Wake Forest University School of Medicine

Wake Forest University School of Medicine

Department of Internal Medicine

Second Annual

Resident and Fellow

Research Day

May 1, 2008

Peter R. Lichstein, M.D. Director, Internal Medicine Residency Program

Research Day Chairperson

Thomas D. DuBose, Jr., M.D. Tinsley R. Harrison Professor and Chair of Internal Medicine

Professor of Physiology and Pharmacology

Jimmy Ruiz, M.D. Chief Resident for Research

David P. Miller, M.D. Director, Primary Care Residency

Poster Judging

Sherri Keith Research Day Coordinator

DEPARTMENT OF INTERNAL MEDICINE

The Department of Internal Medicine is dedicated to excellence in

research, education and patient care. To maintain our reputation as a

nationally prominent research department, the Department of Internal

Medicine at Wake Forest University School of Medicine is committed to

providing a collegial learning environment for residents and fellows to

foster career development of the clinical scholars of the future. A

number of opportunities are available for research training in our

program. The most recent example, the Tinsley R. Harrison

Translational Research Program, was established in 2006 to provide

residents and fellows with the opportunity for initial research training

and to encourage translational research as a career path. Consistent

with the NIH Roadmap, this Program provides formal research

experience and mentored opportunities for patient-centered or bench

projects.

Internal Medicine residents and subspecialty fellows participate

actively in this and other research programs offered by the

Department and its dedicated faculty. Faculty mentors provide

guidance and support for the scholarly efforts of our residents and

fellows and serve as role models for the dedication that is necessary to

succeed in this field.

The posters exhibited at this second annual Resident and Fellow

Research Day represent a small but significant fraction of the research

activities of our trainees. We dedicate this program to the success of

our resident participants and faculty mentors and thank them for their

extra effort.

SCHEDULE OF ACTIVITIES

12:00 pm – 2:00 pm Poster Viewing and Judging

Exhibit Hall, E Level, Commons Building

2:00 pm Winners Announced

RESEARCH DAY JUDGES

Basic Research

Richard F. Loeser, M.D. Professor – Molecular Medicine

Raymond B. Penn, Ph.D.

Associate Professor – Pulmonary, Critical Care, Allergy and Immunologic Diseases

Clinical Research

David M. Cline, M.D. Associate Professor – Emergency Medicine

Thomas D. DuBose, Jr., M.D.

Tinsley R. Harrison Professor and Chair – Internal Medicine

Edward F. Haponik, M.D. Professor – Pulmonary, Critical Care,

Allergy and Immunologic Diseases

Sonal Singh, M.D.

Assistant Professor – General Internal Medicine

John H. Stewart, M.D.

Assistant Professor – General Surgery

Clinical Vignettes

Nancy Denizard-Thompson, M.D. Instructor – General Internal Medicine

Peter R. Lichstein, M.D. Professor – General Internal Medicine

James L. Wofford, M.D. Associate Professor – General Internal Medicine

INTERNAL MEDICINE

RESEARCH COMMITTEE

Richard F. Loeser, M.D. – Co-Chair Professor – Molecular Medicine

Raymond B. Penn, Ph.D. – Co-Chair

Associate Professor – Pulmonary, Critical Care, Allergy and Immunologic Diseases

Eugene R. Bleecker, M.D.

Professor – Pulmonary, Critical Care, Allergy and Immunologic Diseases

John R. Crouse III, M.D. Professor – Endocrinology and Metabolism

David M. Herrington, M.D.

Professor – Cardiology

Stephen B. Kritchevsky, Ph.D. Professor – Gerontology and Geriatric Medicine

Peter R. Lichstein, M.D.

Professor – General Internal Medicine

Antonius A. Miller, M.D. Professor – Hematology and Oncology

Stephen P. Peters, M.D. Professor – Pulmonary, Critical Care,

Allergy and Immunologic Diseases

ABSTRACTS

1.

Evaluation of RARß1' Expression in Tumor Cell Lines: Implications for

Targeted Drug Therapy

Catherine B. Swift, Will R. Voelzke, Jason Graves,

John L. Hays, Glenn J. Lesser, and W. Jeffrey Petty

Basic Research - Resident

Background: Retinoids, the natural and synthetic derivatives of vitamin A, mediate

a variety of essential cellular processes. Due to growth suppressive effects in

epithelial tissues, these drugs have been used for chemoprevention and treatment of

certain cancers.

We have shown that retinoid sensitivity in the lung is linked to expression of a

previously unrecognized isoform of retinoic acid receptor β (RARβ) termed RARβ1’.

Previous studies have shown that RARβ1’ is expressed in normal lung tissue and in

retinoid-sensitive human bronchial epithelial cells but is not expressed in retinoid-

resistant human bronchial epithelial cells or in retinoid-resistant lung cancer cells

(Figure 1).

Methods: We developed and validated an isoform-specific antibody for detection of

RARβ1’. Using this antibody, we compared RARβ1’ expression in a panel of cancer

cell lines including breast (ZR-75-1 and MCF-7), colon (HCT-116 and HT-29),

prostate (LNCap and PC-3), glioblastoma multiforme (U-138 and U-251) and lung

(A549 and H358). RARβ1’ expression was also assessed in an extended panel of

GBM cell lines. We then studied the activity the retinoid, 13-cis-retinoic acid, alone

and in combination with erlotinib for the treatment of glioblastoma multiforme

(GBM).

Results: RARβ1’ expression was detected only in the glioblastoma multiforme cell

line U-251. No expression was detected in the breast, colon, prostate, or lung tumor

cell lines (Figure 2). RARβ1’ expression studied on several types of GBM cell lines

revealed expression in all cell lines (Figure 3). Co-treatment with CRA at 2μM and

erlotinib at 5μM led to statistically significant growth suppression in each cell line

[SNB19 – 65 %, P = 0.049; T98G – 37%, P = 0.008; U-138 – 65%, P = 0.012; U-

251 – 36%, P=0.022] (Figure 4).

Conclusions: RARβ1’ was found to be repressed in all examined lung cancer cases

and in most of the cancer cell lines studied, which may help explain resistance to

retinoid therapy in many epithelial cancers. Preserved RARβ1’ expression and in

vitro retinoid sensitivity in GBM cell lines suggests that retinoids may be useful for

treating patients with GBM. Combining the 13-cis-retinoic acid with erlotinib leads to

cooperative growth suppression in vitro, and a phase I clinical trial in GBM patients

combining 13-cis-RA and erlotinib is currently being developed.

2. Use Of Inhaled Corticosteroids And The Risk Of Pneumonia In Patients With Chronic Obstructive Pulmonary Disease- A Systematic Review And Meta-Analysis

A. Amin1; S. Singh2; Y.K. Loke3

Clinical Research – Resident

BACKGROUND: Inhaled corticosteroids are widely used in patients with Chronic Obstructive Pulmonary Disease. Our objective was to determine the risk of pneumonia with the use of Inhaled corticosteroids in patients with Chronic Obstructive Pulmonary Disease. METHODS: We conducted a systematic review and meta-analysis of Randomized Controlled Trials of Inhaled Corticosteroids in patients with Chronic Obstuctive Pulmonary Disease. Search strategy: We identified relevant trials from Cochrane systematic reviews of inhaled corticosteroids in chronic obstructive pulmonary disease. We also retrieved unpublished company trial reports from the GlaxoSmithKline and Astra Zeneca trial registries. Selection criteria: Randomized controlled trials of more than 6 month´s duration, involving fluticasone or budesonide in chronic obstructive pulmonary disease. Included trials had to report on pneumonia adverse events. Data Analysis: we recorded the number of patients with pneumonia, and mortality, and calculated the pooled relative risk (RR) in a fixed effects meta-analysis. RESULTS: We identified 8 relevant trials covering 11800 patients, ranging from 44 weeks duration to 3 years. For Inhaled Corticosteroid used in combination with long-acting beta-agonist versus long-acting beta-agonist (5 trials), the pooled RR for pneumonia = 1.62 (95% CI = 1.37 to 1.92; p< 0.0001). The Number needed to harm (NNH) per year was estimated at 56. (95%CI: 38-92). There was no significant difference in overall or pneumonia-related mortality. For Inahled corticosteroid alone versus placebo (6 trials), the pooled RR for pneumonia = 1.76 (95% CI = 1.45 to 2.14; p< 0.0001). The NNH per year was estimated at 50 (95%CI 34-90). There was no significant difference in overall or pneumonia-related mortality. We did not find any significant statistical heterogeneity in the above analyses.

CONCLUSIONS: Inhaled corticosteroids significantly increase the risk of pneumonia

in patients with Chronic Obstructive Pulmonary Disease, irrespective of whether they

are used alone, or in combination with a long-acting beta-agonists.

3.

Epicardial Adipose Tissue As It Correlates With Atrial Conduction

Abnormalities In The Multiethnic Study of Atherosclerosis

Michael J Babcock, MD; David Goff, Jr., MD, PhD;

Elsayed Soliman, MD, MSc; Jingzhong Ding, MD, PhD

Clinical Research - Resident

Background: Epicardial and Pericardial Adipose Tissue (EAT/PAT) serves as a lipid

depot with pro-inflammatory implications for the myocardium. EAT has been

correlated with diastolic filling abnormalities, atrial enlargement, and atrial

arrhythmias. These depositions overlaying much of the conduction system might

also predispose to conduction abnormalities.

