2007-2008 Fellows of the University of Texas Southwestern Doris Duke
Clinical Research Fellowship Program for Medical Students
(UT Southwestern-Doris Duke-CRF)

Aditya Bagrodia
University of Tennessee Health Science Center
Mentors: Margaret Pearle, Jeffrey Cadeddu
Urology

Project 1: Impact of BMI on Cost and Clinical Outcomes following Percutaneous Nephrolithotomy, Mentor: Margaret Pearle, MD, PhD

Urolithiasis is a major health issue in the United States with a prevalence of 12% in men and 6% in women. Kidney stone disease also carries a significant financial burden. Total annual expenditures in 2000 were estimated at $2.1 billion, including $971 million spent on inpatient services. Obesity is an expensive, pandemic health concern affecting more than 30% of Americans. It is a known risk factor for many systemic diseases including diabetes mellitus, gout, and coronary artery disease. In addition, there is clear data suggesting obesity is an independent risk factor for developing kidney stones.
The AUA best practice guidelines recommend ESWL and PCNL for large and staghorn stones, with PCNL showing better stone-free rates for renal stones > 30mm. ESWL is attractive due to low short-term complication rates and its non-invasive nature. However, in high volume centers with experienced surgeons PCNL demonstrates excellent stone free rates and low morbidity. Concerning obese patients, ESWL is problematic due to limitations in targeting the stone by ultrasound or fluoroscopic imaging and by the increased skin to stone distance. Many studies show that BMI has an impact on surgical outcomes. Interestingly, however, this statement does not seem to apply to PCNL, as several series demonstrate that obesity does not influence outcomes following this operation.
With health care expenditures reaching record levels, medical practice is increasingly affected by economic concerns. While previous work has shown favorable outcomes in obese patients undergoing PCNL, there are no studies specifically addressing the impact of obesity on costs of PCNL. In this study, we present a contemporary series of PCNL and determine how obesity impacts both clinical outcomes and associated costs.

Project 2: Development of Single Access Keyhole Nephrectomy and comparison to traditional laparoscopy, Mentor: Jeffrey Cadeddu, MD

Laparoscopic nephrectomy has assumed a more central role in the management of benign and malignant kidney diseases. Advantages of laparoscopic nephrectomy in comparison to open surgery are well established. Retrieval of laparoscopic nephrectomy specimens typically requires extension of an existing incision or creation of an additional incision. As such, at the conclusion of the surgical procedure, patients generally have three or four incisions each extending 1-4cm in length. In an effort to reduce the morbidity and improve the cosmesis of laparoscopy, Gill and colleagues have described their success with transvaginal extraction of nephrectomy specimens.
Natural orifice translumental endoscopic surgery (NOTES) is an extension of this concept by approaching abdominal surgery through natural orifices, thus obviating external scars. In 2002, Gettman and colleagues described their experience with transvaginal laparoscopic nephrectomy in a porcine model using standard instrumentation. More recently, Clayman et al. presented their experience with single-port NOTES nephrectomy with purpose-built equipment.
An alternative to NOTES is single access surgery utilizing flexible laparoscopic instruments. Such instrumentation would obviate the need for triangulation of trocars allowing for the creation of a solitary portal of entry into the abdomen. We intend to evaluate our initial experience of single keyhole umbilical nephrectomy and compare this new technique to traditional laparoscopy.

Rachael Cayce
UT Southwestern
Mentor: Heidi Jacobe
Dermatology

Autoantibody and Human Leukocyte Antigen (HLA)locus profiling in adult and children with Morphea
Morphea is frequently classified as the skin only manifestation of scleroderma. The current classification system of morphea divides it into five categories based solely on cutaneous clinical findings without reference to other considerations such as associated systemic manifestations, concomitant or familial predisposition, or autoantibody profile. This conception of morphea is based on little evidence, and may even be false. This negatively impacts patient care. A number of studies report an increased prevalence of autoantibodies, concomitant autoimmune disorders, and systemic findings in some subtypes of morphea patients. The usefulness of these reports are limited due to sample size, lack of a control group, referral bias and their observational nature.2-7 Thus, there are hints that morphea represents a systemic autoimmune disease, but the nature of this association by subtype is still undefined. In this study we will test for clinical associations of morphea with serological autoantibody profiles and HLA allelotyping via an initial case-control study.
The central hypothesis is that although morphea is thought to consist of one disorder with only cutaneous manifestations, it is comprised of distinct syndromes defined by subtype with characteristic clinical, serological, and genetic traits. Specifically, generalized morphea and mixed (specifically the combination of linear and plaque) morphea represent distinct entities with an increased risk of familial and concomitant autoimmune disorders with corresponding distinct immunological and genetic profiles.

Project Summary
This is a case-control study of adult and pediatric morphea patients (3 years or greater) comparing the frequency of systemic manifestations, concomitant autoimmune disorders and family history of autoimmune disorders in morphea against age, sex, and race matched normal and scleroderma controls. We will also collect baseline autoantibody profiles and HLA types to define those associated with the disease and its subtypes. The demographic, clinical, and laboratory features are being ascertained using validated instruments and state of the art technology. Cases will be enrolled regionally from Texas, Oklahoma, and Arkansas, as well as nationally with anticipated enrollment of 250 subjects regionally and 250 subjects nationally (total 500). Subjects enrolled regionally will be evaluated at the University of Texas Southwestern Medical Center Department of Dermatology's Clinical Research Office, while those enrolled nationally will send all completed forms, medical release forms, and blood collections to the Department's Research Office. These patients will be invited to enroll in a prospective cohort of patients to be followed annually will repeat measurements of these values and to assess what their significance is to the prognosis of these patients.

Shana Elman
Medical College of Wisconsin
Mentor: Marlyn Mayo
Liver and Digestive Diseases

TREATMENT OF CHRONIC PRURITUS

Background: Pruritus is a common and potentially disabling symptom. Current treatments for pruritus are not consistently effective and thus, further treatment modalities need to be explored. The subjective nature of pruritus makes its quantification difficult; however testing of improved therapies for pruritus requires a descriptive and quantitative measure that can evaluate the effects of treatment over time. Current measures assess intensity, but do not adequately assess other components, such as how often or where patients itch, sense of improvement or worsening, and impact on quality of life. Also, current measures have not been validated to assess changes in pruritus over time.

Project #1: A New Measurement of Pruritus
This research project aims to develop and validate a new scale, the 5-D Itch Scale, that provides a descriptive measure of pruritus that can be applied to any patient presenting with pruritus, and can be used as an outcome measure in clinical trials of pruritus. The 5-D measures 5 domains of pruritus: duration, degree, direction, disability, and distribution. The 5-D was administered to patients complaining of pruritus related to liver disease, kidney disease, AIDS, burn wounds, or other primary skin disease at enrollment, 3-days, and 6-weeks later. We are currently analyzing the data to assess construct validity, internal consistency, test-retest reliability, responsiveness, acceptability, and precision of the 5-D.

Project #2: A Study of INT-747 (6-ECDCA) in Combination with Ursodeoxycholic Acid in Patients with Primary Biliary Cirrhosis
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by inflammation, progressive destruction of the hepatic bile ducts and fibrosis. Typically, patients present with pruritus and fatigue. The only FDA-approved drug therapy for cholestasis, specifically for PBC, is the bile acid ursodeoxycholic acid (UDCA). Although UDCA provides sustained therapeutic effects in a subset of patients with PBC whose serum liver biochemistry values normalize over time, the majority of patients experience an incomplete response with continued disease progression and UDCA appears to do little to improve the main symptoms of PBC, pruritus, and fatigue. The farnesoid X receptor (FXR) is involved in the bile acid regulatory pathway, and therefore has been suggested as a potential target for new treatments for PBC. This research study aims to assess the safety and efficacy of a new FXR agonist , INT-747, as an adjunct to UCDA in the treatment of PBC. Multiple outcome measures will be used to determine efficacy and safety of this novel therapy, including the new 5-D Itch Scale that we have developed to assess improvement in pruritus.

MECHANISMS FOR PROMOTING RESEARCH CAREERS IN MEDICAL STUDENTS

Background: Advances in biomedical research have occurred at unprecedented rates over recent years providing a ballooning of opportunities for translational and clinical research. However, the supply of physician-scientists has not been able to keep up with this demand. Organizational and cultural barriers within the practice of medicine (e.g. economic pressures on the healthcare system, increased clinical responsibilities for academic faculty, etc.) have been cited as reasons for this steady decline in physician-scientists. In addition, the age of funded NIH investigators has continued to rise since the mid-1980s, suggesting that early intervention is necessary to encourage young physicians to explore careers in research and to provide them with the necessary skills to become successful young investigators.

Project #1: Effect of Medical Student Research Programs on Interest in Research Careers
Several strategies are currently used to expose medical students to research (e.g. summer research opportunities, "year-out" programs, MD-PhD programs); however little research has been done to compare the effectiveness of these methods in increasing medical student interest in research careers. The present study will compare the change in level of interest in research as a career activity at the beginning and end of medical school for UT Southwestern medical students completing summer research projects, students taking a year off to conduct research ("year-out" program participants), and students completing the MD-PhD program. Each group will also be compared to UT Southwestern students who do not participate in one of these research programs. In addition, student characteristics, such as demographic variables, will be assessed to determine whether certain students benefit from particular types of research activities. The results of this study should provide much needed insight into the effects of three of the most common medical student research experiences.

Charu Gupta
UT Southwestern
Mentor: Mark Drazner
Cardiology

Disease Background: Heart Failure

Heart Failure is a growing epidemic in the United States. The American Heart Association estimates that of people forty and older, one in five individuals has a risk of developing heart failure in his lifetime. Estimates of incidence are 550,000 individuals, with a total of 5 million affected nationwide. Currently, 10% of individuals die within one year of heart failure diagnosis and 50% die within 5 years of diagnosis. Though multiple pharmacologic therapies are used in combination for the treatment of congestive heart failure, increased ability to sense changes in patients' health status rests on monitoring subtle subjective symptoms and evaluating new modes of diagnosis and treatment. In the following year, multiple projects are proposed - all focused around the problem of heart failure.
Project #1: Phono-electrocardiography in Heart Failure: evaluation of a new technology that detects diastolic heart sounds in patients and defines alternate parameters of heart functioning. A new technology promises information that can be used to more quickly diagnose new-onset heart failure, to detect an acute heart failure decompensation, or to increase pacer efficiency through cardiac resynchronization. We intend to evaluate the reliability and validity of machine readings and correlate with clinical information to assess prognostic value over time.
Project #2: Consideration of "Bendopnea" as a new heart failure symptom: the prevalence and hemodynamic implications of shortness of breath in varying positions. Stevenson and Perloff's research from 1989 showed that the combination of rales, edema, and elevated JVP had a 58% sensitivity and 100% specificity for PCWP greater than or equal to 22. This study recognized the tendency of physicians to use physical signs as markers of disease severity; however, this demonstrates that the current signs and symptoms provide an incomplete assessment of a patient's status. We intend to define a novel symptom in HF and investigate its physiological basis.

Project #3: Implications of Public Opinion on Organ Donation: Louise King, a Doris Duke Research Fellow, described the ethical paradox of uninsured donors (25% of organ donors) contributing to the donor pool despite the limitation of organ recipients to individuals with insurance (Journal of the American College of Cardiology, May 2005). The authors hypothesized that this unequal allocation of resources may contribute to public unwillingness to donate organs and distrust of the medical community. We intend to investigate whether the public recognizes this unequal distribution of resources, and whether this impacts the willingness of the public to donate organs.

Anshu Jain
University of Kentucky College of Medicine
Mentors: Hak Choy, David Chen, Chaitanya Nirodi
Radiation Oncology

Project 1: Radioresistance and EGFR Therapeutics in Non-Small Cell Lung Cancer

Non-small cell lung cancer, especially in its late stages, presents a significant treatment challenge to the clinician. Recently, there has been much interest in novel therapeutics like cetuximab, geftinib, and erlotinib. These drugs exert their effects by acting on plasma membrane EGFR. Recently, it has been shown that EGFR plays a role in the repair of double stranded DNA breaks induced by ionizing radiation. This introduces an important role for these drugs as potential radiosensitizers in combined modality treatment of NSCLC. Our work aims to: A) Characterize the role of EGFR in DNA repair induced by ionizing radiation, and assess the radiosensitizing effects of these novel chemotherapeutic agents, and B) further characterize the exact interactions of EGFR in the context of DNA repair to identify a potential target for future therapeutics.

