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BEAUMONT LEADERS The 2007–08 offcers of the William H. Beaumont Medical Research Honor Society include, front row from left, Amrita Karve, MSI representative; Najma Khorrami; Talya Bordin-Wosk, secretary. Middle row from left, Amit Bhakoo, treasurer; Steven V. Kardos, co-president; Ajay Wadgaonkar, co-president; Kasra Adham, vice president. Back row from left, Andrew H. Gordon, PhD; Sumi Bose.

The William H. Beaumont Medical Research Honor Society is an honorary research society of medical students that was established to 1935 honor Dr. William H. Beaumont, a pioneer in physiology research. The organization seeks to foster a continuing interest in biomedical research and to promote its value in the practice of medicine. As a part of this mission, the Society integrates current research topics with the curriculum; develops a research journal showcasing GW student research; makes available information on research opportunities and seminars throughout the area, including the William T. Gill Summer Fellowship for GW medical students; and highlights student and faculty research accomplishments at the annual GW Research Day. inside this issue. . .

VOLUME II SPRING 2008

Fusion is a publication of The George Washington FusioN University Medical Center’s William H. Beaumont Table of Contents Medical Research Honor Society. FROM THE EDITORS This research journal is published Steven V. Kardos, Ajay Wadgaonkar, Andrew H. Gordon, PhD...... 3 by students in collaboration with the Offce of the Dean; Offce of FROM THE DEAN’S OFFICE Health Research, Compliance and Technology Transfer; and Medical James Scott, MD, dean of the School of Medicine and Health Sciences ...... 4 Center Communications and Marketing. FROM THE RESEARCH OFFICE University President Anne Hirshfeld, PhD, associate vice president for Health Research ...... 5 Steven Knapp, PhD BASIC SCIENCE ABSTRACTS Provost and Vice President What Role Do Androgens Play in Bone Growth? Adrian A. Woo, MSI ...... 6 for Health Affairs John F. Williams, MD, Anti-Proliferative Properties of Tymosin Fraction 5 in HL-60 Human EdD, MPH Promyelocytic Leukemia Cells, Ali A. Damavandy, MSI ...... 7 ER-targeted Bcl-2 Mitigates Ethanol Toxicity More Signifcantly than Wildtype Dean, School of Medicine and or Mitochondria-targeted Bcl-2, Andreea G. Balan, MSI ...... 8 Health Sciences James Scott, MD, FACEP A New Focus in Breast Cancer Bone Metastasis: NF-κB Gene Suppression, Andrew H. Gordon, PhD, MSII ...... 9 Associate Vice President for Certain Piperazines Mimic Stimulant or Hallucinogenic Efects of Ecstasy, Health Research Elyse Katz, MSI ...... 11 Anne N. Hirshfeld, PhD Anatomical Bases for Auditory Projections to Suprasylvian Visual Areas Editors in the Cat Cerebral Cortex, Giriraj K. Sharma, MSI ...... 12 Andrew H. Gordon, PhD A Role for Chemokine Gene Variants in Muscle Strength?, Steven V. Kardos Kasra Adham, MSII; Justin Larkin, MSII; and Ronak Patel, MSII...... 14 Ajay Wadgaonkar Cloning and Expression of Human Adenovirus Precursor Protein VI Editorial Board and Mature Protein VI, Michelle Louie, MSI ...... 15 Sumit Bose Te Role of Retinoic Acid in Neuronal Phenotype Determination, Amit Bhakoo Negin Daneshpayeh, MSI ...... 16 Kasra Adham A Potential Role for DHEA in Prostate Cancer, Patricia Reutemann, MSII. . . . 17 Najma Khorrami Talya Bordin-Wosk Middle Ear Epithelial Cell Secretion of Cytokines with Cigarette Smoke Condensate Exposure, Samaneh Ashktorab, MSII ...... 18 Amrita Karve Development of an In Vitro Model of Respiratory Tract Submucosal Glands, Managing Editor Sumit Bose, MSII ...... 19 Thomas Kohout A Tree-Dimensional Model of Epicardial Development, Production Editors Tresa L. Nesbitt, PhD, MSI ...... 21 Linda Dent Debbie Goldstein TABLE OF CONTENTS Continued on p. 2

