (ITT) was the primary endpoint. PFS,
complete response (CR) rate and rate of TRM were secondary endpoints.
Results:
We identified 6 trials meeting entry criteria. There were 1192 patients assigned to TA and 630
patients to AR. Relative to TA, AR patients were more likely to experience TRM (OR = 3.1,
95% CI = 2.1 to 4.5), but not more likely to achieve CR (OR = 1.2, 95% CI = 0.9 to 1.7). There
was no statistically significant difference in PFS within the first 36 months (HR = 1.1, 95% CI =
0.9 to 1.3) or beyond 36 months from transplant (HR = 0.9, 95% CI = 0.7 to 1.3). Similarly, there
was no significant difference in OS between the arms within 36 months (HR = 1.2, 95% CI = 0.9
- 1.5) or beyond 36 months (HR = 1.1, 95% CI = 0.7 - 1.6).
Conclusion:
We conclude that AR is associated with substantially higher TRM but with no improvement in
PFS or OS over TA transplantation in the initial management of patients with MM. Allogeneic
transplantation in this setting remains experimental. Innovative approaches are needed to
improve the safety and efficacy of this strategy.
Category: Junior Faculty, Clinical Science
Email: [email protected]
Clinical Junior Faculty
Poster #82
Demographic description of patients testing positive during non-targeted HIV testing in an
academic tertiary care emergency department.
Glover, Neil, Shapshak D, Green M, Navarro R, Houck R, Fesperman C.
Division of Emergency Medicine, Department of Medicine
Objective: Describe the HIV population diagnosed by non-targeted HIV testing in the
emergency department.
Methods: The MUSC Emergency Department is an academic, tertiary care facility with a 40 bed
capacity. From May 2008 to November 2011, MUSC offered routine, non-targeted testing at no
cost for Emergency Department patients aged 18 to 64. Trained research assistants offered UniGold™ Recombigen® HIV, rapid immunoassays to patients during their ER treatment course.
Patients diagnosed with HIV were linked to follow-up care with infectious disease specialists.
Results: Of 10,985 patients approached, 7543 accepted testing and 3,442 declined. 44 patients
were newly diagnosed with HIV infection. The age distribution of newly positive patients ranged
from 18 to 64. 10 were female; 34 were male. Race distribution was 2 White, 2 Latino and 40
African-American. 35 patients presented with symptoms related to infectious diseases. 22
patients had initial CD4 counts less than 200. 15 patients had AIDS defining illnesses. 73%
percent were uninsured compared to 47% of the general emergency department population.
Conclusions: The 2006 CDC guidelines recommend routine HIV screening in emergency
departments where the incidence of undiagnosed HIV infection is greater than 1 in 1000. An
incidence of 6/1000 supports continued HIV screening of our ED population. Being male,
uninsured, African American presenting with infectious and constitutional complaints appears to
be associated with positive HIV testing in our population.
Type of Research: Clinical Research
Corresponding Author: Dag Shapshak MD
Email: [email protected]
Clinical Junior Faculty
Poster #83
Impact of Long-Term Medication Non-Adherence on Mortality Differs by
Race/Ethnicity among Veterans with Diabetes
Lynch MD, MPH, Cheryl P1, Mulugeta Gebregziabher, PhD2, Kelly J Hunt, PhD2, Patrick
D Mauldin, PhD1, Leonard E Egede, MD, MS1
1
Division of General Internal Medicine & Geriatrics, 2Division of Biostatistics &
Epidemiology, Department of Medicine, MUSC
OBJECTIVE: Medication non-adherence (MNA) is linked to adverse outcomes including
poor glycemic control, increased hospitalization, and higher all-cause mortality. The
longitudinal effect of MNA on all-cause mortality by race/ethnicity was examined in a
national sample of veterans with type 2 diabetes.
METHODS: A longitudinal cohort of veterans with diabetes was created by linking
patient and administrative files from 2 large Veterans Administration databases. The
outcome was time to death (in months) between date of study entry and date of death (or
censored or May 2006). Predictors were race/ethnicity and mean medication possession
ratio (MPR) categorized into quintiles for each veteran. Cox regression models assessed
time to death and MPR by race controlling for sociodemographics, medication class (oral,
insulin, both), and medical and psychiatric comorbidities. Hazard ratios (HR) for mortality
risk were computed for race and MPR quintiles and the race-MPR interaction was tested.
RESULTS: The cohort comprised a total of 629,563 male (97.8%) veterans with type 2
diabetes followed over 5 years. After covariate adjustments, HR for veterans in the lowest
MPR versus highest quintile was 12.21 (95%CI 11.89,12.55) for non-Hispanic white
(NHW), 10.01 (9.18,10.91) for non-Hispanic black (NHB), 12.65 (11.10,14.43) for
Hispanic and 10.41 (9.06,11.96) for Other race veterans. Compared to oral medication only,
combined therapy was linked to lower mortality risk among NHW 0.90 (0.89,0.92), NHB
0.91 (0.87,0.95), and Hispanics 0.88 (0.82,0.95), but insulin use showed lower mortality
risk among NHW 0.94 (0.93,0.96) and higher in Hispanic veterans 1.09 (1.03,1.16).