Project 2: Novel Chemoradiation Regimens for the Treatment of Advanced Stage Non Small Cell Lung Cancer

There are no clearly superior treatment options for later stage NSCLC, especially inoperable cases. We seek to identify new combined modality regimens of chemotherapy and radiation for the treatment of Stage III onward NSCLC. We begin our investigations through a number of Phase I trials designed to assess the toxicity of novel regimens and phase II trials to assess potential efficacy. Regimens involve using newer chemotherapies including Taxol, Taxotere, and newer platinum agents in combination with varying methods of radiation administration.

Dhruti Patel
Northeastern Ohio Universities College
Mentors: Abhimanyu Garg
Center for Human Nutrition

Title: Mechanisms of lipodystrophy in highly active antiretroviral therapy in HIV infected patients.

Background: In the developed world, HIV has become a chronic rather than a fatal diagnosis. However, the treatment does come at a risk of metabolic derangement. One such change is a lipodystrophy syndrome which includes progressive loss of subcutaneous fat from the arms, legs and face with excess fat in the dorsocervical, neck and trunk regions. The precise underlying mechanisms related to HAART-induced lipodystrophy are currently unknown although some progress has been made. Dr. Garg and his colleagues have completed a 2 year randomized, double-blind, placebo-controlled, prospective trial of newly diagnosed HIV infected patients on either Efavirenz (a non-nucleoside reverse transcriptase inhibitor)-based or nelfinavir (a protease inhibitor)-based highly active anti-retroviral therapy (HAART).

Project: In an attempt to elucidate these criteria, analysis of body fat changes from anthropometry, dual energy X-ray absorptiometry and magnetic resonance imaging (MRI) performed annually for each patient will be completed. The hypothesis is that PI-therapy is associated with loss of subcutaneous fat in the extremities. Secondary hypothesis is that PI therapy is associated with accumulation of fat in the trunk, neck and dorsocervical regions of the body. We will also test the hypothesis that changes in adipokines such as, adiponectin, leptin, retinol binding protein 4 and visfatin, will correlate with the changes in body fat distribution. We will measure these adipocytokines in stored plasma and correlate these with changes in body fat distribution.

Teddy Youn
Brown University School of Medicine
Mentors: Ramon Diaz-Arrastia, Christopher Madden
Neruology, Neurosurgery

Diffusion Weighted Imaging and Biological Fluid Biomarkers in Acute Traumatic Brain Injury

Diffuse Axonal Injury (DAI) results from high velocity deceleration and shear strain, and is believed to be the predominant mechanism of injury in 40 - 50% of TBIs requiring hospital admission in the US. DAI is poorly imaged by CT scanning, and conventional MRI, the current method of choice, has not been carefully studied and is of uncertain sensitivity and specificity. The inability to accurately identify and measure DAI during life is a major limitation in the clinical management of TBI. Additionally, clinical trials of neuro-protective and axono-protective therapies directed at DAI are unlikely to be successful unless there are reliable and validated biomarkers which will allow subphenotyping of injury mechanisms, including DAI. The goal of our proposal is to develop and validate Diffusion Weighted Imaging (DWI) as a biomarker of DAI. The anatomy and integrity of white matter fiber tracts can be determined noninvasively with DWI, providing new information about brain networks. Preliminary data from our group indicates that Diffusion Tension Imaging (DTI), a variant of DWI, is more sensitive than conventional structural MRI for identifying DAI lesions. A secondary objective is to determine if certain biological fluid biomarkers (S-100B protein, Tau protein, and Myelin Basic Protein [MBP] can be effective biomarkers when used in conjunction with neuroimaging modalities like DWI. We will accomplish our objectives through the following specific aims:

(1). Obtain MRI scans on patients with DAI in the acute period (within 24 hours after injury). Patients enrolled will have suffered moderate and severe closed head injuries during high-velocity motor vehicle collisions. Patients requiring craniotomies as well as those with significant midline shift will be excluded. We plan to enroll 15 patients in the study over a 7-month period. Patients will be scanned at 3T and DWI as well as DTI performed in 18 - 30 directions. Additional image measures will include high resolution T1 weighted, FLAIR images, and susceptibility weighted imaging. An additional 15 controls matched by age and gender to the patients will also be recruited and scanned.

(2). Obtain repeat MRI scans 10 - 14 days later and repeat MRI scans and outcome information 6-months after injury. Patients who survive the acute period will be asked to return for a repeat MRI 6 months after injury. Additionally, outcome will be assessed using a focused neuropsychological battery and validated structured interviews. We anticipate a 10% acute death rate and a 15% loss to FU rate, thus we anticipate obtaining 12 - 13 follow-up scans.

Role of the Doris Duke Fellow:

The fellow will be primarily involved in identifying eligible patients, prospectively collecting clinical information relating to the severity of the initial traumatic injury, following the patients and collecting biological fluid biomarkers daily for the first five days during their acute hospitalization as well as obtaining outcome data at 6 months post-injury. These tasks will be accomplished by having the fellow attend daily morning rounds with the neurosurgical service at Parkland Memorial Hospital, identifying patients who meet eligibility criteria for the study, obtaining informed consent from patients or family members, and collecting intake information. Afternoons will be spent obtaining outcome information via telephone interviews and analyzing MRI data using the programs MRICro, DTI Studio and Freesurfer.

2006-2007 Fellows of the University of Texas Southwestern Doris Duke
Clinical Research Fellowship Program for Medical Students
(UT Southwestern-Doris Duke-CRF)

John Anderson
UT Southwestern
Mentors: Robert Timmerman
Hak Choy
Radiation Oncology

Stereotactic Radiotherapy of Brain and Paraspinal Metastases

Background:

Cone Beam Computed Tomography (CBCT) is an imaging technique that is employed for accurately targeting tumors for radiotherapy by quantifying changes in patient anatomy from the treatment plan immediately prior to treatment. There are a number of imaging methods that are currently in use for this purpose, but the advantage of CBCT is its capability to image soft tissue, especially neoplastic tissue, on the treatment table. Presently, CBCT is only utilized to determine the degree of displacement of anatomical and/or implanted markers from an initial planning CT scan obtained on a conventional CT scanner. By also utilizing the CBCT scanner to obtain the initial image for treatment planning, it may be possible to set up the patient at the treatment table and generate a plan without moving the patient.

Project Description:

We are investigating the feasibility of utilizing CBCT images for treatment planning for extracranial external beam radiotherapy. A process for obtaining CBCT images and planning treatments with the patient remaining on the treatment table will be developed. Studies utilizing anthropomorphic phantoms will be performed, evaluating the timing of individual steps. Plans and dose distributions generated from CBCT images of the phantoms and patients will then be compared to helical CT images to determine the accuracy of the treatments plans. Time permitting, we intend to also investigate CBCT images for treatment planning in cranial sites.

Sarah Davis
UT Southwestern
Mentor: Susan Iannaccone
Pediatric Neurology

Quality of Life Validity Testing of the Neuromuscular Module in Duchenne Musucular Dystrophy

Disease Background
Duchenne muscular dystrophy (DMD) is the most common genetic neuromuscular disorder, affecting 1:3500 live male births. It is an X-linked recessive disease that manifests as progressive proximal weakness due to an insufficient quantity and quality of the protein dystrophin. A defect or deficiency in this large protein located near the sarcolemmal membrane leads to cell breakdown in muscle cells. Diagnosis typically occurs around 3-5 years of age with mild weakness that progresses over the course of several years to the point of loss of ambulation and need for respiratory assistance. Multiple organs are affected, potentially resulting in cardiomyopathy, restrictive lung disease, mental retardation, and osteoporosis. Death typically occurs when the patient is in his twenties due to aspiration, respiratory infection, or heart failure. Treatment is limited to corticosteroids that slow the progression of muscle weakness but incur other side effects such as weight gain. Symptomatic treatment for disease-associated processes are also used as indicated, such as enalapril for heart complications and positive pressure ventilation for sleep apnea. There is currently no cure for this disease.

Patient Population
DMD patients seen in the pediatric neuromuscular clinic undergo a full evaluation, including assessment by a physician, functional testing and recommendations by physical and occupational therapists, pulmonary function tests, and referrals as needed to pediatric cardiology and pulmonology subspecialists. Patients and parents also are requested to complete two quality of life (QOL) surveys: the generic and neuromuscular pediatric modules. The generic form addresses issues faced by the child such as his general health, emotions, relationships with peers, and school. The neuromuscular module assesses more disease-related facets of the patient's well-being including activities of daily living (ADLs), ability to communicate about his disease, and the status of the family unit as affected by the pressure of the disease. This survey has been implemented for several years in the child neuromuscular clinic but has yet to be validated.

Project Summary
Both the parent(s) and the child will complete both a general pediatric QOL survey as well as the pediatric neuromuscular survey. The modules are to be administered by the research fellow to ensure consistency between patient encounters. This baseline assessment will then be compared to a second administration of the same surveys six weeks later. The two sets of responses for the individual will then be compared. In addition, this subjective data will be compared to objective measurements of functioning specific to the disease such as ambulatory status, activity level, ventricular ejection fraction, and forced vital capacity.

Christopher De Renzo
Robert Wood Johnson Medical School
Mentor: John Minna
Hematology/ Oncology

Lung cancer is common widespread and deadly. It is the number one cancer killer in the United States and worldwide. With expected 5 year survival rates for all patients with the disease being about 15 %, new insights into lung cancer pathogenesis and progression are welcome.
A relatively new focus, in the field of lung cancer research, is the role of the microenvironment on development of the malignant lung cancer phenotype. A microenvironment is defined by three parts: 1)stromal cells, such as fibroblasts, endothelial cells and lymphocytes 2)Insoluble extracellular matrix of collagen and other proteins and 3) growth factors and cytokines. Our laboratory has used in vitro 3-Dimensional models to study normal bronchial epithelial cells and lung cancer cell within a manipulatable microenvironment. However, an obstacle to practical use of such models has been a large time requirement to complete such experiments, which led to contamination issues and difficulty in result replication. The goal of my current project is to validate a procedure for creating such 3-D models in a time efficient manner.

In our laboratory 3-Dimensional models of normal human bronchial epithelium are constructed by first plating collagen and fibroblasts on a transwell plate. The collagen and fibroblasts are incubated until they form a semisolid, contracted gel. Bronchial epithelial cell lines are plated on top of the fibroblast-collagen gel and incubated in growth media. After incubation, the cultures are fixed, sent for histology, and observed by a trained clinical pathologist. The main difference of the new method is incubation time has been decreased from 21 days to 7 days. If the 7 day incubation method produces histological results similar to the 21 day method, use of the model to study the lung microenvironment should be more practical.
If the method is validated, I will manipulate the source of fibroblasts to see if the microenvironment has an effect on epithelial cell invasion. For example, past evidence from our lab shows that normal human bronchial epithelial cells are more likely to invade through fibroblasts from a patient with lung cancer, than they are to invade through fibroblasts from a patient without lung cancer. However, results of this study were preliminary and have not been replicated. If such results can be replicated, the next step would be to decipher genetic differences between the fibroblast types that may lead to the invasive phenotype.
The overall aim of this project is to create a practical method for studying lung epithelial cells within a manipulatable microenvironment. If this is successfully accomplished the model will serve as a convenient method to test hypotheses on the role of the microenvironment on lung cancer progression.

Shana Elman
Medical College of Wisconsin
Mentor: Marlyn Mayo
Internal Medicine/ Liver and Digestive Diseases

Pruritis in liver disease

Pruritus is a common and potentially distressing symptom. Itching affects quality of life and when severe, can be disabling-interfering with daily activities, resulting in significant skin irritation from scratching, leading to sleep deprivation, and/or contributing to psychological disturbances. Current treatments for pruritus are not consistently effective and thus, further treatment modalities need to be explored.