There is a notable lack of research in the current literature on arrhythmias in

patients with high amounts of EAT/PAT. Atrial fibrillation is often paroxysmal, hence

other electrical characteristics, such as p-wave abnormalities may be useful as a

surrogate marker of AF. We evaluated the association between PAT and measures of

p wave morphology in the Multi-Ethnic Study of Atheroslerosis.

Methods: Participants in the MESA sub-cohort (MESA 1,000) with pericardial fat

measurement and good quality EKGs were included in this study (N=996). Pearson

correlation coefficients were calculated for the correlations between pericardial fat

and the P wave morphology variables. Differences between the means of each P

wave morphology variable across pericardial fat quartiles were calculated using

analysis of variance (ANOVA).

Results: After adjusting for age, sex and ethnicity, greater pericardial fat was

associated with longer p wave durations with greater p wave terminal force, but not

with PR duration. Adjustment for body mass index, or waist circumference

attenuated these associations.

Conclusion: PAT may play a local role in promoting conduction delay in the atrium.

4.

Increasing Screening diabetic eye examinations in North Carolina

(ISEEinNC): Description and First Two Year’s Experience (October 2005 –

September 2006)

Ramon Velez, MD, MSc; Marshall E. Tyler, BS, CRA;

John Chen, MD, PhD; Michael Babcock, MD; and William Moran, MD, MPH


Background: Diabetic retinopathy is the leading cause of preventable blindness in

adults as well as the most dreaded complication diabetic patients’ fear. Evidence-

based guidelines recommend that patients have annual or bi-annual eye

examinations by healthcare professionals to screen for vision-threatening

retinopathy. A recent study examining the quality of diabetic care among low-

income patients in North Carolina, dilated eye examination were documented in only

6% of these patients.

We report on the first two year’s of operations of project “I See in NC”.

Project “I See in NC” was designed to evaluate the feasibility and cost-effectiveness

of the use of high resolution digital photography in screening for sight-threatening

diabetic eye disease among Medicaid enrollees in two Medicaid Community Care

Networks. The intervention was to place a trained photographer in each network to

screen Medicaid and uninsured diabetic patients using a high resolution digital fundus

camera. We report on our first two years of operation.

Methods: We queried 2,004 Medicaid claims data and identified 856 adults with

diagnoses of diabetes eligible for inclusion in this study in the Central Piedmont

Access II Network and 1,071 in the Lower Cape Fear Access III Network. Screening

was performed in primary care offices and at health departments and free clinics

serving uninsured patients. At screening, all participants had their vision checked,

then had their pupils dilated. At least two retinal photographs were obtained and

each patient completed a questionnaire that included their age, sex race, previous

history of dilated eye examination, duration of diabetes, self-reported vision changes

in the previous year, knowledge of co-morbid conditions, and whether they were

aware of any existing retinopathy.

Photographs were uploaded on the internet using secured methods and stored in a

central computer at Wake Forest University School of Medicine. These photographs

were read by trained readers with the back up of an ophthalmologist. Reports were

generated and recommendations regarding referrals to ophthalmologist for further

evaluation and/or treatment of sight-threatening diabetic retinopathy.

Results: Currently in analysis

Conclusion: Pending analysis

5.

Impact of Nursing Education and Assessment on a Population of Diabetic

Patients

Christina Bellinger, MD; Karla Brown, RN; Carolyn Pedley, MD


Background: In the setting of a residency training clinic, nursing staff is often

underutilized in the education, management and tracking of diabetics.

Nurses are present in the clinic full time and represent an untapped resource in the

field of diabetic management that needs to be better developed. Through a

standardized screening and educational questionnaire a program was implemented

to improve outcomes in managing a diabetic population.

Methods: In a residency training clinic in Winston Salem, NC, nurses conducted a

questionnaire of 269 diabetics to assess weight, blood pressure, yearly eye exams,

flu shots, daily self-foot exams, self-reported exercise, glucometer use, and bringing

a record of the readings to clinic. During the questionnaire, nurses educated the

patient individually on blood glucose monitoring training, insulin administration,

nutrition, and the importance of medical compliance. One year after the intervention,

these parameters were reassessed including noting before and after hemoglobin A1c

and patient weight.

Results: In this residency setting, initial analysis of 269 diabetic patients revealed a

majority with hypertension (77 to 86%) and obesity (average BMI = 34, average

weight 209). After nursing education intervention, more patients owned glucometers

(98% vs 84%) but there was no increase in bringing blood sugar records to clinic

(18% vs 22%). The frequency of eye exams within the last year remained the same

(68%) while the frequency of yearly flu shots declined (66% to 29%). Weight and

BMI remained the same, as did HgbA1c (8.1 from 8.2).

Conclusion: In this study, education of a diabetic population by nursing staff did

not achieve improvement in weight/BMI, yearly eye exams, yearly flu shots, bringing

blood sugar records to clinic, or hemoglobin A1c. Perhaps a more intensive approach

to diabetic management is needed to achieve improvement in patient compliance,

weight management and hemoglobin A1c.

6.

Resident Survey of Transfusion Thresholds

Bellinger C, Passmore L, Pomper G and Morris P


Background: Transfusions are associated with multiple risks ranging from mild

reactions to life-threatening complications. Retrospective studies show that

physicians routinely over-transfuse, likely producing adverse outcomes. This study

assessed residents’ transfusion thresholds for platelets, plasma and blood in various

scenarios to build future educational interventions and reduce unnecessary

transfusions.

Methods: An IRB-approved web-based survey was designed using software

developed by Survey Monkey and was electronically mailed to all Internal Medicine,

Surgery, Emergency Medicine and Radiology residents within North Carolina Baptist

Hospital (NCBH). It assessed residents' transfusion thresholds for platelets, plasma

and blood in various scenarios. The responses were compared to hospital guidelines

at this institution which represent current standards of care.

Results: The overall response rates was 64% (119 of 185 residents). For platelet

transfusion threshold in the setting of an impending procedure, the hospital guideline

is 50,000 platelets/µL. Forty-five percent of residents entered 50,000 platelets/µL,

while 49% entered lower platelet thresholds. For plasma transfusion in the setting of

an impending procedure, the hospital guideline is an INR of 1.5. Forty-two percent

of residents entered 1.5 for this scenario while 45% entered higher INR transfusion

thresholds. For blood transfusion in the setting of known coronary artery disease,

the hospital guideline is a hemoglobin goal of 8g/dL. Thirty-four percent of residents

entered 8g/dL as their transfusion threshold in this scenario, while 53% entered a

higher hemoglobin goal. For blood transfusion in the setting of active coronary

ischemia, the hospital guideline is a hemoglobin goal of 10g/dL. Eighty-one percent

of residents entered 10g/dL as their transfusion threshold in this scenario.

Conclusion: Although literature has shown the tendency of physicians to over-

transfuse, this survey demonstrated a variation in transfusion thresholds for

platelets, plasma and blood ranging among residents. A more structured learning

program may decrease transfusion discrepancies between specialties and post-

graduate year and create a more unified approach to reach the standard of care in

transfusion medicine.

7.

The Prognosis of PCWP and CVP Discordance among Patients with Systolic

Heart Failure

Harris W, Thohan V, Kumar R


OBJECTIVE: To determine whether patients with left ventricular systolic dysfunction

(LVSD) and discordance between right atrial pressure (RAP) and pulmonary capillary

wedge pressure (PCWP) have a worse prognosis when compared to those with LVSD

and concordance between RAP and PCWP.

BACKGROUND: The prognosis of patients with LVSD and congestive heart failure

has long been studied so as to guide treatment guidelines and help allocate scarce

resources most appropriately. In attempts to better stratify these patients, multiple

authors have published data on hemodynamics as prognostic indicators in chronic

heart failure patients. Anecdotal observation at our center seemed to suggest that

chronic heart failure patients with high PCWP and discordance (defined by the PCWP

being at least 12 mm Hg greater than the RAP) in their measured RAP and PCWP

pretends a poor prognosis and higher mortality when compared to those with

hemodynamic concordance (difference of 11 mm Hg or less). The purpose of this

study was to determine the relationship of this phenomenon to prognosis.

METHODS: We analyzed the charts of all patients that received right heart

catheterizations between 1999 and 2007 who had a PCWP of 18 mm Hg or greater.

We excluded those with left ventricular ejection fraction (LVEF) > 35% as

determined by subsequent left ventriculogram or 2D Doppler Echocardiogram. We

also excluded patients with severe right ventricular failure, mitral valve prosthesis

and significant mitral valve stenosis.

RESULTS: After all patients were screened for complete recording of hemodynamics

and limited by inclusion and exclusion criteria, there were 76 in the discordance

group and 51 in the concordance group. Though the 365 day mortality was 23.7%

(18/76) and 17.6% (9/51) in the discordant and concordant groups respectively, the

concordant group had a higher rate of death and rehospitalization combined (76.5%)

than did the discordant group (65.8%).

CONCLUSIONS: This study has significant limitations in sample size and the sole

reliability of our center’s records for sufficient follow up of rehospitalization rates.