CONCLUSIONS: This study demonstrates clear evidence of a substantially higher
mortality risk in the lowest MPR quintile relative to the highest quintile for all racial/ethnic
groups; the association being strongest in NHW veterans. These findings suggest a need for
novel interventions to improve medication adherence in diabetes, more aggressive titration
of medications, and early use of combined therapy across racial groups.
Type of Research Project: Clinical Science
Email: [email protected]
Clinical Junior Faculty
Poster #84
Differences In Perception About Access To Care Between Patients Who Choose An Urban
Academic Emergency Department Over A Community-based Student-run Free Clinic For
Non-urgent Care
Saef, Steven H.1, C. Cohen2, M. Dettmer3, E. C. Jauch1, B. Walker1, W. Gonsalves1, K. N.
Simpson1;
1
Medical University of South Carolina, Charleston, SC, 2UC Davis Health System, Sacramento,
CA, 3Washington University Medical Center/Barnes-Jewish Hospital, St. Louis, MO.
Abstract:
Background: Uninsured patients often choose the Emergency Department (ED) over other
suitable venues for non-urgent care. Understanding patient preferences and obstacles to nonurgent care can improve access to care.
Objectives: Characterize differences in perception about access to non-urgent care by uninsured
patients who present to an urban academic ED vs. a community-based student-run free clinic
(FC).
Methods: We compared responses of uninsured patients with non-urgent complaints presenting
to an urban academic level I trauma/tertiary care ED with those of a FC using a prospective,
anonymous survey. Survey items evaluated patients' perceptions about access to care which
might explain their choice of venue. ED patients with Emergency Severity Index (ESI)
categories 4 or 5 and selected category 3 patients (ambulatory, normal mental status, skin warm
and dry, no signs or symptoms of vital organ compromise) were deemed non-urgent. All patients
presenting to the FC were deemed non-urgent. The study instrument was a 10 item survey
addressing Desirability of a FC over the ED (DFE); Transportation Status (Access to a Car);
Perceived Quality of Care; Usual Place of Care; Importance of Cost; Self-Perceived Level of
Illness (SPLOI); distance to ED or FC, and patient demographics. All items were answered on a
5-point Likert Scale. Scores from like items addressing similar concerns were combined. A
convenience sample of 100 patients was obtained from each site. Comparisons were made using
Student’s t-Test. Logistic regression was used to adjust for the effect of significant variables,
demographics, and distance on the response to the item about DFE.
Results: Differences were noted between the ED and FC patients for items regarding Cost (ED
mean 4.31, FC mean 3.68; p=0.03) with ED patients showing less concern about cost;
Transportation (ED mean 7.00, FC mean 8.01; p=0.003) with ED patients showing greater
concern about access to a car; and SPLOI (ED mean 2.87, FC mean 3.40; p=0.01) with ED
patients perceiving themselves as more ill. No difference was noted between the groups
regarding DFE after adjustment (p=0.68).
Conclusion: Non-urgent, uninsured patients presenting to the ED showed less concern about the
cost of care, greater concern about transportation, and felt themselves to be more ill than those
presenting to a FC. No difference was noted between the groups regarding DFE after adjustment.
Clinical Junior Faculty
Poster #85
Copper Surfaces (CuS) Significantly Lower Rate of Hospital Acquired Infections (HAIs) in
the Medical Intensive Care Unit (MICU)
Salgado, Cassandra1, KA Sepkowitz2, JF John3, JR Cantey1, U Rappo2, H Baig3, S Singh2, HH
Attaway4, HT Michels5, MG Schmidt4
1
Division of Infectious Diseases, Department of Medicine MUSC, 2Division of Infectious
Diseases, Department of Medicine MSKCC, 3Department of Medicine RHJVA, 4Department of
Microbiology and Immunology, 5MUSC, Copper Development Association
Background: The role of environmental surface contamination to HAIs has not been well
defined. Previously we reported that CuS reduced environmental bioburden by >90% in MICU
patient rooms. We now report the effect of CuS on HAIs among MICU patients.
Methods: Patients admitted to the MICU in 3 hospitals from 7/12/10 - 5/13/11 were randomly
placed into rooms with either standard (plastic, wood, stainless or chrome) surfaces or rooms
with CuS (bedrails, IV pole, overbed table, chair, monitor bezel and call button). Patients were
followed prospectively for HAI or for new MRSA or VRE colonization.
Results: 564 patients were admitted over the study period; 269 (47.7%) to rooms with CuS.
There was no significant difference in age, sex, race, APACHE II score or MICU LOS between
study groups. The overall HAI rate was 12.23 per 1000 patient days and was significantly lower
in copper vs. standard rooms [8.95 vs. 15.16, OR 0.55 (95%CI 0.41-0.73), p=0.00003].
Additionally, the overall MRSA or VRE acquisition rate was 7.55 per 1000 patient days and was
significantly lower in copper vs. standard rooms [6.12 vs. 8.8, OR 0.67 (95%CI 0.47-0.96),
p=0.03]. In the subpopulation of patients admitted to rooms where all 6 objects with CuS
remained in the room for the entire MICU stay, there was an even greater effect on reduction of
HAIs vs. those never exposed to CuS [6.88 vs. 15.72, OR 0.40 (95%CI 0.29-0.54), p<0.0001].