Fusion • 2008 1 inside this issue. . . FusioN FusioN THEWlWAM H BEAUMONTMEDICAL RESEARCH HONOR SOCIETY TABLE OF CONTENTS Continued from p. 1

CLINICAL RESEARCH ABSTRACTS Improving MRI Detection of Creutzfeldt-Jakob Disease, Andrew Degnan, MSI ...... 22 Small Molecules that Induce p53 Signaling in Retinoblastoma Preclinical Animal Models, Audra K. Miller, MSII ...... 23 Surgical Correction of Spinal Deformities after Heart Transplantation: A Case Series Report, Brian Kaufman, MSII ...... 24 Hip Arthroscopy and the Treatment of Femoroacetabular Impingement, Cory M. Czajka, MSII...... 26 Novel “Non-Fusion” Technologies May Help Patients with Spinal Stenosis, vf ,SJudmt-run,ScirntificJoumal,Serving77,e (yorge 'Ubsl,ington Univmity c.5'.tedicafVnter David Goodwin, MSII...... 27 ON THE COVER: Clockwise from right, Efect of Bone Density on Mechanical Properties after Percutaneous Vertebroplasty, Surgical Correction of Spinal Deformities after Nabila Hai, MSII ...... 28 Heart Transplantation: A Case Series Report, Brian Identifying the Correlation between Pseudo-bulbar and Cognitive Impairment Kaufman, MSII, p. 24; What Role Do Androgens in Primary Lateral Sclerosis, Kimberly N. Capers, MSII ...... 29 Play in Bone Growth? Adrian A. Woo, MSI, p. 6; A Three-Dimensional Model of Epicardial Development, Clopidogrel in a Pediatric Population: Safety and Efcacy Results from a Single Tresa L. Nesbitt, PhD, MSI, p. 20; and, Effect of Bone Center, Lily A. Maltz, MSI...... 30 Density on Mechanical Properties after Percutaneous Development of Class I HLA Typing Assay for HIV Clinical Trials in East Africa, Vertebroplasty, Nabila Hai, MSII, p. 28. Olalesi Osunsade, MSI ...... 31 Gastric Stimulation for Vomiting, Nausea and Related Symptoms Associated with Gastroparesis using Enterra™ Gastric Stimulation System, Ricky Singh Harika, MSII ...... 33 Breast-Specifc Gamma Imaging as an Adjunct Modality for the Diagnosis of Invasive Breast Cancer, Rigved V. Tadwalkar, MSII ...... 34 Religious Experience in Epilepsy, Shivani M. Bhatt, MSII ...... 35 A Geometrical Forefoot Model: Relationship to Foot Function, Steven V. Kardos, MSII ...... 37

PUBLIC HEALTH ABSTRACTS Barriers to Terapeutic Cancer Vaccine Development, Robert C. Ward, MSII . . .38 Increasing Awareness and Access to Emergency Contraception, Jalan Washington, MPH, MSI ...... 39

TRAVEL EXPERIEINCES Medical Relief Eforts in Jammu, India, Cherie-Priya Dhar, MSII...... 41 A Place of Learning: Te Mondaña Clinic, Ecuador, M. Matthew Neimat, MSI . 42

OTHER ABSTRACTS Development of a Longitudinal Genetics Curriculum, Nisha Chadha, MSII . . . 43