There is not a significant increase in the 365 day mortality among the discordant

group to support the hypothesis. The increase in the rate of death and

rehospitalization rate for the concordant group over the discordant group may

reiterate longstanding evidence that right heart failure predicts a worse prognosis in

patients with congestive heart failure. Evaluating the right ventricular function of

these patients using 2D Echocardiography would help to ensure that this discrepancy

can be contributed to right ventricular dysfunction.

8.

Hepatic Steatosis and Subclinical Cardiovascular Disease in a Cohort

Enriched for Type 2 Diabetes: the Diabetes Heart Study

Ryan L. McKimmie MD1, Kurt R. Daniel DO MS2, J. Jeffrey Carr MD MS3, Donald W.

Bowden PhD4, Barry I. Freedman MD5, Thomas C. Register, PhD6, Fang-Chi Hsu,

PhD7, Kurt K. Lohman, MS8 Richard B. Weinberg, MD9, Lynne E. Wagenknecht PhD10


Background: To explore possible mechanisms whereby hepatic steatosis (HS) is

associated with increased cardiovascular risk in persons with diabetes, we

investigated the cross-sectional relationships between HS, regional fat distribution,

inflammatory biomarkers, and subclinical measures of atherosclerosis in the Diabetes

Heart Study (DHS), a family study of sibling pairs concordant for type 2 diabetes.

Methods: The following parameters were obtained in 623 randomly selected DHS

participants: computed tomography (CT) liver attenuation density (a liver:spleen

attenuation ratio (L:SAR) < 1.0 is indicative of HS, and decreasing values signify

worsening HS); visceral and subcutaneous fat distribution by CT; Body Mass Index

(BMI); serum C-reactive protein (CRP) and adiponectin; coronary, aortic, and carotid

artery calcium by CT; and carotid atherosclerosis by B-mode ultrasound.

Associations between the L:SAR and these factors were expressed as simple or

partial Spearman correlations, and generalized estimating equations (GEE) were

used to adjust for familial correlations.

Results: After adjustment for age, race, gender, BMI, and diabetes status, the

amount of HS expressed as the L:SAR correlated with the amount of visceral fat (r: -

0.22, p <0.0001) and subcutaneous fat (r: -0.13, p: 0.031). HS was positively

associated with an atherogenic lipid profile, including lower HDL (r: 0.21, p <0.0001)

and higher triglycerides (r: -0.25, p <0.0001). Higher CRP (r: -0.095, p: 0.004) and

lower serum adiponectin (r: 0.34, p <0.0001) were observed in the setting of HS,

indicating a pro-inflammatory state. There were no statistically significant

associations between the L:SAR and coronary, aortic, or carotid calcium or carotid

intimal thickness when controlling for age, gender, race, diabetes status, smoking

history, visceral adiposity, and CRP.

Conclusions: The strong correlations observed between HS and pro-atherogenic

biomarkers and characteristics of the metabolic syndrome suggest that HS reflects

more than just general adiposity, but represents a systemic, inflammatory, pro-

atherogenic adipose state. Our data suggest that HS is less likely to be a direct

mediator of cardiovascular disease and may be more appropriately described as an

epiphenomenon.

9.

The Evaluation of Bronchoscopy in Patients with Acute Leukemia: A

Retrospective Chart Review

John Piede, MD; Doug Case, PhD; Kevin High, MD;

Leslie Ellis, MD; Bayard Powell, MD


Background: Pulmonary infiltrates are a well-documented complication in acute

leukemia patients and are treated according to guidelines established for the febrile

and neutropenic patient. However, obtaining specific identification of the causative

organism, and therefore identifying the optimal treatment for the infection, has

posed a significant challenge. Bronchoscopy has remained an option for a more

definitive diagnosis, but the yield from this invasive method is limited and not

without risk. Although some diagnostic yield has been shown, it remains unclear

whether the data obtained from bronchoscopy affects clinical management. This

information is of great clinical importance should the data reveal that bronchoscopy

does not significantly affect medical management, thus allowing us to spare patients

from an unnecessary, invasive, and risky procedure. The primary objectives of this

study are to characterize the data obtained from bronchoscopy and to determine if

this information alters antimicrobial therapy.

Methods: In this study, we have begun a retrospective chart review of 207 adult

acute leukemic patients who underwent bronchoscopy at Wake Forest University

Baptist Hospital between 2001-2007.

Results: Thus far, 65% (95% CI, 54-76%) of all gram stains and 89% (95% CI,

83-93%) of all cultures yielded no pathogen. Further, only 11% (95% CI, 4-23%) of

positive bacterial cultures and 4% (95% CI, 0.4-13%) of positive fungal cultures

resulted in a directed change in medical therapy.

Conclusion: This data suggests there is a low yield in the identification of a

definitive pathogen and few cases of a directed change in antimicrobial therapy in

patients with acute leukemia who undergo bronchoscopy at our institution.

10.

Meta-analysis: Gastrointestinal Bleeding Due To Interaction Between

Selective Serotonin Reuptake Inhibitors And Non-steroidal Anti-

inflammatory Drugs

Apurva Trivedi, MD; Sonal Singh, MD; Yoon Loke, MBBS, MD


Background: Selective serotonin reuptake inhibitors (SSRIs) have been associated

with upper gastrointestinal haemorrhage (UGIH) but the magnitude and

characteristics of this reaction and possible interaction with concurrent Non-Steroidal

Anti-Inflammatory Drug (NSAID) therapy are unknown. The aim of this study was to

evaluate systematically the risk of UGIH with SSRIs, including interaction with

NSAIDs. We searched PubMED, Science Citation Index, and trial registries for data

on SSRIs, NSAIDs and UGIH.

Methods: We evaluated spontaneous case reports from pharmacovigilance

databases.

Results: Random effects meta-analysis of four observational studies involving 153

000 patients showed an odds ratio of 2.36 (95% CI: 1.44–3.85; P = 0.0006) for

SSRI associated UGIH. The odds ratio increased to 6.33 (95% CI: 3.40–11.8; P <

0.00001) with concomitant NSAIDs. In patients aged above 50 years with no UGIH

risk factors, the Number-Needed-to-Harm per year is 411 for SSRIs alone, and 106

with concomitant NSAIDs. Analysis of 101 spontaneous reports showed that UGIH

occurred after a median of 25 weeks with SSRIs. Around 67% of these patients were

on NSAIDs.

Conclusion: Selective serotonin reuptake inhibitor use, alone and in combination

with NSAIDs, substantially increases the risk of UGIH. Clinicians should consider this

when managing patients at risk of, or presenting with UGIH.

11.

Fluid resuscitation volume for septic shock patients was not decreased for

Echocardiogram-determined left ventricular (LV) systolic dysfunction

patients when managed with Early Goal Directed Therapy (EGDT)

Updaw R, Passmore L, Pierce C, Ross A, Mitten-Long D, Wells G, Morris P


Background: We sought to determine whether LV systolic dysfunction might inhibit

physicians from administering protocolized fluid resuscitation in septic shock

patients.

Methods: Medical ICU (MICU) patients (Pts) were reviewed prospectively for a 12

month period for the presence of severe sepsis. A sepsis-EGDT protocol was

available with specific recommendations for volume of administration and

hemodynamic endpoints. Pts with echocardiograms (echos) within the 1st 24 hrs of

admission were analyzed for fluid resuscitation volumes in the 1st 6 hrs. Pts with

echos were separated into abnormal (Ejection fraction <45%; severe aortic

regurgitation; severe mitral stenosis) and normal LV systolic function, excluding poor

quality studies. Volume of resuscitation, ventilator days, MICU days and mortality

were compared by t-test using log transformed data when appropriate, significance

was considered at p<0.05.

Results: 398 severe sepsis patients were reviewed, 169 with echos in the 1st 24

hrs of MICU admission. 42/169 were in septic shock with evaluable echos. The

resuscitation volume within the first 6 hours for the LV systolic dysfunction (n=23)

group was 542 cc's/hr and 692 cc's/hr for the normal LV function (n=19) group,

respectfully (p = .36). No significant difference existed between the groups in terms

of ventilator days (med 4 vs 9, p = .14), hospital days (med 16.4 vs 10.4, p = 0.55),

or mortality (37% vs. 35%, chi square, p= .89).

Conclusions: LV systolic dysfunction was not associated with reduced volume of

fluid resuscitation administered to septic shock patients compared to normal LV

function patients. Additionally, with a sepsis-EGDT protocol in place, there were no

statistically significant differences between groups in regards to hospital days, MICU

days or mortality.

Clinical Implications: LV Systolic dysfunction Septic Shock patients were managed

with similar fluid resuscitation volumes as normal LV function septic shock patients

and demonstrated similar hospital outcomes in this pilot study, which appears to

support the notion that fluid administration to septic shock patients with LV systolic

dysfunction can be guided by EGDT guidelines without untoward outcomes.

12.

The Utility of Dobutamine Cardiovascular Magnetic Resonance Results for

Identifying Cardiac Prognosis in Women

Eric L. Wallace, Timothy M. Morgan, Thomas F. Walsh, IV, Erica Dall` Armellina,

William Ntim, Craig A. Hamilton, W. Gregory Hundley


Background: Dobutamine cardiovascular magnetic resonance (DCMR) has been

demonstrated to be suitable noninvasive stress imaging modality for identifying

cardiac risk. To date the majority of participants have been men in these studies

indicating that inducible ischemia identified during dobutamine cardiovascular

magnetic resonance (DCMR) is associated with future myocardial infarction (MI) and

cardiac death. Whether inducible ischemia during DCMR predicts cardiac events in

women is unknown.