Conclusion: CuS reduce environmental bioburden when placed into MICU patient rooms. In
this study, patients admitted to MICU rooms with CuS were significantly less likely to develop
HAIs or to acquire MRSA or VRE compared to those admitted to rooms without CuS. This
suggests that environmental bioburden contributes substantially to risk of HAI in the MICU and
that by reducing bioburden (through placement of CuS) this risk can be significantly lowered.
Clinical Research: Junior Faculty
Corresponding Author: Cassandra Salgado, MD, MS
Email: [email protected]
Clinical Junior Faculty
Poster #86
β3 integrin/PDGF receptor synergistic signaling mediates cardiac fibrosis in a
mouse model of pressure overload hypertrophy
Balasubramanian, Sundaravadivel, Harinath Kasiganesan, Lakeya Quinones, Amy
Bradshaw and Dhandapani Kuppuswamy
Dept. of Medicine/Cardiology, Medical University of South Carolina, Charleston, SC.
The precise role of integrins in the process of cardiac fibrosis is not well
understood. We hypothesized that upon cardiac hypertrophic stimulation, the synergistic
activation of β3 integrin and platelet-derived growth factor receptor (PDGFR) leading to
nonreceptor tyrosine kinase (NTK) signaling in cardiac fibroblasts contributes to fibrosis.
In response to pressure-overload induced by transverse aortic constriction (TAC), β3
integrin knockout (β3 KO) mice exhibited reduced fibrillar collagen, fibronectin, and
fibroblast specific protein (FSP1) levels in comparison to wild-type (WT) mice. Isolated
cardiac fibroblasts (Cfb) from β3 KO mice exhibited a reduction in cell adhesion and
spreading as well as PDGF-induced cell proliferation and migration when compared to
Cfb from WT mice. Next, we analyzed the phosphorylation state of PDGFR and NTK
upon PDGF stimulation in Cfb. Our data indicated a marked reduction in the activation of
PDGFR, Pyk2, Src and FAK in β3 KO Cfb when compared to WT Cfb. These data
suggest that β3 integrin provides a necessary co-stimulation for fibrotic signaling in Cfb.
Furthermore, our studies in the mouse TAC model where dasatinib, an inhibitor of
PDGFR and NTK, was administered via a mini-osmotic pump, exhibited a preserved
ventricular geometry and function and reduced fibrosis upon 4 wk TAC. NTK inhibition
with dasatinib also reduced the proliferation, migration and mitogenic signaling of Cfb.
These data indicate that integrin-PDGFR synergism could be a potential target to treat
cardiac fibrosis.
Presenter: Sundaravadivel Balasubramanian, PhD
Category: Basic Sciences, Junior Faculty
Basic Junior Faculty
Poster #87
Cytoskeletal Role in Protection of the Failing Heart by Beta-Adrenergic Blockade
Cheng, Guangmao, Harinath Kasiganesan, Catalin F. Baicu, J. Grace Wallenborn, Dhandapani
Kuppuswamy and George Cooper, IV
Gazes Cardiac Research Institute, Cardiology Division, Department of Medicine, Medical
University of South Carolina and the Department of Veterans Affairs Medical Center. Charleston,
South Carolina 29401
Abstract: Formation of a dense microtubule network that impedes cardiac contraction and
intracellular transport occurs in severe pressure overload hypertrophy. This process is highly
dynamic, since microtubule depolymerization causes striking improvement in contractile
function. A molecular etiology for this cytoskeletal alteration has been defined in terms of type 1
and type 2A phosphatase-dependent site-specific dephosphorylation of the predominant
myocardial microtubule-associated protein, MAP4, which then decorates and stabilizes
microtubules. This persistent phosphatase activation is dependent upon ongoing upstream
activity of p21-activated kinase-1, or Pak1. Because cardiac β-adrenergic activity is markedly
and continuously increased in decompensated hypertrophy, and because β-adrenergic activation
of cardiac Pak1 and phosphatases has been demonstrated, we asked here whether the highly
maladaptive cardiac microtubule phenotype seen in pathological hypertrophy is based on βadrenergic overdrive and thus could be reversed by β-adrenergic blockade. The data in this study,
which was designed to answer this question, show that such is the case. That is, β1- (but not β2-)
adrenergic input activates this pathway, which consists of Pak1 activation, increased phosphatase
activity, MAP4 dephosphorylation, and thus the stabilization of a dense microtubule network.
These data were gathered in a feline model of severe RV pressure overload hypertrophy in
response to tight pulmonary artery banding (PAB) in which a stable, two fold increase in RV
mass is reached by 2 wk after pressure overloading. Following 2 wk of hypertrophy induction,
these PAB cats during the following 2 wk either had no further treatment or had β-adrenergic
blockade. The pathological microtubule phenotype and the severe RV cellular contractile
dysfunction otherwise seen in this model of RV hypertrophy (PAB No Treatment) was reversed
in the treated (PAB β-Blockade) cats. Thus, these data provide both a specific etiology and a
specific remedy for the abnormal microtubule network found in some forms of pathological
cardiac hypertrophy.
Basic Junior Faculty
Poster #88
Racial/Ethnic Disparities in Access to VA Services As a Pathway to Mortality Differentials
Among Veterans Diagnosed with TBI
Dismuke, Clara E., PhD, Center For Disease Prevention and Health Interventions for Diverse
Populations, Department of Veterans Affairs and Center For Disparities Research, Medical
University of South Carolina.