2 Fusion • 2008 from the editors. . .

Medical students attending The George We thank James Scott, MD, FACEP, and Washington University School of Medicine and W. Scott Schroth, MD, MPH, in the Offce of Health Sciences routinely engage in biomedical the Dean; Anne Hirshfeld, PhD, our faculty research of a high quality. We are proud to advisor in the Offce of Research; Linda Dent present a diverse sampling of these research and Debbie Goldstein in Medical Center of efforts with this publication, authored by our Communications and Marketing; as well as the fellow medical students for presentation to The numerous GWUMC faculty members who took George Washington University Medical Center time from their hectic schedules to review sub- (GWUMC) community. The articles in the fol- missions. We also thank the editors of last year’s lowing pages span several disciplines, including debut edition of Fusion: Andrew Lerner, Vivek Andrew H. Gordon, PhD, MSII basic science “bench” research, clinical “bedside” Patil and Rahul Arya. Their ingenuity, hard efforts, endeavors in global and public health, work and guidance helped lay the foundation and medical education. From elaborate studies for the journal you read today. Finally, we espe- of leukemic cells, to new technologies in spinal cially thank Thomas Kohout, in the Offce of surgery, to health travel experiences in rural Communications and Marketing, for serving as India, GW medical students continue to impress our wonderful managing editor, and our editorial in both the depth and scope of their work. board for their diligence and hard work. Putting together this journal was both Medical research is an incredibly exciting rewarding and challenging. Members of the stu- endeavor, paving the way for important break- dent editorial board, composed of offcers of the throughs that expand our knowledge of the William H. Beaumont Medical Research Honor human body and enhance all dimensions of Steven V. Kardos, MSII Society, solicited submissions from the medical patient care. We hope the second annual edition school Classes of 2010 and 2011. We received a of Fusion conveys this excitement to you. strong response. The editors and editorial board, along with selected faculty, collectively and rigor- Warm regards, ously reviewed each submission. Responsibility for the content of the articles, however, remains with the respective author(s). In this second edition of Fusion, we are pleased to publish 31 submissions, refecting an extraordinary range of our peers’ research experiences. The Dean’s Offce and Offce of Student Ajay Wadgaonkar, MSII Opportunities continually offer superb guidance to medical students interested in undertaking research, and both deserve special recognition. In particular, both offces jointly fostered the creation of track programs in research, global health, health policy, and medical education, among others, to focus student interest and generate connections with experienced and tal- ented faculty—at GWUMC and throughout the Ai" Q/ country. The diversity and quality of research in Fusion is a testament to their vision. 'J)/°

Fusion • 2008 3 from the dean’s offce. . .

While it is indisputable that guidance and mentorship of the Beaumont medicine is based on the Society and her encouragement of the students foundations of science, how working on this journal. We are also indebted we defne that science is any- to the Offce of Student Opportunities which thing but narrow in scope and arranged many of these projects for the students, quality. Laboratory research, and the generous individual supporters in that clinical studies, community- offce, specifcally Dr. and Mrs. Gerald Lazarus, based projects and outreach Dr. Christopher Barley, Dr. Keshav Narain, across the globe all qualify Dr. Charles Walkoff and Dr. Robert Rosenberg. as scientifc endeavors, if the In addition, none of this would have been pos- results of these activities are sible without the active involvement of so many scrutinized in an organized of our faculty in the research and other activities way, discussed openly and form of our medical students. To all of you, a collec- the beginnings of ongoing tive thank you. inquiry. The frst step in that I encourage you to take your time as you process is to publish something journey through these pages getting a glimpse based on the work and begin a of the variety of activities that are available to dialogue about its importance, students at The George Washington University relevance and future directions. In this second School of Medicine and Health Sciences. There edition of Fusion, students from The George is no doubt that this school has a unique geo- Washington University School of Medicine graphic location which creates extraordinary and Health Sciences (SMHS) have gathered an opportunities for students to participate in ways impressive collection of contributions that span that are much more diffcult at other institutions. the experiences of scientifc endeavors for SMHS It is also true that, with those opportunities, students. I can say that I’m not only delighted comes a responsibility to discuss our discoveries to read about the activities of our students, but in science, policy and health outreach in an open also extremely proud of their many and diverse and critical way and to make our fndings acces- accomplishments. sible to a larger audience. This journal, thanks to This journal was conceived by medical all those who contributed, is a great beginning. students in the William H. Beaumont Medical My congratulations to you all. Research Honor Society and I commend them for their work. Specifcally, I want to recognize Steven Kardos, Ajay Wadgaonkar and Andrew Gordon for their creativity and thoroughness in gathering, editing and organizing these projects. This journal would not exist without their hard James L. Scott, MD work and vision. I also want to thank Associate Dean, School of Medicine and Health Sciences, Vice President Anne Hirshfeld, PhD, for her Professor of Emergency Medicine