Methods: Two hundred twenty-one women, aged 32 to 88 years, underwent DCMR

in which left ventricular wall motion (LVWM) was assessed at rest and after

intravenous dobutamine and atropine administered to achieve 80% of the maximum

predicted heart rate response for age. Inducible ischemia was defined as

deterioration in LVWM during infusion. Women were contacted to determine the

incidence of a cardiac death, MI, revascularization, unstable angina or congestive

heart failure, with a mean follow-up of 6.2 years. All events were confirmed by

review of their medical record.

Results: Demographics of the patients’ risk factors, medications, and study results

were recorded. Twenty-seven percent of women experienced had new wall motion

abnormalities indicative of inducible ischemia during testing. In those with and

without inducible ischemia, the all event rate was 63.0% and 30.0% while hard

event rate was 33.3% and 7.5%, respectively. The hazard ration (HR) for

experiencing a cardiac event was 3.3 (p<0.0001) and hard event was 5.4,

(p<0.0001), for those with versus without inducible ischemia. Prior

Revascularization (p=0.05) and LVEF less than 40% (p=0.002) were also significant

predictors of all cardiac events.

Conclusions: Inducible ischemia during DCMR predicts cardiac death and MI in

women. DCMR is a suitable noninvasive stress imaging modality for identifying

cardiac risk in women.

13.

A Case of a Spontaneous Coronary Artery Dissection (SCAD)

Benjamin Susco, MD; Rahul Kumar, MD; Vinay Thohan, MD

Clinical Vignette - Resident

Learning Objectives:

Recognize coronary artery dissection as a potential diagnosis in patients with

chest pain.

Understand the three groups with the highest risk.

Discuss the clinical presentation, diagnosis and therapy.

Case: A 33 year old Hispanic female with no significant past medical history or

cardiac risk factors presented to the hospital after collapsing due to acute chest pain

of 1 hour duration. The pain was sudden in onset, described as “sharp,” and was

associated with diaphoresis, nausea, vomiting, and eventually transient loss of

consciousness. She did not take oral contraceptive pills, herbal supplements or illicit

drugs. Upon arrival, she was hypotensive, tachycardiac, and tachypneic. The exam

showed a faint S1 / S2, bibasilar crackles, flat jugular veins and weak peripheral

pulses. The initial EKG was negative for any ischemic changes; however within ½

hour of presentation, she developed ST-elevations in her anterolateral leads with a

troponin I of 22.1 ng/mL. Emergent catheterization revealed left main coronary

artery dissection with extension into the proximal LAD and occlusion distal to this

site. The patient required a bare metal stent in her left main coronary artery. Due

to persistent cardiogenic shock, the patient required mechanical ventilation, an

intraaortic balloon pump, and vasopressor agents.

Discussion: SCAD is a rare occurrence and is defined by a separation of the tunica

media by hemorrhage with or without an associated intimal tear, and can obstruct

flow distally causing ischemia and infarction. SCAD has been observed in 3 groups

of patients: in those with atherosclerotic disease, in women during the peri- and

early postpartum period, and in a third group without any risk factors (idiopathic).

Most SCADs occur in women during the peripartum period with the LAD artery most

frequently involved. The RCA is most commonly involved in males. The mechanism

of dissection is likely a combination of factors including inflammatory infiltrates, lytic

enzymes and shear stress at the vessel walls. Diagnosis is made primarily by cardiac

catheterization, but CT coronary angiography is a new noninvasive approach to

diagnosis. The treatment of SCAD is tailored specifically to the patient’s clinical

course, hemodynamics along with the location and extent of coronary dissection.

14.

Malignant Phyllodes Tumor Metastatic to the Heart: a case report

Andrew Farland, MD; Joseph Foley, MD; Jimmy Ruiz, MD;

Daniel Entrikin MD; William Ntim, MD


Learning Objectives

1. Describe an unusual presentation of a rare form of breast cancer, Phyllodes

Tumor

2. Discuss prevalence and typical presentation of Phyllodes Tumor

3. Publish novel images of Metastatic Phyllodes Tumor to the Heart

Case: A 51-year-old white female presents to our institution with positional,

substernal pleuritic chest pain and a three-month history of scant hemoptysis. Three

years earlier, she was diagnosed with phyllodes tumor of the breast and underwent

right mastectomy with reconstruction. No evidence of metastatic disease was

detected on sentinel lymph node biopsy at that time. Two years after her initial

presentation, she was found to have pulmonary nodules with FNA confirming

metastatic phyllodes tumor. She received 6 cycles of CIVI-CAD and depsipeptide

with progression of disease to pelvic bones and scalp.

Her physical exam was unremarkable except for a low-grade fever and

evidence of skin metastases. There were neither cardiac murmurs nor findings

consistent w/ tamponade/pericardial effusion physiology. Cardiac markers and EKG

were unremarkable. CT of the chest with contrast noted a left atrial filling defect,

left pulmonary artery superior segment occlusion, moderate pericardial effusion, and

progression of pulmonary metastases. Cardiac MRI revealed multifocal cardiac

masses with lesions in the apical septum, anterior lateral wall of the left ventricle,

and a large cystic appearing lesion in the left atrium near the origin of the left

superior pulmonary vein.

The patient was treated supportively for her pain and started on palliative

chemotherapy prior to being discharged home.

Discussion: Phyllodes tumor, also known as Cystosarcoma Phyllodes, is an

uncommon fibroepithelial sarcoma of the breast and accounts for less than 0.5% of

all breast malignancies. These tumors display a wide range of clinical behavior and

are classified as malignant in 25% of all cases. In one study these tumors displayed

metastasis in less than 5% of cases.

Typical presentation of these tumors is that of a rapidly growing, painless breast

lump which can often cause superficial ulceration through the skin. Metastatic

spread to the pericardium or heart is quite rare and these patients usually present

with symptoms based on the location of their metastasis. Review of the literature

yielded only 3 case reports with only 7 cases total reported of this occurrence. All of

these were diagnosed at autopsy. Based on our review, there are no published

Cardiac CT or MRI images available of this clinical scenario as we have presented.

15.

Community Acquired Methicillin Resistant Staphylococcus Aureus (CA-

MRSA) and Infectious Endocarditis - A case report and systematic review

Eric Wallace, DO; Elizabeth Palavechino, MD; and Sonal Singh MD, MPH


Learning Objectives: To describe the emerging clinical spectrum of Community

Acquired- Methicillin Resistant Staph Aureus (CA-MRSA) endocarditis

Case: A 33-year-old male, previously healthy, was admitted with a cough, fever, and

multiple necrotic skin lesions for one week. On admission blood cultures were

positive for MRSA and physical exam noted an II/VI holosystolic murmur at the apex

and two necrotic skin lesions. TTE demonstrated a 14 mm vegetation on the anterior

leaflet of the mitral valve and patient later underwent annuloplasty ring placement.

The phenotype was consistent with CA-MRSA and PCR confirmed the genotype with

SCCmec IV and PVL positivity. Patient received six weeks of vancomycin and

gentamicin and survived to follow up at 2 months.

Discussion: A systematic review was performed by searching PubMed for all CA-

MRSA endocarditis. Only cases with documented Staphylococcal Cassette

Chromosome (SCC) IV mec patterns and known CA-MRSA phenotypes were

included. Seventeen reported cases of CA-MRSA endocarditis were identified. Data

was extracted on demographics, predisposing factors, clinical presentation, valvular

involvement, treatment, and outcome.

The presentation of CA-MRSA is variable. 7 patients had concomitant soft

tissue infections, and 12 patients presented with signs and symptoms consistent with

septic emboli. 10 patients were known intravenous drug abusers (IVDA), 6 of whom

had tricuspid valvular involvement. Among 3 patients who had mitral valvular

involvement, the anterior leaflet was involved in all these cases. Antibiotic regimens

included Vancomycin (n=14), Linezolid (n=2), or Daptomycin (n=1). Eleven patients

also received concomitant antibiotic therapy with Gentamicin (n=5), Rifampin (n=5)

and Clindamycin (n=1). 5 patients required surgical repair of the valves. 16 of the 17

patients survived to hospital discharge.

Conclusion: IVDA may be a risk factor for CA-MRSA endocarditis. The treatment is

usually medical with dual antibiotic therapy including vancomycin and the prognosis

appears favorable. Prospective epidemiological studies urgently needed.

16.