Carrae Echoles, MS, Center For Disease Prevention and Health Interventions for Diverse
Populations, Department of Veterans Affairs.
Mulugeta Gebregziabher,PhD, Department of Medicine, Medical University of South Carolina
Leonard E. Egede, MD, MS, Center For Disease Prevention and Health Interventions for
Diverse Populations, Department of Veterans Affairs and Center For Disparities Research,
Medical University of South Carolina
Background: The VA health care system has been proposed as a potential health reform model
in the US. Even so, there is recent evidence of racial/ethnic disparities in mortality among
Veterans diagnosed with Traumatic Brain Injury (TBI). This study examines the association of
race/ethnicity and utilization as a moderator of the association of race/ethnicity with mortality
among Veterans with TBI.
Methods: The study examined a national cohort study of 7,885 Non-Hispanic White, 1,748 NonHispanic Black, 314 Hispanic, and 4,743 other/missing race/ethnicity Veterans clinically
diagnosed with TBI between January 1, 2006 and December 31, 2006 in VA medical centers and
community based outpatient clinics. All Veterans were followed from January 1, 2006 through
December 31, 2009 or until date of death. Utilization was tracked for 12 months. Comorbidity
adjusted mortality was compared by race/ethnicity using cox regression while service access was
compared using logit regression analysis.
Results: Overall mortality at 48 months was 6.7% in Hispanic, 2.9% in Non-Hispanic White, and
2.7% in Non-Hispanic Black Veterans. In a mortality model adjusting for demographic and
comorbid conditions, Hispanic ethnicity was associated with a higher likelihood of mortality.
However, upon including utilization, race/ethnicity was no longer significant. In access models
adjusting for race/ethnicity, Hispanic ethnicity was associated with a higher likelihood of not
accessing TBI clinic (HR 2.21; 95% CI 1.40:3.49), neurology (HR 2.18; 95% CI 1.38:3.45),
imaging (HR 2.40; 95% CI 1.53:3.75), mental health (HR 2.46: 95% CI 1.57:3.85) and
rehabilitation (HR 2.32; 95% CI 1.49:3.63) services in VA hospitals and clinics.
Conclusions: Racial/ethnic disparities in access to services account for racial/ethnic disparities
in mortality rates among Veterans diagnosed with TBI. Further research is needed to identify
interventions which may improve access to VA services for minority Veterans.
Acknowledgement: We acknowledge and appreciate the resources provided by the Center for
Disease Prevention and Health Interventions for Diverse Populations HSR&D program (grant
REA 08-261) and the Ralph H. Johnson Veterans Affairs Medical Center. The views expressed
in this article are those of the authors and do not necessarily represent the views of the
Department of Veterans Affairs.
Basic Junior Faculty
Poster #89
Remodeling of the Peripheral Cardiac Conduction System in Response to PressureOverload.
Harris PhD, Brett S1, Catalin F Baicu, PhD2, Nicole Haghshenas MS1, Harinath Kasiganesan
PhD2, Mary S Rackley, BS2, Rupak Mukherjee, PhD3, Terrence X O'Brien, MD1,2,4.
Departments of Regenerative Medicine and Cell Biology1, Medicine 2 and Cardiothoracic
Surgery3, Medical University of South Carolina; Ralph H. Johnson Veterans Administration
Medical Center4, Charleston, SC.
How chronic pressure-overload affects the Purkinje fibers of the ventricular peripheral
conduction system (PCS) is not known. Here, we employ a Connexin40 knock-out/Enhanced
Green Fluorescent Protein knock-in transgenic mouse model to specifically label the PCS. We
hypothesized that the subendocardially-located PCS would remodel following chronic pressureoverload and therefore analyzed cell size, markers of hypertrophy as well as PCS-related ion
channel expression patterns.
Left ventricular hypertrophy with preserved systolic function was induced by 30 days of surgical
trans-aortic-constriction (TAC). After TAC, we observed that PCS cardiomyocytes
hypertrophied by 23% (p<0.05) and that micro-dissected PCS tissue exhibited upregulated
markers of hypertrophy. PCS cardiomyocytes showed a 98% increase in the number of
Connexin40 positive gap junction particles with an associated two-fold increase in gene
expression (p<0.05). In addition, we identified a 50% reduction in Connexin43 gap junction
particles located at the interface between the PCS and the working cardiomyocytes. Finally, we
measured a four-fold increase of the ion channel, HCN4, throughout the PCS (p<0.05).
These novel findings characterize PCS cardiomyocyte hypertrophy after chronic pressureoverload. We identified significant hypertrophic growth accompanied by remodeling of three
key ion channels within PCS cardiomyocytes. Our findings provide proof-of-concept that
pressure-overload induces specific cellular changes, not just within the working myocardium but
also within the specialized PCS.
Corresponding Author: Brett S. Harris
Type of Research: Basic Science Junior Faculty
Email: [email protected]
Basic Junior Faculty
Poster #90
Effect of HDAC Inhibitor Treatment on Left Ventricular Contractile Dysfunction in
Coronary Artery Occlusion Induced Myocardial Infarction.