4 Fusion • 2008 from the research offce. . .

It is with great pleasure that I invite readers to the student researchers into explore the 2008 edition of Fusion, the second their programs and mentored volume of a publication that was conceived their research activities and and implemented by offcers of The George progress. Finally, we need to Washington University’s Beaumont Society. The recognize contribution of the William H. Beaumont Medical Research Honor W.T. Gill Endowment, which Society was established at the GW School of provided summer stipends for Medicine in 1935 to promote student research. most of the students whose Although I have the honor of serving as this work is described in this group’s faculty advisor, the Society is entirely journal. Our gratitude for this student run. invaluable resource cannot be Fusion came into being because Beaumont overstated. Society offcers wanted a vehicle for capturing Many of the students and preserving the variety of experiences students whose work appears on these had while carrying out research rotations and pages are among the best and summer research projects, activities that many of most enthusiastic in their our students undertake during their pre-clinical class. Some will undoubtedly years. The offcers wanted to communicate the go on to careers in research, excitement and value of these experiences to joining the ranks of our many GW alumni who a wider audience. Last year’s frst edition was have made major contributions to collective received with great enthusiasm and, as a result, knowledge about improving the health and well members of the Society have decided that the being of humankind. Others will not choose a publication should become an annual tradition. research career, but will make their contributions This project is entirely student driven, and in the clinical realm or in other forms of service. therefore a real testament to the students them- Whatever the future holds for these talented and selves who devoted a tremendous amount of dedicated students, their research experience time and effort to its production. Considering will remain with them for the rest of their lives, the demands of their medical education, this informing their understanding of the nature and publication represents an outstanding achieve- pursuit of knowledge. ment for those involved. In acknowledging all those who made this second volume of Fusion a reality, thanks go to the Offce of Medical Center Communications and Marketing, who contributed their expertise in assuring the professional appearance of this publication. Acknowledgements and thanks are also due Anne N. Hirshfeld, PhD to the faculty research advisors who welcomed Associate Vice President for Health Research