A Case Report of Amlodipine Induced Myoclonus

Kevin C. Lingle, MD; Eric L. Wallace, DO;

Dwayne A. Pierce, PharmD; Scott Satko, MD


There have been 7 reported cases of calcium channel blocker induced myoclonus in

the literature since 1978. It has been associated with verapamil, diltiazem, and

nifedipine. The symptoms described usually include uncontrollable, irregular,

symmetric jerking movements of the face, arms, legs, and/or torso. The onset of

symptoms have ranged from immediate to up to 10 months from the initiation of

therapy and have usually resolved within 24 hours of the cessation of the

medication; however some have taken up to 3 weeks to resolve. We describe the

first reported case of amlodipine-associated myoclonus. Our patient was a 79 year

old African American male admitted to the hospital with acute on chronic renal failure

and hypertension. He had previously been on an coreg, diovan and spironalactone

to control his hypertension; however secondary to his increased potassium and

elevated creatinine, his ARB and spironalactone were held. Off these medications,

his blood pressure got as high as 179/89 and norvasc 2.5 mg was added, which was

then titrated up to 10 mg daily. Within 72 hours of the addition of norvasc the

patient developed myoclonic jerking of his extremities. Norvasc was discontinued

and within 24 hours of discontinuing the medications his jerking movements

stopped. It appears that Amlodipine can cause Myoclonus and this may represent a

class effect with calcium blockers.

17.

MRSA Orbital Cellulitis presenting in a patient with untreated Graves

Hyperthyroidism

Michael J Babcock MD; Peter B Lichstein, MD


Learning Objectives

Rapid recognition of preorbital vs orbital cellulitis by appropriate imaging

modilities.

Staging of preorbital cellulitis.

Appropriate antimicrobial selection for typical bacteria seen in preorbital

cellulitis

Case: 24 year old Caucasian female with history of hyperthyroidism and remote

history of Hepatitis B and nasal cocaine use who initially presented to an outside

hospital with complaints of 3 days of increasing left sided nasal swelling that extends

to her forehead and involves left eye. Three days prior she noticed a pustule on the

left nare with increasing edema and rapidly tracking to the left side of her nose,

lower forehead, and eye with blurry vision, headaches, fevers, chills and general

malaise. She has baseline proptosis and was initially unalarmed by her

symptomatology. Blood cultures revealed initially staph aureus. Facial CT without

contrast demonstrated ethmoid and maxillary sinusitis, bilateral osteomeatal unit

disease and a deviated septum. MRI revealed left periorbital cellulitis and proptosis,

cellulitis of the left nasal bone and face as well as enhancement in the left optic

foramen with meningeal enhancement of the anterior left middle cranial fossa, a 1cm

abcess in left frontal sinus within the left supraorbital space and possible thrombosis

of the superior ophthalmic vein. She was initiated on ceftriaxone and vancomycin

and sent to our tertiary institution.

Upon arrival she had continued headaches and complete vision loss and severely

restricted eye movements in her left eye and near complete vision loss in her right

eye. She was found to be hyperthyroid with a TSH < 0.004 and free T4 of 5.6, free

T3 of 20.9. On reimaging her MRI revealed left-sided periorbital and retro-orbital

cellulitis with superior ophthalmic vein thrombosis and probably partial left cavernous

sinus thrombosis. Final blood culture results were obtained from the outside hospital which revealed MRSA. Her hyperthyroidism was treated with PTU and propranolol. Over the next several days she had an interval decrease in her swelling and proptosis as well defervescing. CT demonstrated decrease in edema and cellulitis. Upon discharge she had regained vision in both eyes and had significant clinical improvement. Follow up CT scan revealed no inflammatory process, or other abnormality of the orbit or visualized portion the brain and face and no dilated ophthalmic vein.

18.

Seizures: A Not So Rare Cause

Xanthia Samaropoulos, MD and Nancy Denizard-Thompson, MD

Clinical Vignette – Resident


1. Recognize that “active and remote” cysticercosis is one of the leading causes

of adult onset seizures worldwide.

2. Cysticercosis should always be considered in any patient from an endemic

area presenting with seizures.

Case: A 46yo Hispanic Female from Ecuador with a past medical history significant

for a known seizure disorder who presented to primary care clinic with signs and

symptoms consistent with anemia. She was found to have a profound microcytic

anemia. Patient was admitted to the hospital for a blood transfusion as well as a

workup for anemia. During her transfusion she had a syncopal episode. As part of

the subsequent syncope workup she had a routine head CT which showed

calcification within the left superior frontal gyrus at the cortical surface suggestive of

a prior infection with neurocysticercosis. Per the patient, she had previously been

seen by neurology two years prior for seizures and was thought to have

pseudoseizures, as no source for her seizures were identified at that time.

Discussion: Cysticercosis is the most common parasitic disease worldwide, with an

estimated prevalence greater than 50 million persons infected. It is endemic in

Mexico, Central and South America, and parts of Africa, Asia, and India.

Neurocysticercosis is the most prevalent infection of the brain world wide and more

than 1,000 new cases are diagnosed in the United Sates each year. Definitive

diagnosis is one absolute criterion (pathologic demonstration of parasite; cystic

lesion with scolex on neuroimaging; direct visualization on fundoscopic exam) or two

major criteria (lesions highly suggestive on neuroimaging; positive cysticercal

antibodies; resolution cysts after antiparasitic therapy) plus one minor criterion

(lesions compatible on neuroimaging; clinical manifestations suggestive of infection)

and one epidemiologic criterion (living or traveling to an area where cysticercosis is

endemic). Once thought to be clinically insignificant, there is growing evidence that

cerebral calcifications (as in our patient) are an important cause of seizures and focal

neurologic symptoms, particularly in light of an absence of other etiologies.

19.

A Rare Presentation of Hypothyroidism

Laurel Kilpatrick, MD; Nancy Denizard-Thompson, MD

Clinical Vignette - Resident Learning Objective: Recognize galactorrhea as a presenting symptom of hypothyroidism. Case: 33yo Hispanic female presented to the clinic for follow up of abdominal pain after evaluation in the Emergency Department. At the end of her visit, she mentioned she was concerned about a dark, milky discharge from both of her breasts. Her last menstrual cycle was 2 months prior and she denied pregnancy. Review of systems was positive for anorexia related to abdominal pain and diarrhea. She denied any symptoms of heat or cold intolerance, and no vision changes. A prolactin level returned elevated at 32.2 ng/ml and her pregnancy test was negative. Subsequent testing revealed an elevated TSH at 96.199 mciu/ml and positive thyroid antibodies. Patient was diagnosed with Hashimoto’s thyroiditis and started on levothyroxine therapy. At return visit she reported improvement in her symptoms while taking the levothyroxine. Discussion: Galactorrhea is a recognized, although uncommon, presentation of hypothyroidism. It is thought that low serum TSH levels disinhibit the release of thyrotropin releasing hormone (TRH), thus also increasing the release of prolactin. However, the incidence of hyperprolactinemia in the setting of hypothyroidism varies widely. Elucidating the underlying cause behind an elevated prolactin level becomes significant when patients present with associated pituitary enlargement. Confirming hypothyroidism and treatment with levothyroxine has shown to decrease prolactin levels as well as shrink the pituitary, thus preventing unnecessary and invasive procedures.

20.

A Modern Presentation of an Ancient Disease

Ryan L. McKimmie, MD


A 37-year-old Caucasian female with a history of multiple reported food allergies was

accepted in transfer to a Hematology service due to anemia and ecchymoses. She

reported a 3 week history of worsening lower extremity pain with easy bruising.

When she presented to her primary care physician’s office, she was noted to have

large ecchymoses extending from her bilateral knees to her ankles. A CBC revealed

a hemoglobin of 6.4 and a platelet count of 646. She was transferred to a tertiary

care center for workup of a presumed hematologic disorder.

Further history revealed that the patient had consumed a diet consisting

solely of hamburger meat, pretzels, cheese, and diet coke for several months. She

reported allergies to all other foods, although previous skin testing was positive only

for chicken and mustard. On physical exam, in addition to the prominent

ecchymoses, there was evidence of gingival hypertrophy and mild gingival bleeding.

A full hematologic work-up was initiated which was notable only for a microcytic,

hypochromic iron-deficiency anemia. A peripheral blood smear was normal,

coagulation studies were normal, and LDH and haptoglobin were within the reference

range. Computed tomography of the patient’s lower extremities demonstrated

findings suggestive of aggressive osteoporosis. Given the patient’s dietary history,

several vitamin levels were obtained. All were normal with the exception of the

patient’s vitamin C level which was measured at <0.12. Therefore, the patient’s

symptoms were attributed to ascorbic acid deficiency, historically known as scurvy.

She was treated with high dose vitamin C supplementation (2 g per day for one week

followed by 500 mg per day thereafter). She was also referred for intensive

outpatient nutritional counseling. Her gingival bleeding had already begun to

improve at the time of discharge.

This case illustrates the importance of including on one’s differential diagnosis

ancient diseases which modern medicine has supposedly rendered obsolete. Given

the patient’s history and physical findings, she was at high risk for scurvy. However,

few laboratory tests are useful in confirming the diagnosis other than the vitamin C

level. A microcytic, hypochromic anemia and findings of osteoporosis are features of

scurvy but are non-specific. Maintaining clinical acumen in the era of modern

medicine is invaluable for diagnosing conditions that have slipped from most

clinicians’ radar.

21.

Idiopathic CD4 Lymphopenia and Behçet’s Syndrome

Brian Shaffer, MD

Clinical Vignette – Resident

Introduction: We report a patient with idiopathic CD4 lymphopenia and Behçet’s

disease consisting of uveitis, recurrent oral and scrotal aphthous ulcers, and a

central nervous system vascular inflammatory process. The relationship of T-cell

lymphocyte function and the pathogenesis of Behçet’s disease is discussed.