Kasiganesan Harinath, Ludivine Renaud, Santhosh K Mani, Donald R Menick
Research Assistant Professor, Gazes Cardiac Research Institute
Coronary heart disease, which is the single largest cause of cardiovascular disease, is the
narrowing of arteries over time caused by atherosclerotic plaques or the acute occlusion of the
coronary artery by thrombosis, both of which lead to myocardial infarction (MI), which leads to
contractile dysfunction and heart failure. Protection from coronary heart disease–induced
damage of the myocardium during MI injury has been a target of investigation for the
development of innovative cardioprotective therapies. Histone deacetylases (HDACs) are a class
of enzymes that affect the transcriptional regulation of genes during pathological conditions.
Diverse cellular functions are regulated by changes in acetylation status of histones and non
histone proteins. Tricostatin-A (TSA) is an antifungal antibiotic with cytostatic and
antiproliferation properties and has been shown to block adverse cardiac remodeling and
inflammation via inhibition of HDACs. The present goals were to a) develop a simple and
effective in vivo myocardial infarction model linking coronary artery occlusion mediated
contractile dysfunction and heart failure, b) test the hypothesis that TSA prevents these
pathophysiological changes occurring during myocardial infarction. Four groups of CD1 mice
(N=10) aged 5 months were randomly selected for the study. The group 1 served as non
treatment controls. Group 2 received vehicle twice a day intraperitoneally for 3 weeks. Group 3
received TSA at the dose of 1 mg/kg twice a day for 3 weeks and also served as sham control for
the MI group. Group 4 received TSA 12 hrs before surgery and underwent MI surgery and the
TSA treatment was continued for 21 days. The left ventricular mass and cardiac systolic and
diastolic functions were assessed using two dimensional echocardiography in all the groups
before and after a 21 day study period. Initial results show TSA treatment at the dose of 1mg/kg
is effective in preventing the deterioration in cardiac function in 3 wk MI mice.
Corresponding Author: Harinath Kasiganesan
Email: [email protected]
Basic Junior Faculty
Poster #91
Histone Deacetylase Inhibitor Suppresses Matrix Metallo Proteinase-1and Protects the
Retina.
Mani, Santhosh K1, Craig E Crosson2, Michelle Haracznak2, Ludivine Renaud and Donald R.
Menick1.
1
Gazes Cardiac Research Institute, Department of Medicine, 2Deparment of Opthomology,
MUSC.
Protein acetylation is an essential mechanism for regulating transcriptional cell signaling and
inflammatory events. The current studies investigate if reduced histone deacetylase (HDAC)
activity can limit ischemic retinal injury. Glaucoma is a common cause of blindness affecting
approximately 2% of Americans over the age of 40 and over 60 million people worldwide.
Studies have provided evidence that dysfunction within retinal ganglion cell bodies,
photoreceptors, lateral geniculate nucleus or visual cortex can contribute to the pathogenesis of
glaucomatous optic nerve degeneration; however, it is changes within the lamina cribrosa of the
optic nerve head that are thought to play the central role in this disease. Previous studies have
provided evidence that the secretion and activation of matrix metalloproteinases (MMPs) from
astrocytes contribute to retinal damage induced by inflammation, and ischemic injury. The
purpose of these studies was to investigate the impact of histone deacetylase (HDAC) inhibitors
on MMP expression induced by the inflammatory cytokine TNFα. To stimulate MMP secretion,
cultured primary human astrocytes were incubated with TNFα (10 ng/ml) for 24 hours. Cells
were pretreated with HDAC inhibitor trichostatin A (TSA,100 nM) for 1 hour prior to the
addition of TNFα to investigate the role of HDACs. The secretion of MMP-1 and histone H4
acetylation were determined by Western blot analysis. The addition of TNFα for 24 hours
significantly increased the secretion of MMP-1 over control levels, by 270%. Pretreatment with
TSA blocked the TNFα-induced secretion of MMP-1. The MMP-1 promoters contain AP1,
STAT1 and NFκB consensus elements, which are critical to MMP induction in response to
cytokines and proinflammatory stimuli. TSA treatment does not significantly disrupt either the
NFκB or AP1 activating pathways in human astrocytes. Importantly, TNFα induces the
activation of the JAK/STAT1 pathway, which was completely inhibited by TSA treatment. In
addition pre-treatment of astrocytes with the JAK1/2 inhibitor AG 490 inhibited TNFαstimulated expression of MMP-1 and MMP-3. These data provide evidence that the JAK/STAT
pathway is critical for TNFα- stimulated upregulation of MMP-1 and MMP-3 in optic nerve head
astrocytes and the activation of this pathway is inhibited by TSA treatment. Further studies
elucidate that SOCS1 acetylation plays an important role in the regulation of MMP-1 expression.
Hence, protein acetylation/deacetylation may represent a central step in the JAK/STAT mediated
secretion of MMPs from optic nerve astrocytes, and the use of HDAC inhibitors may provide a
novel approach for the treatment of optic neuropathies.
Type of Research: Basic Research
Email: [email protected].