Fusion • 2008 5 basic science. . . What Role Do Androgens Play in Bone Growth? Osteoporosis causes deterioration of bone tissue, a result of premature closing of the epiphyseal resulting in an increased fragility of bone and growth plate in bone.6,7 Thus more defnitive corresponding increased risk of pathologic bone studies are necessary to elucidate the role of fracture. Osteoporotic bone fracture, therefore, androgens in bone growth and maintenance. has become a serious public health dilemma To examine specifc androgen effects on bone, and a leading cause of disability worldwide.1 we genetically altered androgen receptors (ARs) Studies suggest a link between osteoporosis and otherwise normally present in F2 populations* a hypogonadal state, potentially with reduced of inbred mice. ARs in specifc populations of amounts of circulating androgens, in both men osteoblasts were altered using different sections and women.2,3 Therefore, androgens could play of the type I collagen promoter coupled to a rat Adrian A. Woo, MSI a role in the treatment of osteoporosis, yet the AR gene sequence. A 3.6-kb portion of the type Principal Investigator: specifc role of androgens in bone growth and I collagen promoter directed AR expression in Kristine M. Wiren, PhD maintenance remains unclear. osteoblasts throughout the lineage, from bone Oregon Health Sciences Hypogonadal elderly men appear to beneft marrow mesenchymal stem cells through to University, Portland, OR from anabolic steroid treatment, developing mature osteoblasts, while the 2.3-kb compo- increased lean body mass and gradual, yet nent targeted only the mature osteoblasts.8 AR progressive, increases in bone mineral density overexpression in male AR3.6-transgenic mice (BMD).4 In a separate study, treating severely exhibited a complex phenotype, notably increased burned children with the androgen oxandrolone trabecular bone mass caused by reduced osteo- also increased BMD within three to six months.5 clast activity. Also, cortical bone expansion was However, studies of anabolic steroid abuse in observed due to periosteal bone surface expan- developing teenagers suggest stunted growth as sion, but without increased endosteal deposition. Femoral long bones of male AR3.6-transgenic FIGURE 1: RATES OF BONE FORMATION IN MALE AR2.3-TRANSGENIC mice demonstrated a more brittle phenotype, After femurs were sectioned and polished partially attributable to inhibition of bone growth MICE BY DYNAMIC HISTOMORPHOMETRY. 9 to 40 mm, sections were subjected to fuorescent microscopy and labels were measured. A. Bone formation on the endosteal surface. rate. B. Mineral apposition rate. C. Percentage of eroded surface. D. Percentage of labeled perimeter. Labels Overexpression of ARs in mature osteoblasts were measured at both periosteal and endosteal surfaces and show a signifcant lack of endosteal labeling mimics the high level of endogenous AR expres- in male AR2.3-transgenic mice. Data is shown as mean ± SEM. n = 8-20. *, p < 0.05 **, p < 0.01; ***, sion documented at this stage of differentiation.10 p < 0.001 (vs. gender-appropriate wild-type controls). High-resolution micro-computed tomography A B showed no differences in total cross-sectional c:::::Jwt c:::::Jwt area. Cortical bone width and area were reduced 3 -AR2.3tg .!! -AR2 .3tg .!! ~ with increased marrow cavity in male AR2.3- ~ C 3 ... transgenic mice. These femurs also showed 2 ••• ~li=- ·;;;~-li 0-0 0-0o..-.... 2 decreased biomechanical strength and quality in ..E' E o..e ...0 _::L