The elusive pathophysiology of pruritus and the subjective nature of pruritus further complicates the process of development and testing of new therapies. Currently, few measures are available to assess itching. The visual analogue scale (VAS) for pruritus is the most commonly used measure, which asks patients to rank their degree of itching on a visual analog scale from 1 to 10 (1=no itching, 10=intolerable itching). While this scale allows easy quantification of itching, it does not provide much description of the distribution, duration, direction, or disability of the itching. The VAS has also been criticized for its weak ability to demonstrate changes over time. Recently, the PBC-40 was developed, which is a questionnaire that assesses six domains (itch, fatigue, emotional, social, and cognitive functioning, and general symptoms) of primary biliary cirrhosis (PBC). The itch domain of the PBC-40 inquires about the impact of itch on sleep, skin irritation, and psychological factors. However, the PBC-40 was developed and validated specifically for patients with PBC. This scale also lacks validation for use in tracking changes in pruritis over time. Further investigation of the pathophysiology of pruritus and evidence-based assessment of potential therapies requires validated methodologies to be available for description and quantification of symptoms in diseases other than PBC and a validated method to assess changes in pruritus over time.

Project #1: A New Measurement of Pruritus

This research project aims to develop and validate a new scale that provides a descriptive measure of pruritus that can be applied to any patient presenting with pruritus, and can be used as an outcome measure in clinical trials of pruritus. Itching can be related to many types of disease. This questionnaire will be administered specifically to people who complain of itching related to liver disease, kidney disease, AIDS, cancer, intrahepatic cholestasis of pregnancy, or a primary skin disease. Subjects will be sent a follow-up questionnaire 6 weeks later to determine the questionnaire's ability to track changes in pruritus over time.
Specifc Aims: 1) To develop a new measure of pruritus, the 5-D (Distribution, Duration, Degree, Direction, and Disability) Descriptive Pruritus Measure. 2) To compare the 5-D to current pruritus measures-the visual analog score and the itch domain of the PBC-40. 3) To validate the 5-D in multiple patient populations, specifically patients with liver disease, renal disease, AIDS, cancer, intrahepatic cholestasis of pregnancy, and primary skin disorders. 4) To validate the ability of the 5-D to track changes over time.

Project #2: Treatment of Metabolic Pruritus

Patients with liver disease taking sertraline were noted to have a decrease in symptoms of pruritus. Serotonin receptors are located in both the sensory nerve terminals and the dorsal horn and may be important in the regulation of itch. Therefore, it is possible that selective serotonin reuptake inhibitors (SSRIs), such as sertraline, may be useful as an anti-pruritic agent.
The purpose of this research is to determine the safety and efficacy sertraline as an anti-pruritic agent in patients with liver disease and kidney disease. Data has previously been collected on patients with liver disease. The current focus of this project is to enroll patients with kidney disease. Patients will receive 8 weeks of treatment with sertraline in a randomized, double-blind placebo-controlled, cross-over design. Throughout the study patients will keep a daily diary to track their pruritus. They will also be seen at weeks 2, 10, 14, and 22 weeks for evaluation of their pruritus and for blood tests (CBC, chemistries, plasma sertraline and desmethylsertraline levels).
Specific Aims: 1) To determine whether sertraline, as compared to placebo, improves the symptom of pruritus in patients with liver or kidney disease. 2) To determine the optimal dose and time to response of sertraline in the treatment of pruritus.

Allison Jordan
UT Southwestern
Mentor: Jodi Dashe
Ken Leveno
Obstetrics and Gynecology

Serotonin Reuptake Inhibitor Use During Pregnancy: Perinatal Outcomes

Purpose: This is a retrospective evaluation of pregnancy outcomes and neonatal complications following maternal use of serotonin reuptake inhibitor medications during pregnancy.

Background: Approximately 10% of pregnant women suffer from depression.1 Serotonin-reuptake inhibitors are the most commonly used antidepressants, and because of their side-effect profile, these agents are the first-line treatment in pregnancy. There has been increasing concern that maternal use of SRI's prior to delivery can lead to a potentially-serious neonatal behavioral syndrome in exposed neonates. The syndrome, also called neonatal withdrawal or poor neonatal adaptation, is generally mild and self-limited, though it may require supportive care in a special care nursery and increase hospital stay. Signs may include one or more of the following: jitteriness or irritability, temperature instability, hypoglycemia, poor tone or increased tone, respiratory distress, weak or absent cry, or difficulty feeding2,3 Features of this syndrome have been compared those of adults with either SRI discontinuation symptoms or SRI toxicity. 4
Recommendations regarding management of neonates exposed to SRI's in-utero, vis-à-vis duration of observation, evaluation or testing for evidence of behavioral maladaptation, or even treatment, are limited. Oberlander and colleagues found that 25% of 28 neonates exposed to an SRI alone, and 39% of 18 neonates exposed to an SRI and benzodiazepine combination had symptoms reflecting poor neonatal adaptation. 5 In all cases, findings resolved within 48 hours. Using the Neonatal Abstinence Scoring system, 6 Levinson-Castiel and colleagues recently reported that 30% of 60 exposed neonates had evidence of withdrawal; however, no neonate was felt to require treatment with medication, and maximum scores were recorded within 2 days after birth. 7
In addition to the neonatal behavioral syndrome, investigators have described (1) a slight increase in congenital cardiac anomalies associated with paroxetine use only 8; (2) a small increase in the neonatal risk of persistent pulmonary hypertension 9; and (3) an increased risk preterm birth and fetal death. 10,11. With the exception of preterm birth, the above outcomes have been reported to occur in 1% or less of exposed pregnancies.8-11

Concise Summary of Project: The Parkland Obstetrical Psychiatry Complications clinic is a multidisciplinary clinic providing care for pregnant women who require initiation of psychiatric medication(s) or who have recently been hospitalized for a psychiatric diagnosis and are in need of out-patient care. The clinic sees approximately 150 women per year, and the majority of women seen (> 80%) receive treatment with serotonin reuptake inhibitor medications.
We propose to review the computerized appointment logs for this clinic to obtain a list of women seen from September 2005 through August 2006. Using this list, we will obtain data from 3 sources to evaluate the effects of SRI's on pregnancy and neonatal outcomes: maternal medical records, neonatal medical records, and our division's obstetrical database. Records will be reviewed only following delivery and hospital discharge, to assure complete ascertainment of data. Women who are seen in this clinic but who do not need SRI's will also be included as a control group. Rates of selected pregnancy and neonatal complications in these 2 groups will also be compared with complication rates for our overall population, which we will evaluate using our division's obstetrical database. Specific data collected and procedures to assure confidentiality are listed below.
Our goals are to evaluate the prevalence of pregnancy complications and the neonatal behavioral syndrome (and any other neonatal complications) according to maternal medication and dosage. Other variables that might affect neonatal adaptation, such as prematurity or low-birth weight, will also be evaluated. We hope to provide physicians and their patients with a better understanding of what to expect if these medications are needed during pregnancy, specifically what type of care is needed, duration of hospitalization needed, and potential sequelae.

Sources of research material: Data from 3 sources will be included: maternal medical records, neonatal medical records, and our division's obstetrical database. From the maternal medical records, variables extracted will include identifiers (name and medical record number and date of service), gestational age at enrollment for care, gestational age when seen in the Obstetrical Psychiatry Complications clinic, gestational age during which the patient took SRI's and any other medication, medication name(s) and dosage, whether the medication was adequately treating the problem, any substance abuse, and any medical or obstetrical complications. From the division's obstetrical database we will obtain a list of neonatal medical record numbers. Variables we will extract from the neonatal records will include: name and date of birth, any evidence of respiratory difficulty and the treatment required, any evidence of increased or decreased tone, irritability or jitteriness, feeding difficulties, hypoglycemia, temperature instability, or other complications. We will also use the electronic database to obtain the following outcomes: maternal demographic variables, pregnancy outcomes such as gestational age at delivery, indication for delivery, any delivery complications, birth weight, Apgar score, neonatal length of stay, need for special care nursery, and any obvious birth defects.

Potential benefits:
(1) To subjects: As this is a retrospective study, the subjects will not directly benefit. The results of this study do have the potential to impact patient counseling and care in the future. For this reason, it is possible that subjects may benefit in future pregnancies.
(2) To society: Currently, there is limited information available regarding perinatal complications associated with serotonin reuptake inhibitor (SRI) use. Areas in which our study may provide clinically-useful information include: severity of the neonatal behavioral syndrome in SRI-exposed infants, whether it is affected by the specific SRI used, and effects of factors such as medication dosage and gestational age at delivery. Information from this study may assist health-care providers counseling patients and assist providers evaluating newborns-who may use this information to make recommendations regarding level of care in the hospital and length of stay.

Justin Leitenberger
University of Texas - Houston Health Science Center
Mentor: Heidi Jacobe
Paul Bergstresser
Dermatology

Project #1: Morphea database and initiation of observational studies looking at risk factors in the development of disease

Background
Morphea is a disorder characterized by thickening and hardening of the skin and subcutaneous tissue due to excessive collagen deposition. Among the subtypes of morphea is plaque-type, linear scleroderma, and generalized. The cause of morphea is unknown but case reports suggest an environmental factor such as trauma, irradiation, infections, vaccinations, or drugs as inciting factors in the development of this disease.1-5 Case reports also reveal an association with other autoimmune disorders.6-8 The literature describing morphea is limited and epidemiologic data has not been confirmed with larger studies.9 A recent study in a European population of children with juvenile localized scleroderma described the basic relationship of environmental factors (13.3%) and family history of autoimmune diseases (12%) as correlations with localized scleroderma.10 Linear scleroderma is more common in pediatric populations whereas plaque-type morphea is more commonly found in adults. Currently, there is no one therapy for localized scleroderma that has proven to be very effective or significantly disease modifying.11 Broader studies regarding the diagnosis and etiology of morphea may provide unique insights on treating this disease.

Research Questions:
1. Among patients with morphea, is there an inciting event which triggered the disease?
2. What is the association, in patients with morphea, with other concomitant autoimmune disorders?

Project #2: Outcome Measures in Dermatology - A review and call to action for improved clinical trials

Language and interpretation of clinical trial outcomes - surrogates, composites, scores, endpoints, etc.

-Definition of outcome measures
-Concept of surrogate endpoints as outcome measures - definitions, pitfalls, and criteria for surrogates
-Different types of endpoints in Dermatology - Scores, Quality of Life measurements, patient satisfaction, utilities, cost-effectiveness, technology based measures
-Interpreting outcome measures in clinical trials - designation of primary endpoints, secondary endpoints, the problem of multiple primary endpoints, and statistical significance

Christopher Maroules
Indiana University School of Medicine
Mentor: Ron Peshock
Internal Medicine / Radiology

Project 1: MRI characterization and perfusion using vasodilatory challenge in patients with cardiomyopathies at risk for sudden cardiac death.

The purpose of the study is to determine if cardiac magnetic resonance imaging done prior to the implantation of a cardio-defibrillator predicts future firing of the defibrillator for serious cardiac arrhythmias. Recent studies have shown a reduction in sudden death in patients with severe left ventricular dysfunction following treatment with an implantable cardio-defibrillator (ICD) (ref). However, the total event rate in populations at risk is relatively low (ref). In addition, these devices are extremely expensive ($20-30k/device) and it has recently been reported that implantation is associated with a 4% complication rate. Thus, it would be desirable to identify those patients at highest risk who would benefit most from this procedure. It is well established that the presence of focal fibrosis can play an important role in the generation of arrhythmias in patients but it is not known if this is a common feature which predicts the response to ICD implantation. There are now extensive data which indicate that magnetic resonance delayed enhancement imaging with gadolinium can identify areas of cardiac fibrosis due to both ischemic and non-ischemic heart disease. The study will involve 50 patients who are scheduled for implantation of an ICD for clinical indications. Before implantation, each participant will undergo imaging at 1.5 Tesla on a standard clinical system at UT Southwestern. All cardiac images will be obtained during a 12-15 heartbeat breath hold at end-expiration, averaging 10-15 seconds with adequate rest periods between breath holds. Following the acquistion of scout images, a series of short axis and long axis series will be obtained in each patient using a standard tissue tagging protocol for ejection fraction determination. Following MRI tissue tagging, patients will receive a bolus intravenous injection of gadolinium-DTPA. High-resolution delayed enhancement images will be obtained using a previously described inversion-recovery prepared gated fast gradient echo pulse sequence. This will produce high-resolution contrast-enhanced images of the ventricular myocardium that clearly defines the patient's zone of infarction, allowing for accurate measurements of infarct size and transmural extent.