Basic Junior Faculty
Poster #92
Efficacy of Transcranial Direct Current Stimulation (tDCS) and Repetitive Transcranial
Magnetic Stimulation (rTMS) for the Treatment of Fibromyalgia Syndrome: A Systematic
Review
Marlow MSPH, Nicole M.1; Heather S. Bonilha, PhD, CCC-SLP2; E. Baron Short, MD,
MSCR3
1
Corresponding author: Research Associate (Faculty), Medical University of South Carolina (MUSC),
Dept. of Medicine, Div. of Biostatistics and Epidemiology, Charleston, SC, [email protected]
2
MUSC, Dept. of Health Sciences and Research
3
MUSC, Dept. of Psychiatry and Behavioral Sciences
SUBJECT: Comparative Effectiveness Research
OBJECTIVE: To systematically review the literature to date applying repetitive transcranial magnetic
stimulation (rTMS) or transcranial direct current stimulation (tDCS) for patients with fibromyalgia
syndrome (FMS), summarizing procedures (including brain site, frequency, intensity, duration, total
sessions, scheduling), FMS symptom outcomes, and levels of evidence.
METHOD: Electronic bibliography databases screened included PubMed, Ovid MEDLINE,
PsychINFO, CINAHL, and Cochrane Library. The keyword “fibromyalgia” was combined with
(“transcranial” and “stimulation”) or “TMS” or “tDCS” or “transcranial magnetic stimulation” or
“transcranial direct current stimulation”. Reference sections of studies meeting inclusion criteria were
screened for relevant publications.
RESULTS: Nine of 23 studies were included, 5 each for rTMS (high-frequency M1 = 2, low-frequency
DLPFC = 2, high-frequency DLPFC = 1) and tDCS (anodal-M1 = 1, anodal-M1/DLPFC = 3). Eight were
double-blinded randomized clinical trials. Outcomes reviewed included pain, quality of life, tender
points, depression, adverse events, and drop-outs. Most (80%) rTMS studies with pain outcome results
reported significant decreases, while all tDCS studies with pain outcome results reported significant
decreases. Greater longevity of pain reductions was observed for excitatory M1 rTMS/tDCS.
Completion rates ranged from 80% to 100% for active-stimulation groups, much higher than such results
reported in the literature for FDA approved FMS pharmaceuticals.
CONCLUSION: Excitatory rTMS/tDCS at M1 may play a vital role among multidisciplinary treatment
components for FMS, particularly for patients who are unable to find adequate symptom relief with other
therapies. Further work into optimal stimulation parameters and standardized testing methodologies are
needed to clarify the efficacy and effectiveness of these neuromodulation techniques for treating
fibromyalgia.
ACKNOWLEDGEMENTS: Financial support provided by the NIH/NIAMS P60 Grant AR049459 and
NIH KL2 Award RR029880 as well as the MUSC Div. of Biostatistics and Epidemiology, Dept. of
Healthcare Leadership, Dept. of Health Sciences and Research, and Dept. of Psychiatry and Behavioral
Sciences. We are also most grateful for the exceptional mentorship provided by Charles Ellis, PhD,
CCC-SLP, Kit N. Simpson, DrPH, and Richard M. Silver, MD.
Basic Junior Faculty
Poster #93
Angiotensin II Induces Cyclooxygenase 2 (COX-2) Expression in Rat Aorta Vascular
Smooth Muscle Cells via AT1A Receptor Internalization and the NF-κB Pathway.
Morinelli, Thomas A. 1, Linda P. Walker1 and Michael E. Ullian1,2
1
2
Division of Nephrology, Department of Medicine, Medical University of South Carolina and the
Ralph H. Johnson VA Medical Center, Charleston, SC
ABSTRACT:
Activation of the angiotensin II (AngII) AT1A receptor (AT1AR) in rat aorta vascular smooth
muscle cells (RASMC) results in the propagation of multiple intracellular signaling pathways
including increased protein synthesis. One such protein is the pro-inflammatory enzyme
cyclooxygenase 2 (COX-2). We have previously shown that nuclear localization of an
internalized AT1AR results in activation of transcription of the gene for COX-2, PTGS-2. Others
have suggested that AngII stimulation of COX-2 protein synthesis is mediated by NF−κB. In the
present study we utilized three different inhibitors of the NF−κB pathway, each targeting a
specific aspect of NF−κB activation to characterize the role between AT1aR activation, NF−κB
and AngII-induced COX-2 synthesis. Ro-1069920 and parthenolide, agents which inhibit
NF−κB by blocking proteosomal degradation of Iκ Bα, blocked p65 NF−κB nuclear
localization, AngII-induced COX-2 protein expression and inhibited AT1AR internalization,
without inhibiting AngII-induced p42/44 ERK activation. Curcumin, an inhibitor of interaction
of NF−κB with NF−κB /DNA recognition motifs and blocking NF−κB induced transcription,
blocked AngII-induced COX-2 protein expression, without altering AT1AR internalization and
p42/44 ERK activation. Finally, immunoprecipitation and immunoblotting studies show a timedependent AngII stimulated colocalization of AT1AR with p65/ NF−κB. Taken together, these
data demonstrate that activation of the AT1AR by AngII results in colocalization of the
internalized receptor with a subunit of the NF−κB pathway. Interruption of AT1AR
internalization by specific NF−κB inhibitors results in a loss of the ability of AngII to increase
the synthesis of the pro-inflammatory enzyme COX-2, thereby linking the internalization of the
receptor with the NF−κB pathway.
CATEGORY: Basic Research Faculty
CORRESPONDING AUTHOR: Thomas A. Morinelli, Ph.D.