Periosteal Endosteol Periosteol Endosteol BONE GROWTH Continued on p. 7

6 Fusion • 2008 BONE GROWTH Continued from p. 6 5. MURPHY KD, THOMAS S, ET AL. Effects of long-term oxan- drolone administration in severely burned children. was signifcantly inhibited, while the periosteal Surgery, 2004; 136:219–24. surface was not signifcantly affected in this 6. FAIGENBAUM AD, ZAICHKOWSKY LD, ET AL. Anabolic steroid use way (Figure 1A, B). These results indicate that by male and female middle school students. Pediat- effects of androgens differ at these surfaces, and rics, 1998; 101:E6. are inhibitors of growth rather than anabolic 7. JOHNSON MD. Anabolic steroid use in adolescent athletes. in mature bone. This study, therefore, suggests Pediatr Clin North Am, 1990; 37:1111–23. androgen use in treatment of osteoporosis in fact 8. KALAJZIC Z, LIU P, ET AL. Directing the expression of a green could be deleterious rather than benefcial. fuorescent protein transgene in differentiated osteo- blasts: comparison between rat type I collagen and REFERENCES: rat osteocalcin promoters. Bone, 2002; 31:654–60. 1. CUMMINGS SR, MELTON LJ. Epidemiology and outcomes of 9. WIREN KM, ZHANG XW, ET AL. Targeted overexpression of osteoporotic fractures. Lancet, 2002; 359:1761–67. androgen receptor in osteoblasts: unexpected com- 2. DANIELL HW. Osteoporosis after orchiectomy for prostate plex bone phenotype in growing animals. Endocri- cancer. J Urol, 1997; 157:439–44. nology, 2004; 145:3507–22. 3. KENNY AM, RAISZ LG. Mechanisms of bone remodeling: 10. WIREN KM, CHAPMAN EVANS A, ET AL. Osteoblast differentia- implications for clinical practice. J Reprod Med, tion infuences androgen and estrogen receptor- 2002; 47:63–70. alpha and -beta expression. J Endocrinol, 2002; * F2 GENERATION 4. WANG C, CUNNINGHAM G, ET AL. Long-term testosterone gel 175:683–94. MICE were obtained by the (AndroGel) treatment maintains benefcial effects mating of F1 generation mice on sexual function and mood, lean and fat mass, and showing the desired trait. The bone mineral density in hypogonadal men. J Clin gene was inserted into the Endocrinol Metab, 2004; 89:2085–98. embryos of mice from a line of inbred mice from Jackson Labs. Antiproliferative Properties of Thymosin Fraction 5 in HL-60 Human Promyelocytic Leukemia Cells For decades, the thymus gland was thought to HL-60 cells were initially derived from a be a functionless, vestigial organ in mammals. patient with acute promyelocytic leukemia, a Through the pioneering work of Jacques Miller disease in which myeloid precursors undergo in the early 1960s, the thymus became appreci- rapid proliferation without differentiating into ated for its vital roles in maturing T-cells and mature cellular elements. This uncontrolled establishing the immune system. Shortly there- growth results in an accumulation of these non- Ali A. Damavandy, MSI, after, Goldstein and White described the isola- functioning cells in bone marrow and blood, Research Track tion of a family of hormone-like peptides from displacing their mature, active forms, ultimately Advisor: Mahnaz Badamchian, the thymus gland collectively called thymosins.1 leading to systemic complications. Previous work PhD, Department of Since then, these small, biologically active pep- demonstrated the ability of thymosin fraction 5 Biochemistry, The George tides have been shown to possess important roles (TF5), a partially purifed protein extract from Washington University Medical in diverse physiological processes ranging from bovine thymus, to substantially suppress the pro- Center, Washington, DC immunomodulation to wound healing. liferation of HL-60 cells in both concentration Interestingly, a number of these thymic pep- and time-dependent manners by what appears tides have anti-proliferative effects on various to be a distinct, non-lethal cytostatic mecha- human and murine tumor cell lines. This nism.3 Present efforts have been aimed at further fnding, along with age-related correlations of purifying TF5 in order to isolate the effector thymic involution and an increased frequency of peptide(s) responsible for this suppressive activity. cancer, has led some to hypothesize the thymus’s Purifcation by fast protein liquid chroma- role in a possible immune surveillance mecha- tography (FPLC) followed by further purifca- nism of cancer suppression. Most recently, this tion by reverse phase high-performance liquid idea was explored in HL-60 human promyelo- cytic leukemia cells. LEUKEMIA CELLS Continued on p. 8