Following MRI, patients will undergo ICD implantation with transvenous defibrillator systems selected by the patients' clinical physician. Patients will be followed over the course of 1 year and will be evaluated clinically after an ICD firing. The primary endpoint is to relate the MRI parameters of infarct size and transmural extent of infarction to the subsequent risk of "appropriate" ICD firing. Secondary clinical endpoints will also be collected, specifically death (cardiac and non-cardiac), recurrent MI, congestive heart failure, unstable angina requiring hospitalization, need for revascularization by PCI or CABG, and stroke.

Project 2: Comparison of 1.5 and 3.0 Tesla MR imaging in the evaluation of the heart and abdominal aorta

Magnetic resonance imaging at 1.5 Tesla is now a standard tool for the evaluation of cardiovascular disease. It was used extensively in the Dallas Heart Study to evaluate myocardial mass and function and to assess the presence and extent of atherosclerosis in the aorta. Recently, clinical magnetic resonance imaging at 3.0 Tesla has become available which increases the signal which is obtained during imaging. In studies in the brain and body, it has been demonstrated that this additional signal can be used effectively to improve image quality or reduce scanning time. Thus, it could potentially be used in future cardiovascular studies to permit more rapid and extensive evaluation. However, to permit comparison with prior studies, it is important to prove that the imaging at 1.5 and 3.0 Tesla provide equivalent measurements.

Monica Mead
Medical College of Georgia
Mentor: Abhimanyu Garg
Internal Medicine / Center for Human Nutrition

With the introduction of Highly Active Anti-Retroviral Therapy (HAART), HIV has become a chronic illness in developed countries rather than a fatal disease. With the new medications and extended life expectancy come new challenges, including side effects of the drugs. Adverse effects of medications can effect treatment adherence and ultimately lead to emergence of resistant strains of HIV. Questions have arisen concerning the relative effects different classes of antiretrovirals have on metabolic disturbances, fat distribution and quality of life (QoL). My particular area of interest pertains to the effects of non-nucleoside reverse transcriptase inhibitors (NNRTI) versus protease inhibitors (PI) on health-related quality of life, which includes such subcategories as overall function, life satisfaction, health worries, financial concerns, burden of medication regimen, mastery of HIV, disclosure worries and body image. We have taken a cohort of treatment-naïve HIV-infected patients and randomized them to receive either an NNRTI or a PI, collected baseline QoL data and will continue to follow patients for two years. I am investigating which QoL subcategories are effected, to what extent and how do these effects progress during administration of HAART? The knowledge of what medication regimen correlates to adverse effects on QoL, as well as knowing when these events occur during treatment, will allow for administration of interventions at appropriate time periods, increased treatment adherence and decreased emergence of resistant strains of HIV.

2005-2006 Fellows of the University of Texas Southwestern Doris Duke
Clinical Research Fellowship Program for Medical Students
(UT Southwestern-Doris Duke-CRF)

Sarah M. Barber
UT Southwestern
Department of Pediatrics
Mentors: Leah Adix, B.S.
George R. Buchanan, M.D.

Assessment of Risk Factors for Thrombosis in Persons with Hereditary Spherocytosis

1. Hypothesis:

Persons with hereditary spherocytosis (HS) who have had a splenectomy exhibit more risk factors for venous and arterial thrombosis than HS patients who have not had splenectomy.

2. Aim:
The aim of this study is to correlate the results of several laboratory measurements which are surrogates for risk of venous and/or arterial thrombosis in children and adults with HS who have either had or not had a surgical splenectomy. The two groups of patients to be studied are as follows:

1) Children with HS followed in the Hematology-Oncology outpatient unit at Children's Medical Center Dallas (CMCD).

2) Parents and other adult relatives of children with HS followed at CMCD who also have HS.

The study will be conducted in two phases or parts. Part I will be a retrospective chart review of existing records of established hereditary spherocytosis patients. The IRB has provided expedited approval of the study. Part II consists of a prospective component including patient interviews and laboratory testing. This will require a separate IRB submission with the usual informed consent procedures.

3. Background:

HS and its Treatment With Splenectomy

HS is the most common congenital hemolytic anemia in the Caucasian population, with an incidence of approximately 1 in 5,000 (1,2). The disorder is usually inherited in an autosomal dominant fashion. It is due to one of a number of mutations in genes encoding red blood cell structural proteins, most frequently ankyrin or spectrin. These mutations lead to red cell membrane loss and fragmentation, such that the red cell assumes a spherical shape, rendering it inflexible and susceptible to destruction in the spleen. Clinical manifestations of HS include signs and symptoms of anemia, jaundice, gallstones, and acute anemic events. For decades it has been known that splenectomy "cures" the hemolytic anemia, so this operation has been considered by many the treatment of choice for the condition. Persons having had splenectomy are at increased risk of overwhelming bacterial septicemia. Although with appropriate preventive measures, this complication is now less frequent, much controversy and uncertainty remains in the medical community regarding which patients with HS should have splenectomy and when.

Thrombosis Following Splenectomy

During the past decade evidence has emerged that a second major complication of splenectomy is arterial or venous thrombosis. Case reports and small case series have described this complication in persons with HS as well as in patients having splenectomy for other reasons (3-9). Thrombosis also occurs in mice with HS following splenectomy (10). Greater knowledge about the incidence, age, and risk factors regarding thrombosis following splenectomy would be extremely important in helping to decide whether and when this procedure should be performed in affected patients. Our long-range research plan is to conduct a formal case control study of specific vascular complications (stroke, myocardial infarction, venous thromboembolism, pulmonary hypertension, etc.) in persons with HS having had splenectomy or not. There is evidence that splenectomy may increase platelet count, hemoglobin concentration, plasma cholesterol, leukocyte count, and C-reactive protein in persons with HS and possibly in other conditions as well (11-18). Patients with HS and other hemolytic anemias actually have relatively low plasma cholesterol levels, and this finding, plus their lower hemoglobin concentrations (and perhaps slightly lower platelet counts associated with splenomegaly), may protect them from thrombosis.

Laboratory Correlates of Thrombosis Risk

In Part II of this exploratory research study we aim to perform three or more laboratory tests - (1) complete blood count (for determination of the hemoglobin concentration, platelet count, and total leukocyte count), (2) total plasma cholesterol and its fractions (LDL and HDL cholesterol), (3) and C-reactive protein (CRP) in persons with HS of various ages whether they have had splenectomy or not. Values for each parameter will be compared in the two groups (splenectomy or no splenectomy) and corrected for age, gender, and other factors that might affect their results. A brief questionnaire will also be employed for each study subject to obtain health information regarding risk factors for thrombosis. Study subjects will be children with HS and their affected relatives who provide informed consent.

Given that HS is relatively common as a cause of hemolytic anemia, it is surprising that the literature contains so few data regarding laboratory correlates of possible thrombosis risk. The hemoglobin concentration usually returns to normal following splenectomy, since hemolysis is essentially abolished. However, the post- splenectomy hemoglobin values are actually slightly higher than normal (19). This may relate to the increased hemoglobin concentration in the erythrocyte. Few good data are also available regarding platelet count. It is generally acknowledged that platelet count rises immediately after splenectomy, but subsequently returns to normal. However, we have observed persistent thrombocytosis in patients with HS following splenectomy. Finally, the effect of chronic hemolytic anemia on plasma lipid profile has been little studied. Research at our center two decades ago showed decreased plasma cholesterol in children with sickle cell anemia compared to age- matched norms (11). Limited data are also available in HS patients suggesting lower cholesterol and triglyceride values. In sum, the lack of good data regarding these laboratory measures provides sound rationale for acquisition of such information as part of this study.

4. Study Design

Part I (July - November 2005):

" A list of all children with HS seen at Children's Medical Center Dallas since 1975 will be generated from the department's hematology database. Date of birth, medical record number, and other information available from the database will be recorded as well.

" Medical records will be collected from all sources (hematology/oncology shadow charts, files of inactive patients, scanned information from Millennium, and archived data from Children's Medical Records Department) from as many of these patients as possible.

" A flow sheet will be established for each patient that includes the following information: Name, medical record number, date of birth, gender, splenectomy status, family history (if known), and all available laboratory values for the following measurements: hemoglobin concentration, reticulocyte count, and platelet count.

" In select cases the medical record will be further reviewed for information regarding the date of splenectomy and dates of other complications that may have caused acute changes in hematologic perimeters.

Part II (November 2005 - June 2006):

" A prospective study consisting of a brief interview regarding risk factors for thrombosis, disease status (confirmation of diagnosis of HS, splenectomy status, and other illnesses that may affect blood count and cholesterol levels) involving children with HS and any relatives (parents, aunt/uncles, grandparents, etc.) with HS who are available for study.

" The following laboratory studies will be performed without charge, all consenting subjects (regardless of age) in this phase of the study:

1) Hemoglobin concentration, Hematocrit, WBC count with Differential, Platelet
count

2) Reticulocyte count

3) Total, LDL, and HDL Cholesterol, triglycerides

4) Glucose

5) Plasma C Reactive Protein concentration

6) Fibrinogen

" Each patient will be studied only once.

Charles Bruen
UT Southwestern
Department of Surgery
Mentors: Thomas Anthony, M.D.

1. Medical Errors Study

Medical errors and the potential negative effects of these errors have on patient outcome has recently received a great deal of attention. Key studies arising from the Harvard Medical Practice Study, indicated that the number of these errors were significant and introduced a excess burden on the patient and health care costs.

Errors occurring during medication ordering and administration account for, a significant proportion of these errors and much of the attendant morbidity associated with them. Several potential solutions have been proposed include institution of electronic ordering which decreases the likelihood of errors through improved legibility and automated compatible checking when multiple medications are prescribed. The unintended consequences of this system including increased physician and nursing frustration, delayed medication delivery, and decreased personal vigilance. No studies have examined whether such an electronic system of order entry actually reduces medication errors or simply trades one type of error for another. The VAs electronic ordering systems are state-of-the-art and offer a unique opportunity to investigate this issue. Partnering with Nursing service, Pharmacy, and the Intensivist service in the Thoracic and Surgical intensive care units we are proposing a study to test the utility of electronic orders compared with paper ordering.

The Hypothesis of this study is that the error rate has not been reduced by the introduction and of these electronic physician order entry systems as compared to a traditional paper-based system in an ICU setting.

In this study, two different electronic and one traditional paper-based physician ordering systems will each be used for a period of four weeks in the SICU and TICU, and the three systems will be used serially. Using specific definitions of medication errors, data will be collected on the error rate associated with the use of each of these systems will be gathered and compared. There will be three phases of the study, each lasting exactly fours weeks. For each phase, data will only be gathered for patients that have consented to participate in the study. During Phase I of this study, the SICU and TICU will remain on their status quo procedures of recording and executing physician orders using the CPRS system. In Phase II, the physician orders and execution will be done using the CliniComp system. In Phase III, a traditional paper-based physician order entry system will be used. During all phases, patients who are excluded from the study will be treated using the standard procedures of each respective ICU (ie. CPRS).

2. Vascular Health-Related Quality of Life Study

We have been collecting prospectively }IRQoL information on vascular surgery patients for about 2 years. Approximately 150 patients have been entered into this study. HRQoL is measured at the time of diagnosis, and then at 6, 12, and 24 months.
The hypothesis being addressed is that patients with peripheral vascular disease and who undergo re-vascularization procedures will have improved HRQoL compared with patients who do not undergo surgery. Upon completion this study will be among the largest study to address this issue with validated HRQoL instruments.

Jason J. Chang
University of Kentucky
Department of Internal Medicine
Mentors: Gail Thomas, M.D. and Ronald Victor, M.D., Ph.D.

PURPOSE: To characterize the autonomic nervous system dysregulation in relation to the early observed sinus tachycardia in children with Duchenne or Becker muscular dystrophy (DMD/BMD) without any clinical signs of cardiac involvement.