Case: A 27 year old male initially presented with worsening neurologic function and

uveitis. Magnetic resonance imaging of the brain demonstrated multiple areas of

heterogenous enhancement in the right basal ganglia, thalamus, and bilateral pons.

Stereotactic brain biopsy demonstrated perivascular and parenchymal infiltration of T

lymphocytes. The CD4+ T-lymphocyte count was 50 cell/mcL; however, there was

no serologic evidence of HIV or HTLV-1/2. A subpopulation of CD3+CD4-CD8- T

lymphocytes was not noted in this patient. RNA/PCR for HIV was additionally

negative. The patient demonstrated a relapsing course of neurologic decline over the

next eleven months, with partial improvement on short course of systemic

corticosteroids. Eleven months after presentation with central nervous system

vasculopathy and uveitis he developed multiple episodes of oral and scrotal aphthous

ulcers. He was begun on prolonged corticosteroids with clinical improvement

thereafter. His CD4 lymphopenia did not correlate with disease activity.

Conculsion: While Behçet’s disease is frequently associated with HIV induced CD4

lymphopenia, we report a Behçet’s syndrome associated with idiopathic CD4

lymphopenia.1, 2 A previously noted CD3+CD4-CD8- T lymphocyte population was

not noted in this individual.3 We discuss the relationship of T-lymphocyte physiology

and Behçet’s disease.

1. Venzor J, et al. Behçet’s like syndrome associated with idiopathic CD4+ T-

lymphocytopenia, opportunistic infections, and a large population of TCR

alpha beta+ CD4-CD8- T cells. Am J Med Sci. 1997 Apr;313(4):236-8.

2. Zhang X et al. Distinctive rheumatic manifestations in 98 patients with human

immunodeficiency virus infection in China. J Rheumatol. 2007 Aug;

34(8):1760-4.

3. Ling E et al. Increased proportion of CD3+CD4-CD8- double-negative T

cells in peripheral blood of children with Behçet’s disease. Autoimmun Rev. 2007

Mar;6(4):237-40.

22. Prototheca: Revealing Serious Consequences in a Predisposed Host

GiGi MacDonald, MD and Jimmy Ruiz, MD


Learning Objectives: Recognizing the devastating consequences of protothecosis

in an immunocompromised host.

Case: A 75 year old white female presented to a local hospital detailing a 5 month

history of gradual enlarging areas of erythema on her forearms and legs with

dramatic worsening over the previous two weeks. She described areas of

progressive ulcerations as severely painful pin prick holes weeping fluid. Her

presentation was prompted by the development of chills, shortness of breath,

dysphagia, anorexia and fatigue. Significant medical history includes diabetes

mellitus; breast cancer; coronary artery disease; and congestive heart failure.

Pertinent medications included a several day history of keflex and diflucan use. In

addition, oral and topical steroid use for several months, exact time course unknown.

2 weeks prior to presentation the patient was diagnosed prototheca Wickerhamii, as

well as a super-imposed enterococcus Faecalis and coagulase negative staphylococci

infections. During hospitalization the patient’s clinical condition continued to

deteriorate until the time of her death despite appropriate, aggressive care.

Discussion: Protothecosis is an infection caused by achlorophyllous, algae of the

genus Prototheca. Prototheca species are ubiquitous in the environment.

Predisposing factors include diabetes, prolonged steroid use, chemotherapy,

immunosuppressive therapy, and severe underlying illness. Currently, there is no

gold standard for treatment of Protothecosis. Azole antifungals and surgery versus

surgery alone should be employed in a subset of immunocompetent patients with

localized disease. Ampotericin B should be considered as first line therapy with

severe underlying illness, immunocompromise, and/or disseminated disease

Although a few cases of protothecosis have been described, this case

highlights a severe bacterial and protozoan superinfection leading to poor outcome.

Continued identification of protothecosis is warranted and further research is needed

to establish goals of treatment to prevent future deaths.

23.

A Case Report: Pulmonary Artery Dissection

McKay Crowley, MD; April Yasunaga, MD; Joseph Foley, MD;

Gregory Hundley, MD; Frederic Kahl, MD



1. Present a rare case of Pulmonary Artery Dissection.

2. Publish novel images of Pulmonary Artery Dissection.

3. Briefly discuss etiology and treatment options.

Case: A 74-year-old Caucasian female presented to our hospital complaining of

acute onset of shortness of breath and increasing dyspnea on exertion. She was

without chest pain, cough, hemoptysis, increased sputum production, fever, or calf

swelling or pain. Her history was significant for severe COPD requiring continuous

supplemental oxygen and obstructive sleep apnea requiring nightly BIPAP.

Her vital signs and examination were within normal limits except for mildly

decreased breath sounds. Initial diagnostic evaluation revealed negative cardiac

enzymes, compensated chronic respiratory acidosis with pCO2 of 76 and negative

urine drug screen. Her CXR showed signs of severe pulmonary hypertension and EKG

showed nonspecific ST-T wave changes.

CT of the chest with PE protocol showed an enlarged right atrium and right

ventricle suggestive of pulmonary arterial hypertension. The main pulmonary trunk

measured 5.3 cm with a flap indicative of a dissection within the main pulmonary

artery. There was no evidence of pericardial effusion, pulmonary emboli, or thoracic

aorta abnormalities.

TTE failed to show elevated pulmonary pressures or signs of right heart

strain. She had diastolic dysfunction with an ejection fraction of 62%.

Cardiac MRI showed dilated right sided cardiac chambers with reduced RV

systolic function. The main pulmonary artery was dilated from 5.2 to 5.6 cm in

diameter with an inferiorly located dissection again noted. Within the true lumen,

flow was all forward and the output was 3.1 L/min. In the false lumen, flow was

bidirectional and the net flow was negative at 1.25 L/min.

Cardiothoracic Surgery recommended medical management. The patient

remained stable throughout her hospitalization and was discharged without

complication with recommendation for outpatient initiation of ACE Inhibitor therapy if

hemodynamically stable.

Discussion: Pulmonary artery dissection is a very rare entity. Available literature is

limited to case reports. These dissections most commonly develop in the setting of

both primary and secondary pulmonary arterial hypertension. Our patient did not

have pulmonary hypertension and to our knowledge there have been only 12

patients described with pulmonary artery dissections in the absence of pulmonary

hypertension.1 The majority (86%) of cases are diagnosed at autopsy. However,

advances in cardiac imaging such as MRI, as in the case in our patient, may enable

the diagnosis to be made during life. Treatment typically is by surgical repair,

however, conservative medical management with diuretics and vasodilators has been

effective in a small number of patient that have chosen not to undergo surgery.3

24.

Regulation of GP IIA sPLA2 mRNA Production in a Human Monocyte Cell

Model (THP-1)

Russell A. Blair, MD; Robert D. Hite, MD; Michael C. Seeds, PhD

Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases

Basic Research - Fellow

Background: Surfactant dysfunction is recognized as a component of lung injury.

Previous research examining BAL fluid during inflammatory lung injury and ARDS

suggests secretory phospholipases A2 (sPLA2) hydrolyze surfactant phospholipids and

contribute to surfactant dysfunction. Further evidence from BAL fluid suggests that

inflammatory cytokines such as IL-6 and TNF- are also involved in this process. We

hypothesize that sPLA2 IIA may be produced in lung macrophages in response to

inflammatory cytokines during ALI and ARDS. We have tested this hypothesis using

the monocyte cell line THP-1 after stimulation with the cytokines IL-6 and TNF-.

Methods: Cultured undifferentiated THP-1 cells were exposed to TNF- and IL-6 for

a time course of 1-72 hours. At each time point, cells were harvested, total RNA

extracted and Gp IIA sPLA2 mRNA quantified by fluorescent real time RT-PCR. Cell

supernatants were measured for secretion of group IIA sPLA2 by assaying the

hydrolysis of [H3] labeled E. coli membranes.

Results: THP-1 cells stimulated for short time courses (1-6 hours) tended towards

increased expression of Group IIA sPLA2 mRNA. Specifically, at 3 hours 100ng/ml of

TNF produced a 20-fold (p=0.1) increase in sPLA2. However, significant production of

sPLA2 was not seen in undifferentiated THP-1 cells with either TNF- or IL-6.

Incubation with cytokines for 12-72 hours also showed no significant changes in

sPLA2 Gp IIA mRNA expression. Furthermore, hydrolysis data indicates that there

was a non-significant increase in protein secretion.

Conclusion: Expression of Gp IIA sPLA2 was not increased by exposure of THP-1

cells to IL-6 and TNF-, which suggests that undifferentiated monocytes may not be

a source of Gp IIA sPLA2 seen in ALI/ARDS. Future plans include investigation of

cytokine effects on differentiated THP-1 cells in comparison with airway epithelial

cells.

25.

Collagen Type I Fragments Associate with Cytokines and Cell Counts in

Sputum of Severe and Nonsevere Asthmatics.

C.G. Cauthen, MD; A.T. Hastie, PhD; M. Wu; P.L. Vestal, MS; W.C. Moore, MD;

J. Krings, RN; R.V. Smith, RN; E.R. Bleecker, MD and S.P. Peters, MD, PhD



Rationale: Previous reports found that collagen fragments were increased in sputum

of asthmatics and decreased after inhaled steroids. We hypothesized that airway

remodeling in asthma results in collagen degradation, varying with disease severity.