Fusion • 2008 7 LEUKEMIA CELLS Continued from p. 7 factor (thymosin). Proc Natl Acad Sci, U.S., 1966; 56:1010–17. chromatography (RP-HPLC) has yielded a sub- 2. GOLDSTEIN AL, BADAMCHIAN M. Thymosins: chemistry and fraction of TF5 which retains the anti-prolifera- biological properties in health and disease. Expert tive activity of the parent extract. The near-term Opin Biol Ther, 2004; 4:559–73. goals of this work are to sequence and chemically 3. SPANGELO BL, POMPILIUS M, FARRIMOND DD, STEVENS N, NIEVA R, characterize this peptide as well as to see if its SHROFF S, BADAMCHIAN M, JOHNSON CR, JARVIS WD. Presence biological activity can be reproduced with a syn- of a peptide component of thymosin fraction-5 thetic version of the molecule. Interestingly, the manifesting discrete cytostatic properties in HL-60 latest fow cytometry data obtained indicates that human promyelocytic leukemia cells. Int Immunop- , 2005; 5:1317–29. a signifcant number of the suppressed leukemic harmacol cells do indeed undergo apoptosis. Ultimately, 4. SPANGELO BL, ROACH JD, HADI F, DAMAVANDY AA, PLIESKATT J, elucidating the mechanism by which this peptide BADAMCHIAN M. Thymosin fraction-5 possesses antipro- liferative properties in HL-60 human promyelocytic exerts its action will be helpful in determining leukemia cells: characterization of an active peptide. whether it has real therapeutic potential. Ann N Y Acad Sci, 2007; 1112:305–16. REFERENCES: 1. GOLDSTEIN AL, SLATER FD, WHITE A. Preparation, assay, and partial purifcation of a thymic lymphocytopoietic ER-Targeted Bcl-2 Mitigates Ethanol Toxicity More Signifcantly than Wildtype or Mitochondria-Targeted Bcl-2 Apoptosis is the scientifc term for the genetically ethanol toxicity protection is mediated through programmed process of cell death.1 The Bcl-2 mitochondria or inside the ER. family of proteins, which includes both pro- and Our team investigated whether the already anti-apoptotic members, is responsible for the known in vivo protection from ethanol is medi- regulation of apoptosis through control of caspase ated through ER-Bcl-2 or mitochondria — Bcl-2. activity.1 Bcl-2 The team used three protects cells different fusion .2 from apoptosis constructs encoding *' by inhibiting Bax □ control for green fuorescent 0.8 *** and Bak (both D GPF-Bcl-2 wild-typ protein (GFP): Bcl-2 Andreea G. Balan, MSI, 0.6 *** pro-apoptotic ■ GFP-Bcl-2 MAOB fusion proteins were Research Track 0.4 **,:, *** members) from ■ GFP-Bcl-2 Cb5 used to examine the Advisor: Dr. D. Blaine Moore, 0.2 Deptartment of Biology, releasing cyto- 0 Bcl-2 subcellular OmM Kalamazoo College, chrome c, an -0.2 localization and Ethanol concentration (mM) Kalamazoo, MI important co- determination of factor for caspase differential rescue FIGURE 1: ER-targeted Bcl-2 rescues CHO695 from 24 hours of ethanol activation, from from ethanol. A incubation more signifcantly than mitochondria or wildtype-targeted Bcl-2. mitochondria.2 line of Chinese Student’s t-test was used to assess data signifcance. n=32; (*), (**) and (***) Previously, Bcl-2 hamster ovary cells indicate signifcant results with a p<0.05, p<0.01 and p<0.001, respectively. Data was thought to are shown as means ± standard error. (CHO695) was be subcellularly transiently trans- localized only fected with GFP: to mitochondria, however, recent work suggests Bcl-2 wildtype plasmid, GFP: Bcl-2 MAOB that Bcl-2 is distributed in the rough endoplasmic (mitochondria target) and GFP: Bcl-2 Cb5 (ER reticulum (ER) as well.3 Prior in vivo studies have target). Fluorescence microscopy was employed shown that overexpression of wildtype Bcl-2 pro- to verify the localization of the GFP: Bcl-2 tects against ethanol toxicity, a known inducer of apoptosis.4,5 Currently, it remains unclear whether ETHANOL TOXICITY Continued on p. 9