BACKGROUND: DMD and the milder BMD variant is an X-linked condition characterized by progressive muscular wasting and weakness in early childhood leading to death from respiratory failure by early adulthood. While the life expectancy has increased due to the use of long-term noninvasive positive pressure ventilation, a growing prevalence in cardiomyopathy has been observed as well1. Clinically apparent cardiomyopathy may be detected by the age of 10, with all patients over the age of 18 displaying cardiac involvement2. Although advanced cardiomyopathy is often accompanied by arrhythmias and characteristic EKG abnormalities, a labile sinus tachycardia has been commonly observed in children with DMD before any clinical signs of heart failure3. The circadian heart rate variability of children with DMD is apparently blunted as well4. Although the basis of this regulatory imbalance remains unresolved, attenuated vagal efferent activity associated with nitric oxide modulation has been suggested as an major element4,5. Recently our laboratory has been able to demonstrate that children with DMD exhibit a functional muscle ischemia in exercising skeletal muscle not observed in control subjects due to a deficiency of neuronal nitric oxide synthase6. Whether this phenomenon is applicable to cardiac physiology is unknown. More insight regarding the nature of the dysautonomia will be valuable to understanding the significance of the sinus tachycardia relative to the terminal cardiomyopathy and should provide the impetus for more focused studies regarding the increasing prevalence of heart disease in this young population.

BRIEF PROJECT SUMMARY: At the first of two visits subjects will be asked to perform four tests of autonomic nervous system functioning consisting of the lower body negative pressure challenge, cold pressor test, deep metronomic breathing, and sustained handgrip test. Twelve lead electrocardiogram (EKG), blood pressure, heart rate, respiratory rate, hemoglobin oxygenation via near infrared spectroscopy, and blood flow via doppler ultrasound as well as venous occlusion plethysmography will be measured during each test. Twenty-four hour Holter monitoring heart rate variability and twenty-four hour blood pressure measurements will be recorded. We predict that there will be significant differences in autonomic responses compared to control subjects. The subject will be asked to return after a week's time for a magnetic resonance angiography and cardiac perfusion imaging study when he will repeat the cold pressor test and lower body negative pressure challenge while images are recorded from coronary arteries and gadolinium contrast perfusion studies. EKG data will be evaluated for any signs of cardiac ischemia such as ST segment changes during the four tests. If there is a cardiac equivalent of the previously observed functional muscle ischemia, this will be evident on magnetic resonance angiography and perfusion studies as a difference in coronary artery vasodilation and myocardial perfusion compared to control subjects.

Vinu Ipe
UT Southwestern
Department of Internal Medicine
Mentor: Robert Toto, M.D.

Diabetic nephropathy is a public health crisis in the United States. The disease causes devastating complications in approximately 30% of both type 1 and type 2 diabetics, with progression to end-stage renal disease (ESRD) in nearly all of these cases. Diabetic nephropathy has become the primary cause of ESRD in the US and develops insidiously over 10-15 years and the morbidity and mortality are sharply increased with onset of nephropathy in both type 1 and type 2 diabetics. Moreover, death occurs within the first year after onset of ESRD in 17% of type 1 and 23% of type 2 diabetics.

Current standard of care of patients with diabetic nephropathy includes treatment with an ACE inhibitor and lowering blood pressure to < 130 / 80 mmHg. Inhibition of the renin-angiotensin-aldosterone system (RAAS) with ACE inhibitors (ACEi) in type 1 diabetics or angiotensin II type 1 receptor blockers (ARB) in type 2 diabetics have been shown to reduce risk of progression of diabetic nephropathy to ESRD. Unfortunately, in the vast majority of cases, renal function continues to decline at an accelerated rate despite these interventions. There are no well-controlled studies examining the impact of combining agents that inhibit the RAAS in diabetic nephropathy. The purpose of this project is to conduct a feasibility study testing novel drug combinations that block the RAAS at multiple sites, including the ACE enzyme, the angiotensin type 1 receptor and the aldosterone receptor, on proteinuria - a surrogate marker for renal disease activity in patients with established diabetic nephropathy. This feasibility trial could lead to a full-scale phase III clinical trial to test potentially promising strategies on hard clinical outcomes such as ESRD.

Major Hypothesis:
In patients with diabetic nephropathy, the addition of either an ARB or a MRA to a maximally dosed ACE inhibitor-based regimen will afford greater renoprotection than the ACEi-based regimen alone, and the added value of the MRA is specific for aldosterone and is not explained solely on the basis of reduced time-integral BP burden as assessed by 24-hour ambulatory blood pressure monitoring.

Specific Aims:

1. Recruit a multiethnic cohort of 90 adults age 20 to 65 with either Type 1 or Type 2 Diabetes and overt nephropathy (defined as a urine albumin/creatinine ratio > 300 mg albumin/g creatinine) and randomize in a double blind fashion to a control group consisting of ACEi-based therapy alone (lisinopril 80 mg once daily) or one of two experimental groups: 1) ACEi + ARB (lisinopril 80 mg once daily plus losartan 100 mg once daily) or 2) ACEi + mineralocorticoid receptor antagonist. (lisinopril 80 mg once daily plus spironolactone 25 mg once daily).
2. Conduct a 12-month prospective study to determine if proteinuria is reduced to a greater extent when either the ARB or MRA is added to ACEi-based therapy. The study is powered to detect a 40% greater reduction in 24-hour urine albumin/creatinine excretion ratio in either experimental group versus control with 24 patients per group. Secondary endpoints to be examined include: (a) serum potassium and creatinine to assess safety, (b) TGF-beta, as a surrogate marker for ongoing renal injury, and (c) plasma lipids and lipoprotein composition.
3. Perform repeated ambulatory blood pressure monitoring to examine the renoprotective effects of the 3 different regimens at comparable office and 24 hour blood pressure levels of < 125/75 mmHg. Periodic measurements of glomerular filtration rates will be done by overnight in-patient clearance studies at the GCRC.

This feasibility study will provide important new information for design of subsequent large-scale trials of renoprotection in diabetic nephropathy: 1) documenting safety of maximal dose combination therapy; 2) documenting the feasibility of extensively utilizing 24 hour ABPM in large scale trials designed to establish blood pressure independent renoprotective effects of specific antihypertenive therapies; 3) providing promising new data for a future large-scale studies to test the efficacy and safety of combining ACEi therapy with MRA therapy on renal outcomes.

Phillip Kuan
Texas Tech University Health Sciences Center
Department of Internal Medicine
Mentor: Christine Kim Garcia, M.D., Ph.D.

Investigation of Familial Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing disorder of the lungs defined by characteristic pathologic, clinical, radiographic, and physiologic characteristics. It is the most deadly of the idiopathic pneumonias with no known cure and no consistently effective treatment. The prognosis is poor, with a mean survival of fewer than 3 years from the time of diagnosis. The familial form of the disease is rare, accounting for 0.5 - 3.7% of all the cases of IPF. The molecular basis of the familial form of the disease is unknown. We hypothesize that familial idiopathic pulmonary fibrosis is a rare disease displaying an autosomal dominant pattern of inheritance with variable penetrance. To test this hypothesis we have established a collection of families with familial idiopathic pulmonary fibrosis (IPF) through patient contact and referrals. This proposal seeks to characterize affected and at-risk family members by clinical and molecular methods. Each participant will undergo a physical exam, submit blood for routine analyses, have pulmonary function testing, a cardiopulmonary exercise test, a high-resolution CT (HRCT) scan, and undergo bronchoscopy to evaluate bronchoalveolar lavage fluid for markers of inflammation and fibrosis. The pulmonary function testing will include spirometry, body plethysmography, diffusion capacity measurement, and oxygen desaturation with exercise. This is a novel type of study using our unique resources of families with familial IPF. If the pattern of inheritance is indeed autosomal dominant with reduced penetrance, then this type of screening of adult at-risk family members may identify some individuals with early findings of the disease or may identify an intermediate phenotype of the disease. These studies will directly complement our investigation of the genetic basis of this disease by classical linkage techniques and by analysis of candidate genes.


Eugene Limanovich
University of New Mexico School of Medicine
Department of Internal Medicine
Mentor: Ronald Victor, M.D., Ph.D.

African American men suffer more from early cardiovascular disability and death from uncontrolled hypertension in than any other group in the United States. In studies spanning three decades, hypertension awareness, treatment, and control have been consistently worse in Black men than in the general population. Among Black men ages 18-64 with hypertension in the Dallas County, Texas, currently 47% are unaware of their condition, 60% are not being treated with medication, and only 14% are receiving a treatment regimen that lowers their blood pressure (BP) below the minimally acceptable value of 140/90 mm Hg. These age-adjusted rates are much lower than those in Black women, white men, or white women in the same county. To better control hypertension in Black men, we propose a well-informed and feasible behavior theory-based intervention conducted by their barbers, influential peers who will reach out to their customers and model effective strategies for reducing the serious health risks caused by hypertension.

Target Population: Black men who patronize Black-owned barbershops that cater to Black men

Major Hypothesis: Sustained efforts by barbers to continually monitor BP in the barbershop, deliver health messages, and provide social support for desired changes in healthcare-seeking attitudes and behaviors will be more effective than no active intervention for controlling hypertension in Black men.

Specific Aims: Among the adult Black male customers with hypertension, the specific aims are:
1. To increase the proportion of adult Black male barbershop customers with hypertension in whom systolic BP is less than 140 mm Hg and diastolic BP is less than 90 mm Hg.
2. To increase the measurement of BP in the barbershop and the recognition of elevated BP readings.
3. To increase the utilization of regular medical providers for chronic BP management.

Nichole Manhert
University of Wisconsin
Mentors: Jeanne Sheffield, M.D. and Gretchen Stuart, M.D., MPHTM

Oral Contraceptive Pill continuation in a Dallas Family Planning Clinic

Background: Over 30% of reproductive age women are currently using oral contraceptive pills and over 80% of all women born after 1945 have ever used oral contraception. Oral contraception is highly effective when used perfectly, but typical use is associated with an 8% failure rate in the first year. Problems with compliance and discontinuation account for an estimated 1 million unintended pregnancies and associated costs of about 2.6 billion dollars. Previously published literature demonstrates that discontinuation rates range from 32% to 60% in the first year. The continuation rate of oral contraceptives in our clinic is important in that we have a unique population that is predominantly Latina with continuation rates that we suspect are higher than previous literature cites.
Objective: To determine the continuation rate of oral contraceptive pills among female patients at the Maple Community Women's Health Center. Secondarily, we hope to assess the feasibility of a future study to determine if an intervention will increase continuation rates of oral contraceptive pills.
Study Design: This is a descriptive study using medical charts to determine the characteristics and continuation rate of women seen at the Maple Community Women's Health Center to initiate oral contraceptive pills from May 2002 to April 2003.
Results: Once the data is compiled we will use descriptive statistics to assess the study population. We will calculate the baseline continuation rate and then evaluate the characteristics of women who continue birth control versus women who discontinue at three months and at twelve months.
Conclusions: Results may yield important information that can then be used to enhance quality of care delivery and improve continuation rates of oral contraceptive pills in out clinic population.

Brendon O'Neill
Drexel University
Mentor: Abhimanyu Garg, M.D.

1. Primary responsibility for a study titled "Fish Oil for the Treatment of Hyperlipidemia in HIV+ Subjects on Protease Inhibitor Combination Therapy." With the advances in anti-HIV therapy, particularly the multi-drug regimens that include protease inhibitors, long-term survival of HIV infected patients is now expected. However, such therapy has led to the development, in some patients, of a syndrome characterized by lipodystrophy, dyslipidemia, impaired glucose tolerance, and sometimes diabetes mellitus. The dyslipidemia is characterized by hypertriglyceridemia and a lowered concentration of high density lipoprotein cholesterol. In the proposed study, we will investigate the short-term safety and efficacy of fish oil in lowering plasma triglycerides and LDL cholesterol levels in HIV+ subjects with hyperlipidemia (TG > 300) associated with protease inhibitor therapy. Secondary end-point variables will include plasma VLDL-cholesterol, HDL-cholesterol, insulin, and fasting glucose concentrations. The study will be a double-blind, randomized, placebo-controlled cross-over trial. Each of our two treatment arms will be 6 weeks duration with three sets of fasting labs and an outpatient check-up visit at the end of each treatment period. Daily activities will include screening and enrollment of patients for the study, following the patients through the study at their outpatient visits, and managing our database.