Methods: Sputum supernatants from 242 asthmatics, enrolled and fully

characterized in the Severe Asthma Research Program, were analyzed by SDS-PAGE

and Western blots probed with anti-collagen I (Col I) antibody. Col I band densities,

cell counts, cytokine and matrix metalloproteinase ELISA results were analyzed by

standard statistical tests.

Results: Fragments of Col I were observed at 103, 72, 56, 40, 33 kD (bands 1-5,

respectively). The sum total of Col I bands did not differ between nonsevere and

severe asthmatics, however, Col I band 4 (40 kD) was significantly less in severe

asthmatics (% of total, t-test p<0.001). Col I band 4 was negatively associated with

sputum neutrophils (multiple linear regression, R=0.41, coefficient=-.21, p<0.001).

Col I band 4 was also negatively associated with CCL18 (R=0.30, coefficient=-0.04,

p=0.003) and positively associated with MMP9 (R=0.20, coefficient=0.0004,

p=0.04). In addition, MMP1 (which can produce Col I band 4) was reduced in sputum

from severe compared to nonsevere asthmatics (p=0.03).

Conclusions: Total sputum collagen I fragments were observed across all severities

of asthma but did not differ. However, severe asthmatic sputum contained less of Col

I fragment, band 4, which negatively correlated with sputum neutrophils and CCL18,

but positively with MMP9. Furthermore, MMP1 was reduced in severe asthma

sputum. This suggests that collagen degradation is less in more severe asthma.

Funded By: NHLBI 069167,067663

26.

Genetic Variation in Pulmonary and Activation-Regulated Chemokine

(PARC/CCL18) in Asthma

C.D. Perry, MD1, G.A. Hawkins, PhD1, A.T. Hastie, PhD1,

C.G. Cauthen, MD1, A. Diallo1, H. Li, MS1, W.C. Moore, MD1,

D.A. Meyers, PhD1, S.P. Peters, MD, PhD1, and E.R. Bleecker, MD1



Rationale: PARC/CCL18 has been implicated in a number of inflammatory disease

processes. This chemokine is strongly expressed in healthy human lung, mainly

secreted by antigen presenting cells. We observed higher levels of CCL18 in sputum

from Caucasians compared to other races. We hypothesized that genetic variation

may account for this difference.

Methods: Subjects enrolled in the Severe Asthma Research Program (SARP; N=451

Caucasian 165 African American) were fully characterized and genotyped for CCL18

SNPs which were identified from resequencing and HAPMAP. Standard statistical

tests were performed.

Results: Four novel SNPs were identified in all racial groups. Based on frequencies

of novel SNPs and tagging SNPs identified in HAPMAP, 8 SNPs were genotyped in the

SARP population. No significance was observed with severity, healthcare utilization or

lung function measures. An association for CCL18 levels in sputum was observed

with 1 of the novel SNPs (at -669, p=0.01) in African Americans, but not in

Caucasians. These may be in strong linkage disequilibrium with other variations not

genotyped in this study or affected by gene-gene interactions.

Conclusions: New variation was identified in the CCL18 gene. Although no

difference was observed in asthmatics based on severity or other phenotypes, some

association was noted for variation in the promoter region of the gene and levels of

CCL18 in sputum of African Americans.

Funded By: NHLBI 069116, 069130, 069149, 069155, 069167, 069170, 069174,

069349

27.

Quantitative PCR Outperforms Restriction Enzyme Digestion For Detection

of the JAK2 Mutation in Myeloproliferative Diseases

Gregg Shepard, Heather Lawson, John Owen

Section on Hematology and Oncology


Background: The identification of the JAK2 V617F clonal genetic abnormality as a

causative mutation in patients with myeloproliferative disorders (MPDs) promises to

make the diagnosis and management of these heterogeneous disorders simpler.

Expert recommendations now incorporate diagnostic testing for this mutation.

Because the JAK2 V617F mutation presumably does not occur in spurious or reactive

elevations of blood counts, identification of such mutations could confirm a diagnosis

without the need for extensive exclusion criteria or other tests. The mutation status

of over 4000 patients has been reported with the purpose of defining the mutation

prevalence in various disorders. Different laboratory methods have been used to

detect the mutation, and the percent of patients positive depends partially on the

sensitivity of the test.

Methods: All patients provided informed consent for blood specimen analysis and

medical record review, and signed the document approved by the Institutional

Review Board. Clinical data were collected retrospectively at the time of sample

collection and prospectively from July 2005 to December 2007. We employed both a

restriction endonuclease digestion-based assay (Bsa XI digestion) and a quantitative

PCR assay in a population of 67 individuals. Both methods have been previously

described.

Results: Quantitative PCR detected the mutation in more patients than Bsa XI

digestion (37% vs. 31%). Among 33 patients with diagnosis of classic non-CML

MPD, quantitative PCR detected the mutation more often than BSA XI (55% vs.

45%). Sequence analysis of the affected JAK2 gene region in three patients with

positive result by Bsa XI digestion but negative result by quantitative PCR was

normal.

Conclusion: These data suggest that Bsa XI digestion is inferior to quantitative PCR

for JAK2 mutation testing. qPCR has higher sensitivity for detecting low copy

numbers of the mutation, and Bsa XI digestion may result in false positive results.

28.

Self-Assessment of Bronchoscopic Skills in First Year Pulmonary Fellows

Mark R. Bowling, MD; Gordon Downie, MD;

Momen Wahidi, MD and John F. Conforti, DO


Clinical Research - Fellow

Background: Bronchoscopy education is an integral component of the overall

training experience in pulmonary fellowships. Assessment of bronchoscopic skills has

not been standardized and currently relies solely on procedure logbooks and

subjective letters of competency. The multi-state bronchoscopy education project is a

format for competency-based measurements of bronchoscopic cognitive and

technical skills acquisition. We report the initial data on first year fellow's comfort

level for performing bronchoscopy.

Methods: Null Hypothesis: Pulmonary fellows will not feel comfortable by the 50th

bronchoscopy. 25 first year pulmonary fellows from 7 academic institutions

participated in the multi-state bronchoscopy education project and answered an 8

question self assessment tool at their 5th, 10th, 15th, 20th, 30th, 50th, 75th and

100th procedure. This measured the trainee's comfort level in performing

bronchoscopy and related procedures, knowledge of airway anatomy, and ability to

manipulate the bronchoscope. The trainees rated their level of comfort on a scale of

1 through 5, with a score of 1-2 considered not comfortable, 3-4 comfortable, and 5

very comfortable.

Results: The average self assessment score for the fellow's (N=9) bronchoscopic

skills from 2 of the sites are as follows: 5th 1.8, 10th 2.29, 15th 2.8, 20th 2.9, 30th

3.2, 50th 3.4, 75th 3.6, and 100th 4.1.

29.

Spontaneous Clearance of Hepatitis C Virus is More Common with Sexual

than Parenteral Routes of Transmission in HIV-infected Patients

Nathan Shores, MD, Marina Núňez, MD, PhD

Section on Gastroenterology


Background: There are conflicting data regarding the incidence and factors

implicated in spontaneous clearance of hepatitis C virus (HCV) after acute infection.

The goal of this study was to determine the epidemiological factors that predict

resolution of acute HCV infection without therapy in patients with human

immunodeficiency virus (HIC).

Methods: Design: We conducted a retrospective, multivariate analysis of

epidemiological data from HIV-infected patients presenting from 2000 to 2007 with

evidence of past or present HCV infection. Setting: Data was collected from one

American and 2 European HIV treatment clinics. Patients: A final cohort of 769 HIV-

infected patients referred for treatment with available test results for antibody to

HCV, HCV RNA, and hepatitis B surface antigen were included for analysis. Main

Outcome Measures: We calculated spontaneous clearance rates based on race,

geographic location, gender, transmission risk factors and hepatitis B virus

coinfection.

Results: Patients who admitted to a history of injection drug use spontaneously

cleared the HCV infection significantly less often (11.6%) than those in whom sexual

transmission was the presumed route of HCV infection (21.9%) (p=0.004). This

difference was more pronounced when heterosexual contact as the source of

infection was analyzed separately. Multivariate analysis identified heterosexual HCV

transmission (OR 2.81, 95% CI 1.55-5.09) and hepatitis B surface antigen carrier

status (OR 10.3, 95% CI 4.29-24.73) as independent factors predicting spontaneous

HCV clearance. No differences according to gender, race or geographical origin were

observed.

Conclusion: In summary, sexual transmission, particularly heterosexual, and

hepatitis B virus coinfection were the only factors associated with spontaneous HCV

clearance in this HIV-infected population.

30.

The Transplant Iron Score as a Predictor of Stem Cell Transplant Survival

Jonathan A. Storey, Rebecca F. Connor, Zachary T. Lewis, David Hurd,

Yi K. Keung, Manisha Grover, James Lovato, Gregory Pomper,

Suzy V. Torti, Frank M. Torti, István Molnár

Section on Hematology and Oncology


Background: Recent studies suggest that iron overload preceding stem cell

transplant may be associated with worse outcomes. Within each of those studies,

different criteria were used to define iron overload. Given the lack of consensus in

defining pre-transplant iron overload, we sought to methodically examine iron status

among transplant patients.