EMAIL: [email protected]
Basic Junior Faculty
Poster #94
Neuropilin-2 is upregulated during EMT in lung cancer
Nasarre, Patrick, Joelle Roche, Vincent Potiron, Joyce Nair-Menon, Robert Gemmill and
Harry Drabkin
Division of Hematology-Oncology, Department of Medicine, MUSC
Neuropilins (NRP1 and NRP2) are high affinity receptors for the class-3 semaphorins, cell
guidance molecules involved in tissue development, immune responses, angiogenesis and
cancer. Semaphorins affect cell protrusion, spreading and adhesion, and can trigger migratory
responses often in a repulsive manner depending on the cellular context. Interestingly,
neuropilins are also receptors for galectin-1 and growth factors including VEGF, PlGF, EGF and
TGFβ.
We previously cloned the SEMA3F gene from chromosome 3p21.3, which undergoes
homozygous deletion and frequent loss of heterozygosity in lung cancer. We found that
SEMA3F levels were inversely correlated with tumor aggressiveness in human lung cancer and
confirmed its tumor suppressor activity in experimental xenograft models. We subsequently
discovered that SEMA3F is directly downregulated by ZEB1, a transcription factor involved in
the epithelial to mesenchymal transition (EMT). In the present study, we asked whether
SEMA3F specific receptor, NRP2, was also regulated during the EMT process.
TGFβ, a physiologic EMT inducer, stimulated NRP2 expression in two NSCLC cell lines.
Forced expression of ZEB1, but not Snail, also induced NRP2. Conversely, ZEB1 and Snail
inhibition blocked NRP2 upregulation by TGFβ. Importantly, inhibiting NRP2 or ZEB1
expression reduced TGFβ-induced migration in an equivalent manner. In lung cancer tissue
microarrays, NRP1 and NRP2 were preferentially expressed in the tumor compartment, whereas
the EMT-related transcription factors, ZEB1 and Snail, were predominantly expressed in the
stroma. Of note, NRP2 was also expressed in stromal cells and was significantly associated with
both ZEB1 and a higher (worse) tumor grade. Since NRP2 is the highest affinity receptor for
SEMA3F, our results suggest that loss of SEMA3F coupled with increased NRP2 would
facilitate the binding of growth factors to NRP2 to further promote EMT and metastasis.
Therefore, targeting NRP2 could be an important therapeutic approach against EMT in lung
cancer.
Corresponding Author: Patrick Nasarre, Assistant Professor
Type of Project: basic
Email: [email protected]
Basic Junior Faculty
Poster #95
Targeting the amino acid transporter xCT inhibits progression of lymphoma associated
with an oncogenic herpesvirus in vivo
Zhiqiang, Qin1,2, Lu Dai1,3, Bryan P. Toole3 and Chris Parsons1,2
Departments of Medicine1, Craniofacial Biology2, and Regenerative Medicine & Cell Biology3,
Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas St.,
Charleston, SC 29425
Abstract: The Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of
primary effusion lymphoma (PEL)—an aggressive malignancy associated with HIV/AIDS that
portends near 100% mortality within 6-12 months from the time of diagnosis despite control of
HIV infection and standard chemotherapy. The amino acid transporter, xCT, exchanges
intracellular glutamate for extracellular cystine at the cell membrane, resulting in restoration of
intracellular glutathione (GSH) and protection of cancer cells from oxidative stress-induced cell
death. Initial screening of human tumors revealed that xCT is readily expressed on the cell
surface of two patient-derived, KSHV-infected PEL cell lines (BCP-1 and BCBL-1). Two
commercially available compounds, monosodium glutamate (MSG) and sulfasalazine (SUL),
inhibit amino acid exchange through xCT. Initial functional studies demonstrated that MSG and
SUL induced caspases-mediated apoptosis for PEL cells. Subsequent studies revealed that
incubation of PEL cells with either MSG or SUL reduced intracellular GSH content and
increased intracellular reactive oxygen species (ROS) while suppressing phosphorylation of
intracellular signaling molecules critical for PEL cell survival, including PI3K/Akt, MAPK and
NF-κB. Finally, using an established murine model for PEL, we have demonstrated that systemic
administration of SUL significantly reduces PEL tumor growth in vivo. Collectively, these data
identify xCT as an important determinant of PEL cell survival and support evaluation of SUL as
an adjunctive therapeutic agent for PEL in clinical trials.
Category: Junior Faculty (Zhiqiang Qin), Basic Science
E-mail: [email protected].
Basic Junior Faculty
Poster #96
Association of reactive intermediate genes with systemic lupus erythematosus (SLE) varies
across populations with different African ancestries
Ramos, Paula S.1, James C. Oates1, Diane L. Kamen1, Patrick M. Gaffney2, Carl D. Langefeld3, Jennifer A. Kelly2,
Kenneth M. Kaufman4, Robert P. Kimberly5, Timothy B. Niewold6, Chaim O. Jacob7, Betty P. Tsao8, Elizabeth E.