2. The metabolic and molecular basis of lipodystrophy syndrome in HIV-infected patients is not known. Whether besides PIs, other antiretroviral drugs, HIV infection and reduction in viral load contribute to the development of lipodystrophy syndrome is not clear. The project therefore has the following aims: 1) to characterize metabolic abnormalities and changes in body fat distribution, 2) to develop objective criteria for defining the syndrome and to ascertain prognostic indicators and 3) to elucidate the molecular basis of the lipodystrophy syndrome in HIV-infected patients. To accomplish these aims, we will conduct a 2-year long prospective, randomized, double blind, placebo-controlled study in asymptomatic HIV (+) patients to compare two equally effective antiretroviral regimens, one with and the other without a PI. We will study body fat distribution by anthropometry and magnetic resonance imaging and will measure insulin sensitivity (in a subset of patients), plasma lipoproteins, glucose tolerance and other metabolic variables. We will study expression of an array of adipocyte specific proteins/transcription factors involved in adipocyte differentiation, insulin action and lipoprotein metabolism in fat biopsy samples obtained before and after institution of therapy. Identification of the metabolic and molecular basis of lipodystrophy syndrome in HIV (+) patients may lead to better understanding of role of adipocyte-specific genes in insulin action and body fat distribution and may lead to discovery of other antiretroviral drugs that do not cause the lipodystrophy syndrome. My involvement will be in a) recruiting/screening patients, b) conducting inpatient and outpatient visits every three months to follow any changes in metabolic profile/HIV suppression c) monitoring and updating the database d) performing skin fold anthropometry, underwater weight, and oral glucose tolerance tests e) assisting with DEXA, MRI, MRS data analysis f) participating in adipose and muscle biopsy procedures and preparing the samples for molecular analysis.

3. In addition to primary responsibility in the Fish Oil therapy trial, I will participate in the overarching project titled: Therapeutic Interventions in HIV-associated Lipodystrophy. In this larger project, we propose to investigate potentially safe therapeutic lifestyle changes as well as novel therapies for its management. The project therefore has the following aims: 1) to compare acceptability and metabolic effects of diets rich in carbohydrates and cis-monounsaturated fats, 2) to compare effects of a supervised aerobic exercise regimen and dietary advice to dietary advice alone on metabolic variables and body fat distribution, 3) to compare lipid-lowering effects of n-3 polyunsaturated fats to placebo (Fish Oil Study) and 4) to study the efficacy and safety of recombinant methionyl leptin (r-metHuleptin) in improving insulin sensitivity, dyslipidemia and body fat distribution in patients with HAART-induced lipodystrophy. To accomplish these aims, we will enroll ~124 patients with HAART-induced lipodystrophy or metabolic complications in randomized, crossover studies (aims 1 and 3) and randomized, parallel design studies (aims 2 and 4). We will study body fat distribution by anthropometry, dual energy X-ray absorptiometry and magnetic resonance imaging and will measure insulin sensitivity (aims 2 and 4). We will study plasma lipoproteins, glucose tolerance, and other metabolic variables (all aims). Our results may help in designing therapeutic approaches to HAART-induced lipodystrophy and its metabolic complications.

4. I will also see patients with Dr. Garg who have rare, inherited forms lipodystrophy. I plan to learn the process of investigating unknown genetic etiologies through the use of well-defined pedigrees, genome-wide linkage analysis, and the examination of candidate genes for mutations. Studying single-gene disorders of adipose tissue may aide our understanding of how adipose tissue disorders lead to insulin resistance and other metabolic abnormalities.

2004-2005 Fellows of the University of Texas Southwestern Doris Duke
Clinical Research Fellowship Program for Medical Students
(UT Southwestern-Doris Duke-CRF)

Holly Barko
UT Southwestern
Department of Pediatrics
Mentors: Greg Jackson, M.D. and William Engle, M.D.

I. Association of hypocalcemia with a change in gentamicin administration schedule in neonates: (IRB submitted and approved)

Approximately 15-30 neonates are evaluated in the NBN each month with suspected sepsis and are treated with ampicillin and gentamicin for >4 days duration. A previous retrospective study examined the increased incidence of hypocalcemia with a change in gentamicin dosing schedule (from a lower dose every-12-hour regimen, to a higher single-daily-dose regimen). This study will compare changes in serum and urine electrolytes in neonates treated with two different dosing schedules of gentamicin (q 12h vs. q 24h). Based on the results of a previous study, the investigators have hypothesized that q24h dosing of gentamicin results in either altered urinary excretion of calcium and magnesium and/or disruption of the calcium-sensing receptor of the parathyroid gland, thus increasing the risk for hypocalcemia when compared to q12h gentamicin dosing. Fifty term or near-term neonates will be selected for the study who are *35 weeks gestation and *2100 grams, and who do not require NICU care. The study neonates will be given gentamicin in a dosing schedule of either 2.5 mg/kg*dose q12h or 4mg/kg*dose q24h, for 7-10 days. Blood and urine samples will be taken at 0 hours (before gentamicin is administered), 50 hours, and 122-143 hours for each group of infants, and data collected will include serum BUN and Cr, electrolytes, total Ca and ionized Ca, PTH, and albumin; also urine Ca/Cr, FENa, FEK, FEMg, FEPhosphate, and urinalysis. The data collected will help determine whether significant electrolyte and/or parathyroid hormone effects occur as a result of a once-daily gentamicin dosing regimen.

II. Parenteral vs. parenteral-oral antibiotic therapy for term and near-term neonates with suspected pneumonia: (development of the project summary is nearing completion).

This study will compare outcomes of two groups of neonates, each group consisting of approximately 40 neonates, who are being treated with antibiotics for suspected pneumonia and whose symptoms rapidly resolve. One group will receive the standard regimen of 5-7 days of parenteral antibiotics (ampicillin and gentamicin), while the study group will receive parenteral antibiotics for at least 48 hours and then (if the neonates have been asymptomatic for 24 hours) parenteral antibiotics will be discontinued and oral amoxicillin/clavulanate (Augmentin®) will be administered for a total of 7 days. It is anticipated that the neonates in the oral medication group will be discharged after 2 days of beginning oral therapy; these neonates will be examined by one of the investigators within several days after discharge. Pharmacokinetic studies of Augmentin® in this population are also being considered. If the parenteral-oral antibiotic therapy for neonatal pneumonia proves to be as effective for these selected neonates who readily respond, the potential benefits to patients would include fewer needle sticks (for IVs and gentamicin blood levels), decreased exposure to a potentially nephrotoxic drug (gentamicin), and a shorter hospital stay.

III. Antibiotic therapy for neonates exposed to maternal chorioamnionitis (study is in the early stages of conceptualization)

In this study the investigators will identify women who have the obstetrical diagnosis of chorioamnionitis during labor at Parkland Memorial Hospital. All neonates in the study will be asymptomatic; those who develop symptoms will receive more prolonged antibiotic therapy and will not be included in the study. The investigators are considering the entry definition to include a certain time period of intrapartum maternal treatment with antibiotics (e.g., entry criteria may include those neonates whose mothers have received ampicillin and gentamicin at least 4 hours prior to delivery).

Neonates who are not exposed to chorioamnionitis currently receive a single dose of aqueous penicillin within one hour of birth as prophylaxis to reduce the incidence of neonatal Group B streptococcal disease. The control group will consist of continuing the current approach to asymptomatic neonates exposed to maternal chorioamnionitis at PMH , i.e., obtain a blood culture and administer ampicillin and gentamicin intramuscularly (IM) for a 48-hour course. The study group will be given a single IM dose of penicillin (after a blood culture is obtained) and then be observed closely for 48 hours. The clinical outcomes of the two groups will be compared, and will require follow-up examinations and phone contact. If the single IM dose of penicillin (in combination with intrapartum maternal antibiotics) proves to be as effective as the standard therapy of ampicillin and gentamicin IM for a 48-hour course, then asymptomatic neonates exposed to maternal chorioamnionitis could in the future be treated with a regimen that involves fewer painful IM injections and a reduced exposure to broad-spectrum antibiotics.

IV. Accuracy of the BiliStat™ machine compared with the laboratory-measured total serum bilirubin (study has been IRB-approved)

The BiliStat ™ machine, approved for use in Europe to quickly determine serum bilirubin levels as a patient point-of-care device, has not yet been approved for use in the United States. The investigators have been in contact with the manufacturers and distributors of the device, who wish to collaborate on a project in the Parkland Newborn Nursery that will validate the use of the BiliStat™ for FDA approval. Patients will include those who are undergoing a blood specimen for either a bilirubin level to assess jaundice, or those who are undergoing a blood specimen for the routine newborn screening tests.
The study will compare serum bilirubin levels performed at Parkland Memorial Hospital Laboratory (Olympus AU600, which utilizes the Jendrassic-Grof with blank method) with the BiliStat™, which utilizes a centrifuge and concurrent laser spectrophotometry (dual-wave flame photometry) technology. A technical issue involving the safety of the self-sealing glass tube for specimen collection is close to a satisfactory conclusion. In addition, transcutaneous bilirubinometry with the Air-Shields Minolta JM103 Jaundice Meter ™ (FDA-approved) will be performed on the same patients. Comparisons of these 3 determinations (Olympus AU600, BiliStat™, and the JM103 Jaundice Meter™) will then be performed. The advantage of the BiliStat™ is the rapidity of the bilirubin testing, which could reduce delays in hospital discharge.

Suzie Chang
Georgetown University
Department of Neurology
Mentor: Abhimanyu Garg, M.D.
Co-mentor: Anil K. Agarwal.

Title:"Study of molecular heterogeneity of adipose tissue"

Purpose: To determine the underlying heterogeneity of various adipose tissue depots according to respective anatomic location using differential expression of various adipocytokines and adipocyte enzymes.

Background:
Congenital Generalized Lipodystrophy is characterized by a near complete absence of body fat and extreme insulin resistance from birth. Less than 200 cases with CGL have been described in the literature. Other clinical features include acanthosis nigricans, marked hyperinsulinemia, hypertriglyceridemia, and the onset of diabetes mellitus mostly during pubertal years. The patients may have hepatosplenomegaly, acromegaloid appearance (enlarged hands, feet, and prominent mandible), umbilical hernia, and in women, clitoromegaly, hisutism, oligo/amenorrhea and polycystic ovaries. They have extremely low serum leptin and adiponectin levels. Affected children have accelerated growth, voracious appetite, increased basal energy expenditure, and advanced bone age. Fatty infiltration of the liver occurs early and may lead to cirrhosis. Other reported features include mild mental retardation, cardiomyopathy, and hypertrichosis.
Our studies of phenotypic heterogeneity among two types of CGL revealed that patients with CGL1 (with AGPAT2 mutations) have near complete absence of "metabolically-active" adipose tissue located in most of the subcutaneous (sc) areas, intraabdominal and intrathoracic regions, bone marrow, and parathyroid glands, but "mechanical" adipose tissue in the orbis, crista galli, buccal region, tongue, palms and soles, scalp, perineum, vulva, peri-articular regions, epidural area and pericalyceal regions of the kidney is well preserved in them. In contrast, patients with CGL2 (with BSCL2 mutations) have marked lack of both metabolically active and mechanical adipose tissue. The relative expression of various AGPAT isoforms in adipose tissue from different anatomic locations has not been studied. Thus, we will investigate if this particular fat loss in CGL1 patients is due to differential expression of AGPAT isoforms or other adipocyte specific genes.

Concise Summary of Project:
Tissue mRNA expression studies: Adipose tissue from various anatomic sites (where available) and liver, skeletal muscle, lung and pancreas will be excised and analyzed for the global gene expression (gene chip experiments). If a particular gene of interest, e.g., from triglyceride or phospholipids biosynthetic pathways or lipodystrophy genes implicated in humans and mouse models, is not represented on the selected gene chip, mRNA expression for such gene will be studied by real time RT-PCR.
Furthermore, where possible, if enough tissue is available, we will isolate the adipocytes and culture the cells to determine adipocytokines secretion such as leptin, adiponectin, resistin, etc. We may also use to study protein expression in adipose tissue and adipocytes from various sites using global protein analysis (proteomics).
We will obtain human fat from various sites as listed below: scalp, temporal region, cheek, retro-orbital, eyelid, chin, anterior neck (supra-clavicular), posterior neck (dorso-cervical), arm, forearm, palm, axilla, anterior chest, intra-thoracic (around pericardium), abdomen anterior, abdomen posterior, omental, intra-peritoneal, retroperitoneal, peri-renal, pericalyceal (inside kidney), pubic, vulvar, gluteal, thigh anterior, thigh medial, calf, sole, peri-articular (around hip and knee joints).
Small quantities (up to 1.0 gm) of these tissues will also be obtained from the organs involved in insulin action, production and phospholipids synthesis: muscle, liver, lung, and pancreas.
Fat will be collected from patients undergoing elective surgery, from organ donors who consent to donate their bodies for research and from discarded adipose tissue during various surgical procedures. Skeletal muscle, pancreas, lunch and liver will only be obtained from organ donors.