Methods: At our institution, we studied 78 consecutive transplant patients at risk for

transfusion-related iron overload at Wake Forest University. Prior to transplantation,

multiple clinical measures of iron status were collected and later examined for their

association with overall survival. Using this data, three potentially prognostic iron

measures were identified and incorporated into a unified scoring system. A point

was assigned for the following: (1) prior red cell transfusions > 25; (2) serum ferritin

> 1000 ng/ml; and (3) semi-quantitative bone marrow iron stain of 6+.

Results: The resulting Transplant Iron Score (range 0 to 3) was independently

associated with survival (p = 0.01). Using this scoring system, we observed that the

mortality associated with iron overload was attributable to an increase in early

treatment-related deaths (p = 0.02) resulting primarily from lethal infections (p =

0.02). In subgroup analysis, the predictive power of the iron score was most

pronounced among allogeneic transplant patients, where a high score (≥ 2) was

associated with an astonishing 50% absolute decrease in overall survival at one

year.

Conclusion: In summary, The Transplant Iron Score is a rationally developed clinical

scoring system which shows a strong independent association with overall transplant

survival. In our patient group, the iron score proved to be a superior prognostic

marker when compared to other proposed measures of iron overload. Our results

support the Transplant Iron Score as the preferred method to estimate pre-

transplant iron status.

31.

Change in BNP levels in outpatient CHF patients does not predict 6 month

hospitalization for CHF or mortality

A Wahla, J Jacob



Background: Absolute BNP values have been shown to have prognostic value in

patients with Chronic heart failure (CHF). However controversy exists as to whether

serial outpatient BNP testing is useful in managing CHF.

Hypothesis: The degree of change in BNP levels between two outpatient values

taken from a single CHF patient is a predictor of hospitalization or death over the

next 6 months, from the time of the last BNP draw.

Material and Methods: We looked at 114 paired BNP values, drawn at least one

month apart from patients presenting to the heart failure clinic of our institution.

Data was reviewed from 1/24/2004 till 10/24/2006. Clinical outcomes over a 6

month period after the second BNP measurement were measured, including death

and hospitalization for CHF exacerbation. Multivariate Logistic regression analysis

was conducted to estimate the contribution of absolute BNP values and change in

BNP values to risk of hospitalization for CHF or death. Analysis was conducted

separately for patients who had an increase in BNP values and those who had a

decrease in BNP values. Analysis was done after regressing for increase in

medications in response to second BNP value, change in creatinine, change in

Ejection fraction and age.

Results: There was an increase in BNP in 66 cases and a decrease in 48 cases. All

patients were male and mean age was 74 years. See Fig 1 for remaining results.

Conclusion: Percentage change in BNP values is not a good predictor of 6-month

hospitalizations for CHF or all cause mortality.

32.

The efficacy of Active Surveillance and Contact Isolation on the incidence of

Methicillin-Resistant Staphylococcus Aureus (MRSA) infections in ICUs.

Hidetaka Yanagi, MD; Robert Sherertz, MD

Section on Infectious Diseases


Background: MRSA infection can be associated with significant morbidity and

mortality and increased length of hospital stay and health care cost. Since MRSA

colonization often leads to infection, it has been recommended that active

surveillance for MRSA and contact isolation be implemented by the guidelines from

Healthcare Infection Control Practices Advisory Committee in Centers for Disease

Control and Prevention (CDC) and the Society for Healthcare Epidemiology of

America. There have been quasi-experimental studies suggesting active surveillance

and contact isolation could lead to decreased MRSA infections.

Methods: We conducted retrospective segmented time-series analysis on incidence

of MRSA infections in ICUs from September of 2001 through March of 2006. Since

April of 2004, we have been performing active surveillance for all patients staying in

Intensive Care Units for more than 4 days and for patients at risk for acquiring MRSA

outside the ICUs. Patients with positive cultures have been placed on contact

isolation. MRSA Infection rates in the ICUs have been gathered by experienced

infection control personnels. These diagnoses have been made based on CDC

criteria. We compared the slopes of incidence of MRSA infections over time before

and after the implementation of the active surveillance policy.

Results: There have been 333 infections due to MRSA out of 141,101 patient-days

in ICUs (overall incidence rate: 2.36 cases per 1,000 patient-days in ICUs) since

September of 2001 through March of 2006. Segmented time-series analysis on the

incidence of MRSA infections shows that the change in slopes of the MRSA infection

rates before and after the implementation of active surveillance and contact isolation

policy that was initiated in 2004 was not statistically significant. However, the

absolute value of the slope after the intervention was negative, suggesting the total

MRSA infection rate has been decreasing, although it did not reach statistical

significance.

Conclusion: Active Surveillance and Contact Isolation was not associated with

decreased MRSA infections with statistical significance. We may need more

aggressive infection control measures such as decolonization by intranasal mupirocin

and body cleansing by chlorhexidine.

33.

Cannabis Vasculopathy Mimicking Primary Angiitis of the CNS: Angiography

Before and After Abstinence

A. Shane Anderson, MD

Section on Rheumatology

Clinical Vignette - Fellow

Since 1991, multiple case reports have linked marijuana use to radiographic changes

in the vasculature of young healthy adult brains. The exactly etiology of this

condition is still largely a mystery, however it is believed related to cerebral

vasospasm in susceptible individuals. Not uncommonly, this condition is mistaken

for primary angiitis of the CNS or neurologic involvement from a systemic connective

tissue disorder and is inappropriately treatment with immunosuppression. We report

the case of an otherwise healthy 38 year old female admitted to the neurologic

intensive care unit with severe headache, choreiform movements and multiple

bilateral cerebral infarcts. The patient’s MRI demonstrated multiple bilateral infarcts

in the watershed region of the vertex as well as the amygdala. Angiography

demonstrated multiple stenotic lesions of medium and small vessels of the anterior,

middle, and posterior circulation suggestive of CNS vasculitis. Further history,

examination, and laboratory evaluation including sedimentation rate, C-reactive

protein, APL panel, ANA, ANCA, CSF analysis and complement panel were

unremarkable. The patient was started on pulse-dose methylprednisolone for 5 days

due to suspicion of primary angiitis of the CNS. Days after beginning therapy, the

patient’s urine drug screen returned positive only for cannabinoids. With further

questioning, the patient admitted to smoking four to five large marijuana cigars daily

to treat depression after her son tragically died in a motor vehicle accident three

years prior. At this point, the patient was discharged on a 4 week taper of

prednisone and counseled on marijuana abstinence. She received no steroid sparing

agents and experienced complete resolution of her symptoms within days of

discharge and remained symptom free with abstinence from marijuana. Follow up

cerebral angiography four months post discharge demonstrated complete resolution

of all stenotic lesions. We believe this represents the first reported case to

document, with angiography, the reversible nature of cannabinoid-induced cerebral

vasoconstriction. Additionally, this patient’s course suggests that avoidance of long-

term immunosuppression, in the short term, may be a practical consideration when a

detailed evaluation highly suggests a potential reversible cause.

34.

Giant Cerebral Neurocysticercosis Presenting as an Arachnoid Cyst in a

Mexican Immigrant

Michael Morgan, MD and Christopher Ohl, MD

Section on Infectious Diseases

Clinical Vignette - Fellow

Learning Objectives: To educate clinicians on the etiology, evaluation and

management of large brain cysts due to infectious agents in hispanic patients.

Case: A 37 year-old male Mexican migrant worker, presented complaining of 2

months of headache and dizziness. A diagnosis of “swollen nerves” was made in

Mexico and he was treated with gabapentin, carbamazepine, prednisone, and

diazepam. He works in construction while in the U.S. but also spends time on a

small farm in Mexico. While there he is exposed to sheep, chickens and dogs, but not

pigs.

PE revealed quadrantanopsia and CT and MRI of the brain showed a

parietooccipital 6 cm, multi-loculated cystic mass. A tentative diagnosis of arachnoid

cyst was made. A craniotomy with cystectomy was performed and complicated by

cyst rupture. Histopathology showed inflammatory cells and an outer cuticular layer

lined by microtrichia consistent with cysticercosis. No scolex was identified.

Serology confirmed cysticercosis with six of six bands against Taenia solium

antigens . Echinococcus serology was negative. He was treated with two months of

albendazole; MRI after treatment showed no residual disease.

Discussion: Cysticercosis is infection caused by T. solium (pork tapeworm) larvae

cysts that form in soft tissues and the central nervous system. Humans are an

accidental intermediate host for infection that occurs from oral ingestion of T. solium

eggs. The disease is endemic in the developing world where it is a common cause of

seizures, the usual presenting symptom. Cystic lesions are mostly less than 1-2 cm

diameter and are rarely greater than 5 cm. Giant cysticercosis lesions may mimic

benign cyst, neoplasm, and infection due to another cestode, Echinococcus sp. Even

giant cysticerci can be treated successfully with albendazole, while echinococcosis

often requires surgery.

This is the first case of giant cysticercosis reported in the U.S. Although rare,

it is important to consider giant parasitic causes when evaluating giant brain cysts in

immigrants from endemic areas in order to better prevent unnecessary procedures

and improve outcomes.

Health & Medicine

Wake Forest University School of Medicine