Brown9, Michelle Petri10, Rosalind Ramsey-Goldman11, John D. Reveille12, Luis M. Vila13, Judith A. James2, Joel
Guthridge2, Joan T. Merrill14, Susan A. Boackle15, Barry I. Freedman16, Hal Scofield2, Anne M. Stevens17, Timothy
J. Vyse18, Lindsey A. Criswell19, Kathy L. Moser2, Marta E. Alarcón-Riquelme20, John B. Harley4, Gary S.
Gilkeson1
1)
Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina,
Charleston, SC; 2) Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation,
Oklahoma City, OK; 3) Wake Forest School of Medicine and Center for Public Health Genomics, Winston-Salem,
NC; 4) Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 5) Department of
Medicine, University of Alabama at Birmingham, Birmingham, AL; 6) Section of Rheumatology and Gwen Knapp
Center for Lupus and Immunology Research, University of Chicago, Chicago, IL; 7) Keck School of Medicine,
University of Southern California, Los Angeles, CA; 8) David Geffen School of Medicine, UCLA, Los Angeles, CA;
9)
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL; 10) Department of
Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; 11) Division of Rheumatology,
Northwestern University Feinberg School of Medicine, Chicago, IL; 12) Rheumatology and Clinical
Immunogenetics, University of Texas Health Science Center at Houston, Houston, TX; 13) Department of Medicine,
Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico; 14) Clinical
Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK; 15) Division of
Rheumatology, University of Colorado Denver, Aurora, Colorado; 16) Department of Internal Medicine, Wake Forest
School of Medicine, Winston-Salem, NC; 17) Division of Rheumatology, Department of Pediatrics, University of
Washington, Seattle, WA; 18) Division of Genetics and Molecular Medicine, King’s College, London, United
Kingdom; 19) Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, CA;
20)
Center for Genomic and Oncological Research, Universidad de Granada, Granada, Spain.
ABSTRACT BODY Very little is known about the genetic etiology of systemic lupus erythematosus
(SLE) in individuals of African ancestry – in spite of its higher prevalence, incidence, disease severity,
and mortality rates in African Americans (AA). Overproduction of nitric oxide (NO) has been implicated
in its pathogenesis and correlated with disease severity, making NO synthases and other reactive
intermediate genes biological candidates for disease susceptibility. Here, we report the first
comprehensive analysis of reactive intermediate genes for their association with SLE in populations of
African ancestry. One such population is the Gullah of the Sea Islands of South Carolina: a population
isolate with reduced admixture and genetic heterogeneity, which may increase the power to detect
associations in this population. We analyzed 279 SNPs from 55 regions in 133 Gullah cases and 112
Gullah controls, as well as in other 1432 AA cases and 1575 AA controls. These and approximately 300
additional ancestry informative markers were genotyped on an Illumina custom array; principal
components analysis and admixture estimates were computed and adjusted for in association analyses.
While the glutathione reductase GSR (rs2253409, P=0.0014, odds ratio (OR) [95% confidence interval
(CI)]=1.26 [1.09-1.44]) and paraoxonase PON3 (rs17879114, P=0.0016, OR [95%CI]=0.79 [0.68-0.91])
were the most significant single-SNP associations in AA, in the Gullah the NADH dehydrogenase
NDUFS4 (rs381575, P=0.0065, OR [95%CI]=2.10 [1.23-3.59]) and nitric oxide synthase NOS1
(rs561712, P=0.0072, OR [95%CI]=0.62 [0.44-0.88]) were the most strongly associate with SLE. When
analyzed together, GSR remained the most significant effect (rs2253409, P=0.00072, OR [95%CI]=1.26
[1.10-1.44]). Haplotype and two-loci interaction analyses also uncovered different loci in each population.
These results suggest that the patterns of association are distinct and specific loci may be more strongly
associated in specific populations of African ancestry.
Basic Junior Faculty
Poster #97
Deregulation of ceramide chain-length composition affects trafficking and Golgi
morphology
Spassieva, Stefka D.1, * and Lina M. Obeid1,2
1
Department of Medicine, Division of General Internal Medicine/Geriatrics, Medical University
of South Carolina, Charleston, SC, 29425, 2Ralph H. Johnson Veterans Administration Hospital,
Charleston, South Carolina, 29401
In the recent years, the research on ceramide was focused on its role as a second messenger in
regulating cell death. Next to its role as a second messenger, ceramide is a building block of the
biological membranes and precursor of complex sphingolipids. Ceramide consists of a group of
molecules, which can differ in the chain-length of their fatty acid moiety. The chain-length of the
fatty acid of a ceramide influences its biophysical properties, but the significance of that for
cellular homeostasis is largely unknown. In our current project we investigated how decreased
synthesis of very long-chain (VLC) ceramides (C22, C24) affected membrane trafficking and
Golgi organization. For that purpose, we down regulated the enzyme responsible for VLC
ceramides, ceramide synthase 2 (CerS2), by siRNA in cancer cells and applied cell biology
approach to investigate membrane trafficking and Golgi morphology.
Our results showed that down-regulation of VLC ceramide synthesis led to over compensatory
production of shorter chain-length (C14, C16) ceramides. Confocal analysis with ceramide
antibody showed abnormal intracellular ceramide distribution in the treated cells compared to
control. In addition, we followed the trafficking of the temperature sensitive vesicular stomatitis
virus G (VSVG) –GFP fusion protein in cells with down-regulated VLC ceramide synthesis and
in controls. The results showed delay in VSVG-GFP trafficking in the cells with disrupted VLC
ceramide synthesis. Moreover, confocal and electron microscopy analyses revealed abnormal
Golgi morphology in cells with disrupted VLC ceramide synthesis.
*
Corresponding author: [email protected]
Basic Junior Faculty