Anne Chung
University of Arizona
Department of Internal Medicine
Mentor: Mark Drazner, M.D., Ph.D.

Relationship Between Left Ventricular Volume and Ejection Fraction
Left ventricular (LV) ejection fraction (EF) has traditionally been used to classify heart failure (HF) into diastolic and systolic heart failure. However, it has recently been proposed that EF is acting as a proxy for left ventricular (LV) volume and that measuring LV volume is a more accurate reflection of the underlying cardiac physiology and may therefore be a more useful diagnostic and prognostic measure in HF. To our knowledge, there is no prior analysis by cardiac MRI of the relationship of LV volumes and LVEF. The Dallas Heart Study appears ideally suited to address this question. The aim of this work is to explore the linear relationship between EF and LV volume in the Dallas Heart Study (DHS). We also will explore whether other factors (e.g. gender, obesity, ethnicity, and history of heart failure) modulate the relationship of LVEF and LV volume.

Chronic Heart Failure in Patients Treated at an Urban County Hospital
A retrospective chart review will be performed on patients treated at St. Paul's congestive heart failure clinic and Parkland's congestive heart failure clinic. We will compare the outcomes of the patients treated at an urban county hospital to the outcomes of the patients treated at a private hospital. Patients at St. Paul and Parkland are treated by the same physicians. This analysis will help us understand the effect socioeconomic status has on the outcomes of heart failure patients.

Non-Synonymous Single Nucleotide Polymorphisms Associated with Cardiac Outcomes
We will be comparing non-synonymous SNPs to observe for conservation across species and association with cardiac outcomes and risks. We will be using SNP data collected from the Dallas Heart Study to observe frequency of the variants in this population.

Mark Muir
UT Southwestern
Department of Neurology
Mentor: Michael Racke, M.D., Ph.D.

For my Doris Duke research project I will be working in the neuro immunology lab under the direction of Dr. Michael Racke. This lab is closely associated with the Multiple Sclerosis Clinic at St. Paul, which follows roughly 4000 patients on an ongoing basis. This allows for efficient transfer of data and ideas in both directions, with laboratory research being translated directly into clinical trials and clinical observations leading to the design of lab experiments. In this manner, I will be involved with a project that is currently underway, and that is attempting to correlate enormous amounts of patient data into a single database. The study, which has already begun and is still enrolling patients, is currently focused on correlating lab, imaging, and clinical measurements to follow the progression and activity of MS and find more accurate methods of estimating prognosis. The patients in the study are seen on a regular basis, at which time blood is drawn, a gadolinium enhanced MRI is performed, and they undergo a clinical neurological evaluation using a standardized neurological disability scale. The MRI's are evaluated by a blinded neuroradiologist so that presence or absence of enhancing lesions can be correlated with the other data obtained.

My role in this project, in addition to seeing the study patients in clinic with my mentor, entails analysis of a potential new therapy for MS using PPAR agonists, a class of drugs that have been used extensively for decades in the treatment of hyperlipidemia. Two common examples used in humans are gemfibrozil and fenofibrate. These drugs have been shown to cause clinical improvement in the mouse model of MS (Experimental Autoimmune Encephalomyelitis mouse). The mechanism that is believed to be at least partly responsible for this observation is that the PPAR agonists cause CD4+ Th0 cells to differentiate selectively into a Th2 rather than Th1 phenotype in the presence of stimulation by antigen. This is consistent with the current thinking that MS is an autoimmune disease mediated in large part by self reactive Th1 cells specific for certain proteins in myelin. The ultimate goal based on these observations is the development of a clinical trial in human MS patients to test the effectiveness of this class of drugs, either as monotherapy or in combination with other medications. These drugs (PPAR agonists) are an ideal target of a clinical trial because of their long track record of safety and minimal side effect profile established over many years, and additionally they are cheap and widely available to patients and physicians.

But before a clinical trial is begun, these drugs need to be tested in vitro on human leukocytes to determine if they have the same molecular effects as seen in the mouse models. Presumably, if the same effects are seen in human cells and these drugs have a strong effect on the mouse model of MS, the evidence will justify undertaking a clinical trial. My area of research involves determining the specific changes caused by these agents in human T cells using the blood samples from the patients enrolled in the study mentioned above. When blood is collected from the patient, it is spun down and separated into its components. I then take the isolated leukocytes, stimulate them with antigen, and culture them in the presence or absence of PPAR agonists. From these cultured cells, RNA is isolated and run on micro array chips. When analyzed, these chips reveal whether there is up-regulation, down-regulation, or no significant change between the two conditions for 32,000 human genes. In order to analyze the data from a micro-array chip and derive meaningful conclusions, I am working to learn the GeneSpring software used by UTSW. This software not only allows one to analyze data and format it appropriately for either presentation or publication, but also provides for correlation between sets of patient micro-array data and their clinical information, in this case MRI and neurological disability scores. Ideally, we hope to find the same or similar gene activation patterns in the human lymphocytes as in the mouse lymphocytes, suggesting that PPAR- agonists may cause preferential Th2 differentiation in humans as well. The results of these experiments, along with several related experiments being conducted by others in the lab, will pave the way for a full scale clinical trial using the PPAR agonists. The large patient population followed in the MS Clinic provides an ideal setting for recruiting and following patients in this type of study.

Once sufficient data has been gathered on the PPAR- agonists, I will begin experiments with a related class of drugs, the PPAR- agonists. These drugs have also been in use for some time in the form of insulin-sensitizing thiazolidinediones, particularly troglitazone and pioglitazone. While these drugs seem to act through an independent pathway, they have similar effects to PPAR- agonists on T cell differentiation and on the mouse MS model. Another laboratory aspect of this study involves using flow cytometry to determine a quantitative measure of the number of each group of lymphocytes in a given subject. This flow cytometry data is compared between healthy control subjects and MS patients to gain a sense of which types of peripheral blood leukocytes contribute to the pathogenesis of MS. While I will not be directly involved in this aspect of the study, the flow cytometry data may provide clues to other classes of agents to experiment with, particularly drugs known to alter either lymphocyte differentiation or cytokine production by lymphocytes. The ultimate objective of each of these related projects is to initiate a randomized placebo-controlled clinical trial to test the effectiveness of these agents as a potential new therapy for multiple sclerosis. However, the clinical trials are still some way off and may not be entirely underway before the end of my Doris Duke Fellowship. This would give me the opportunity to continue this research during my final year of medical school.

Sandra Saldana
University of Vermont
Department of Internal Medicine
Mentor: Marlyn Mayo, M.D.

TITLE: PREDICTION OF DISEASE PROGRESSION IN PRIMARY BILIARY CIRRHOSIS BY A NOVEL COMBINATION OF SURROGATE MARKERS.

PURPOSE:
The overall goal of this project is to take advantage of the clinical specimens and extensive clinical database being collected in the Primary Biliary Cirrhosis Ursodiol Methotrexate/Placebo Study (PUMPS, NIHR01DK46602) to identify the most accurate surrogate marker of disease progression. Surrogate markers are badly needed to advance clinical, epidemiological, and translational research in the field of primary biliary cirrhosis (PBC), because the progression to hard endpoints, such as death, commonly takes 10 to 30 years.

SPECIFIC AIM:
To compare the ability of novel combinations of serum markers of fibrosis, biochemical tests, clinical factors, and liver histology to predict future development of portal hypertensive complications in PBC patients.

METHODS:
PUMPS is a multi-center double blinded placebo randomized trial that was originally design to compare the effect of ursodiol plus methotrexate vs ursodiol plus placebo on the course of patients with PBC. The study randomized 265 patients at 11 sites and then followed for approximately 8 years. Participants were evaluated every 3 to 6 months, and at each visit blood was collected for CBC with differential, platelet count, liver function test, and extra serum was stored. On a biannual basis patients underwent liver biopsy, abdominal ultrasound and upper endoscopy. Over the years, this study has accumulated an extensive amount clinical data and of samples from patients with PBC. In March 2004, the randomization code was broken and methotrexate was found to have no effect on survival or complications on liver disease. However, a subset of individuals continues to be followed on ursodiol alone at UTSW GCRC.

This study will utilize the PUMPS population to compare the ability of different putative surrogate markers of disease severity to predict progression to clinical endpoints. The surrogate markers to be studied include:
1) A novel algorithm derived from a panel of non-invasive markers, including 10 serum markers of fibrosis (listed below) and other clinical variables such as age, bilirubin, alkaline phosphatase, platelet count, albumin, and INR. The serum markers of fibrosis
were selected primarily on the basis that they have previously being shown to correlate with histological fibrosis in the liver in studies of other chronic inflammatory liver disease. They include hyluronic acid (HA), tissue inhibitor of metalloproteinase (TIMP-1), amino terminal precollagen peptide III (PCPIII), collagen IV, tenascin, undulin (collagen XIV), laminin P1, matrix metalloproteinase-2 (MMP-2), procollagen I carboxyterminal propeptide (PICP), and collagen VI. These measurements will be done in collaboration with Dr. William Rosenburg, M.D. at the University of South Hampton, UK.
2) Four-point histological fibrosis stage (Ludwig)
3) Four point histological fibrosis stage (Knodell)
4) Seven point histological fibrosis stage (Ishak)
5) Frequency of florid duct lesions
6) Risk score from the Mayo Prognostic Model for PBC
7) Age-platelet index
8) European Liver Fibrosis (ELF) Algorithm
The clinical end points that will be evaluated include: Development of varices, variceal bleeding, development of ascites, development of encephalopathy, transplant, and liver-related death.

This project will strive to create a new algorithm that will include a panel of serum markers of fibrosis, which would be superior at predicting future clinical decompensation than histological or other algorithms.

Some of the experiences that will be gained while undertaking this project include but are not limited to: modification and submission of an IRB protocol; seeing PBC patients enrolled in PUMPS at the UTSW GCRC and monitoring their disease progression; collection of clinical data and entry into study database; working with GCRC informatics core and biostatistians to graph disease progression and analyze ability of non-invasive markers to predict decompensation. The latter will include use of binary logististic regression and time-dependent Cox proportional hazards modeling, Sigma Plot graphics software, Microsoft Access, and Microsoft Excel.

Ryan Swinney
University of Southern California
Department of Internal Medicine
Mentor: Gail Tomlinson, M.D., Ph.D.

Introduction Genetic mutations have been recognized as one of the primary etiological factors in the development of cancer. Pediatric cancers present a paradoxical situation wherein cancer is present, yet seemingly insufficient time has elapsed for the sufficient genetic "hits" to accrue for cancer to develop. Recently, heritable genetic mutations have been investigated as potential cancer predisposing factors. Specifically, mutations in the function of TP53, RB1, and VHL genes have all shown functional roles in the development of sarcomas, retinoblastoma, and hemangioblastomas in children. However, research investigating predisposition factors in the etiology of the most common pediatric cancer, leukemia, still remains in its infancy. Preliminary research has suggested the role of mutations in Phase I and Phase II xenobiotic metabolizing enzymes in the development of leukemia. Nevertheless, much more work is needed in order to better elucidate these mutations' role in the etiology of leukemia.

To date, no study to date has specifically investigated differences in mutation prevalence in different populations of children with leukemia. Specifically, little has been done in minority populations such as the Hispanic and African-American populations, which constitute a substantial portion of the leukemia caseloads in our and many other pediatric hospitals. Such variations in mutation prevalence could explain the variable assortment of cancer predispositions in these different populations, and better elucidate why certain children are more/less predisposed to different forms of leukemia. It has also been speculated that the differing prevalences of these mutations in different ethnic groups might account for the variable responses to treatment that children experience when placed on a common chemotherapeutic regimen. Furthermore, current advances in cancer treatment suggest that unique "patient-specific" chemotherapeutic regimens might soon become the model of treatment, but this will only be possible with further elucidation of specific enzymes variations between patients which would effect treatment success and toxicity.

Therefore we have developed this case control study of Hispanic, African-American and Caucasian children, wherein we will seek to determine if different genetic factors might contribute to leukemia development. DNA samples (n ~360) were collected from leukemia patients in the hematology/oncology ward at Children's Medical Center of Dallas (CMC), and these samples will be matched by age, ethnicity, and sex to samples obtained from the out-patient clinics at CMC. All samples will be subjected to PCR-ASO testing for specific, pre-established polymorphisms in phase I and phase II enzymes known to have etiological roles in other cancers:

" CYP3A4, CYP1A1, CYP2D4, CYP1E1
" N-acetyltransferase 1 and 2
" Glutathione-S-transferase mu1, pi1, theta1
" Myeloperoxidase

Upon completion of data collection, these samples will be analyzed to determine:

" If significant differences in prevalence exist between the different ethnic groups
" If any polymorphisms are significantly associated with leukemia when cases are compared to their matched controls
" If different combinations of mutations have synergistic/interactive effects on cancer risk

It is our hypothesis that each ethnic group should have its own novel mutation profile, in a fashion suggested by prior epidemiological research. We anticipate that this study will better elaborate on these prior findings, and more succinctly compare the mutation variations between these communities. In addition, we expect that our study may find novel differences between cases and controls of the same ethnicity, which should elucidate how different mutation profiles may function in the etiology of leukemia. Finally, we anticipate that the effects of combinations of mutations in several xenobiotic metabolizing enzymes should have synergistic effects on leukemia predisposition.

Methods:
Samples: DNA samples were obtained via blood draw from roughly 360 children diagnosed with B-lineage leukemia over the past 5 years. All samples where amplified via PCR and stored as part of a separate investigation protocol, and will be accessed for this study. Matched controls from non-leukemic children will be obtained from residual blood left over from blood draws in the Childrens Medical Center laboratory. Cases and controls will be matched based on sex, age, and ethnicity information that were retained from the patient's medical charts. All other identifying information has withheld from this study's investigators.

The controls and cases will be amplified via standard polymerase chain-reaction, and subsequently sequenced for novel polymorphisms in the prestated enzymes via allele-specific oligonucleotide analysis utilizing primers obtained from prior research studies. Each patient will be identified as either homozygous or heterozygous for the wild-type and mutations alleles. All protocols have been approved by the Institutional Review Board.

Upon completion of data analysis, all data will be analyzed by an independent biostatistician at UT Southwestern Medical Center, who will construct odds ratios, significance values, and confidence intervals for each mutation between the different ethnic groups and the case/control dyads. The alpha value will be set at the standard .05 value, and any value found to have a p-value below this will be considered significant. Currently, power studies are being completed to determine if our sample sizes are sufficient and what the smallest detectable difference in values should be. (need to update after power calculations done)

Jennifer Tang
Baylor College of Medicine
Department of Internal Medicine
Mentors: Gretchen Stuart, MD, MPHTM and Jeanne Sheffield, MD.

1) "Hepatitis B Vaccination of High-Risk Pregnant Women" with Dr. Jeanne Sheffield.

The Hepatitis B vaccine was approved in 1981 and has been very effective in decreasing the incidence of Hepatitis B in certain high-risk groups, such as healthcare workers. Large-scale universal immunization programs for infants and adolescents have resulted in a dramatic decrease in morbidity and mortality in these age groups. However, studies indicate that prevalence rates of Hepatitis B infection have not been significantly reduced in high-risk pregnant women. In 1993, the American College of Obstetrics and Gynecology recommended that high-risk pregnant women be vaccinated for Hepatitis B during pregnancy. This was both to reduce the maternal risk of contracting the disease and vertically transmitting it to the fetus, and to reduce the risk of future infection in the mother. "High-risk" was defined as those women in the healthcare field, intravenous drug users, and those with sexually transmitted diseases. Furthermore, the 1998 "Guidelines for Treatment of Sexually Transmitted Diseases" published by the CDC states that pregnancy is not a contraindication to Hepatitis B vaccination. In fact, pregnancy is an ideal time to target high-risk mothers since it is one of the few periods of time that young women routinely access preventive and prenatal healthcare. Despite these recommendations and their potential for decreasing a life-threatening disease, few centers routinely vaccinate such high-risk women, and no studies have been done to assess either the efficacy of vaccination in this group, or the feasibility of a routine vaccination protocol in such a population.

Therefore, the primary objective of this study is to determine the efficacy of the Hepatitis B vaccine in high-risk pregnant women when given at an accelerated vaccination schedule of 0, 1, and 4 months. The third vaccination is being offered at 4 months rather than at 6 months after administration of the first vaccine. The premise behind this accelerated scheme is that pregnant women often show up for their first prenatal visit during or after the second trimester or deliver early. By offering the third vaccination at an accelerated rate, more pregnant women could potentially receive all three of their vaccinations before delivery. Secondary objectives of the study include assessing the feasibility of implementing a Hepatitis B vaccination protocol for high-risk pregnant women during prenatal care and determining the variables influencing vaccine efficacy. Two hundred pregnant women will be enrolled through the Parkland Medical Hospital OB Infectious Disease Clinic.

2) "A Multi-Center, Randomized, Double-Masked, Comparator Study of the Safety and Contraceptive Efficacy of C31G Vaginal Gel Compared to Conceptrol Vaginal Gel" with Dr. Gretchen Stuart.

Approximately 85% of American women (52 million) between the ages of 15 and 44 are sexually active. With growing awareness of the risk of STDs, increasing numbers of women will require contraceptive methods that provide protection against STDs, in addition to providing basic contraceptive function. Condoms, both male and female, present problems of acceptability for the partners of many at-risk women, and thus, cannot be considered an effective contraceptive and STD preventive for many people. A spermicide that also has the ability to prevent transmission of STDs would be a major advance and of tremendous value to women worldwide. C31G is an effective spermicide with in vitro activity equal to that of nonoxynol-9. It has been found to be a broad-spectrum antibacterial agent, active against both gram-positive and gram-negative organisms, including chlamydia. It is also active against enveloped viruses, including HIV and HSV, giving it the potential to be used as a female-controlled protective method in the fight against global AIDS.

The study is a multi-center, randomized, double-blinded, controlled, Phase III study of the contraceptive efficacy of repeated use of C31G vaginal gel compared to the Conceptrol vaginal gel (nonoxynol-9) as the primary method of contraception over six monthss of use. Secondary objectives include determining the acceptability and safety of C31G vaginal gel; determining the incidence of urinary tract infections, bacterial vaginosis, and yeast vaginitis following the use of the gel; evaluating the incidence of lesions detected by colposcopy in a subset of gel users; and measuring changes in vaginal microflora in another subject of gel users. UT Southwestern is one of fourteen research centers enrolling patients in this study and will be enrolling a total of 50 patients.

Katrina Willie
Baylor College of Medicine
Department of Internal Medicine
Mentor: Rebecca Gruchalla, M.D., Ph.D.

I will be joining the Allergy and Immunology Division of the Department of Internal Medicine beginning July 2004. During the fellowship year, I will be developing clinical investigation skills through participation in community-based participatory research project entitled Community Leadership in Preventing Asthma - CLIP Asthma and will design and implement an observational study looking at caregiver stress and asthma morbidity. In addition, I will participate in specialty clinics, research conferences and Allergy and Immunology teaching conferences and journal clubs.

1). The CLIP Asthma project is three years in duration. I will be joining the study in the year 03, the Community-Based Interpretation Phase which will consist of two parts: 1) interpretation of study results and 2) dissemination and feedback. In particular, I will look at the demographic data, indoor allergen skin test sensitivity profiles and home environment exposure data of the study participants.

2). My mentor and I will design and implement an observational study looking at the impact of caregiver stress on asthma morbidity in the child. A convenience sample of caregivers of asthmatic children treated at a specialty clinic will be surveyed using validated and reliable research instruments. The instruments include the Cohen's Perceived Stress Scale and Juniper's Pediatric Caregivers Quality of Life Questionnaire. Outcomes will include scores on the research instruments and asthma morbidity data. Our primary hypothesis is that increased caregiver stress and decreased caregiver quality of life will be related to increased asthma morbidity in the child.

Brad Butcher
Duke University
Department of Internal Medicine
Mentor: Robert Collins, M.D., Ph.D.

Paul Hess
Emory University
Department of Internal Medicine
Mentor: Ronald Victor, M.D., Ph.D.

2003-2004 Fellows of the University of Texas Southwestern Doris Duke
Clinical Research Fellowship Program for Medical Students
(UT Southwestern-Doris Duke-CRF)

Ten students will participate in the Doris DukeFellowship program at UT Southwestern:

Darin Bell
University of Texas Southwestern Medical Center
Department of Internal Medicine
Mentor: Richard Auchus M.D., Ph.D.

Darin is joining a project studying mechanisms of sodium-sensitive hypertension in African-Americans. We hypothesize that a significant fraction of low-renin hypertension in African-Americans is due to increased activity of the mineralocorticoid-ENaC (epithelial sodium channel) system. To test this hypothesis, we have designed a linked series of four protocols to examine patients with borderline and stage 1 hypertension.

Protocol #1 compares the BP response to amiloride (vs. placebo) in heterozygotes for the ENaC (SCNN1B) mutation T594M and non-polymorphic controls. We will also attempt to recruit and study the three homozygotes for this polymorphism that we have identified in the Reynolds Database. BP response and reproducibility will be determined using 24-hr ambulatory monitoring. Protocol #2 is similar to protocol #1 and will be conducted as an overlapping effort, drawing in part on subjects from the first protocol. Here, we will stratify according to their BP responses to a mineralocorticoid receptor antagonist (either spironolactone or eplerenone). Protocol #3 will be offered to poor responders from protocol 2, and will examine the response to combined amiloride and spironolactone/eplerenone. Protocol #4 will characterize mineralocorticoid production in both poor responders and brisk responders from protocols 1-3.

Brad Butcher
Duke University
Department of Internal Medicine
Mentor: Robert H. Collins, Jr., M.D.

General
Mr. Butcher will be involved in research projects involving hematopoietic cell transplantation immunology. The main project will involve a clinical study of a novel approach to graft-versus-host disease prevention. This will involve extensive interaction with clinical researchers, translational scientists, and patients. Additional work, time permitting, will include laying the groundwork for subsequent studies of this approach and analyzing and preparing for publication previously-collected clinical and laboratory data regarding immune reconstitution in bone marrow transplant patients.

Specific
1. Clinical trial of selective allodepletion. This protocol has already been approved by the IRB and is ready to begin soon. Mr. Butcher's participation in this study will include screening patients for eligibility, bringing patients on the study, and overseeing - along with the clinical research staff, study nurse and translational scientist - all aspects of the clinical trial conduct. Mr. Butcher will follow patients in the clinic, will interact with laboratory personnel who are preparing selectively depleted cell populations and doing studies of laboratory parameters, and will participate in scheduled meetings involving all personnel participating in the project. Mr. Butcher will also be involved in continuing regulatory issues with the IRB and the FDA.
2. Assuming early results from this study are promising, preparation of subsequent studies will be indicated. This will involve literature research, extensive discussion with team members, protocol writing, grant writing, and design of the clinical follow-up plan.
3. Analysis of immune reconstitution in bone marrow transplant patients. Our program has previously collected extensive clinical and laboratory data regarding immune reconstitution after allogeneic stem cell transplantation. At this point, these data require analysis and preparation for publication. Mr. Butcher will be involved in this project and would be expected to be a primary author of the paper.

Anthony Cordaro
The University of Texas Southwestern Medical Center
Department of Psychiatry
Mentors: Robin B. Jarrett, Ph.D.

Prophylactic Cognitive Therapy for Depression: NIMH R01 MH 58397

Anthony Cordaro will join a project funded by the National Institute of Mental Health to evaluate the comparative efficacy of preventive treatments for patien