8 Fusion • 2008 ETHANOL TOXICITY Continued from p. 8 Bax translocation to the mitochondria. Research attempting to understand cellular changes fusion proteins. Apoptosis was examined in induced by ethanol toxicity, and aiming to response to ethanol in the presence of wildtype exploit a cell’s own defense mechanism, could Bcl-2 or organelle-targeted Bcl-2 using the MTT ultimately lead to treatments preventing alcohol apoptosis assay. We tested whether the subcel- toxicity. lular localizations of Bcl-2 to the ER and the mitochondria would confer different levels of REFERENCES: rescue against ethanol toxicity. GFP: Bcl-2 fusion 1. STRASSER A, O’CONNOR L, DIXIT VM. Apoptosis signaling. proteins were appropriately localized, indicating Annu Rev Biochem, 2000; 69:217–45. successful organelle-targeting. Our in vitro 2. ANTONSSON BS, MONTESSUIT S, LAUPER R, MARTINOU JC. Bax model system confrmed the protective role of oligomerization is required for channel-forming Bcl-2 wildtype against ethanol toxicity previ- activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem J, 2002; ously shown only in vivo.4,5 Moreover, we found 345:271–78. that the ER-targeted Bcl-2 signifcantly rescued CHO695 cells from ethanol toxicity, even at 3. ZONG WX, LI C, HATZIVASSILIOU G, LINDSTEN T, YU QC, YUAN J, THOMPSON CB. Bax and Bak can localize to the endo- normally toxic concentrations, whereas wildtype plasmic reticulum to initiate apoptosis. J Cell Biol, and mitochondria-targeted Bcl-2 offered more 2003; 162:59–69. limited protection (Figure 1). The same results 4. HEATON MB, MOORE DB, PAIVA M, GIBBS T, BERNARD O. Bcl-2 over- were confrmed in another line of Chinese ham- expression protects the neonatal cerebellum from ster ovary cells (CHO-Pro5) as well. ethanol neurotoxicity. Brain Res, 1999; 817:13–18. Therefore, our fndings indicate that Bcl-2’s 5. WANG NS, UNKILA MT, REINEKS EZ, DISTELHORST CW. Transient known amelioration of ethanol toxicity is likely expression of wildtype or mitochondrially targeted mediated through pathways in the ER. Such Bcl-2 induces apoptosis, whereas transient expression results could be utilized to elucidate a pos- of endoplasmic reticulum-targeted Bcl-2 is protective sibly new apoptotic pathway in which the ER against Bax-induced cell death. J Biol Chem, 2001; is upstream of the mitochondria and in which 276:44117–28. Bcl-2 embedded in the ER membrane inhibits

A New Focus in Breast Cancer Bone Metastasis: NF-κB Gene Suppression Breast cancer is the most common malignancy intrinsic biological properties favoring mutual seen in women. As many as one-third of women attraction between one another.3 As early as 1889, with early-stage breast cancer will die, with Paget put forth the “seed and soil” hypothesis most developing complications arising from that embodies this phenomenon, referring to the bone metastases, including severe pain, spinal bone microenvironment as a fertile, rich “soil” in cord compression and pathologic fracture.1,2 In which breast cancer cells may grow as “seeds.”4 Andrew H. Gordon, PhD, MSII conjunction with the Center for Musculoskeletal A clinical hallmark of disrupted bone remod- Advisor: J. Edward Puzas, PhD Research and Department of Biomedical eling in aggressive breast cancers is osteoclast- Co-Collaborators: Regis J. Engineering at the University of Rochester mediated bone destruction.1 Osteoclasts are O’Keefe, MD, PhD; Edward M. Medical Center, a novel way of suppressing this bone-resorbing cells native to bone which are Schwarz, PhD; Randy N. Rosier, MD, PhD, Orthopaedic Research tumor burden in bone was discovered. activated in response to cytokines produced by Laboratories and Department This required a tremendous appreciation for breast cancer cells.5 Production of these cytok- of Biomedical Engineering, bone biology and how certain breast cancers ines is tightly controlled by the nuclear factor-κB University of Rochester 6 prefer particular metastatic sites. In fact, some (NF-κB) transcription factor. Medical Center, Rochester, NY breast cancers uniquely display osteotropism, a Targeting the NF-κB pathway holds signif- signifcant ability to proliferate in bone.1 These cant promise in treating various cancers and breast cancers with a preference for bone and the potential host metastatic site must each possess BREAST CANCER Continued on p. 10

Fusion • 2008 9 BREAST CANCER Continued from p. 9 of the proinfammatory, bone-resorbing cytokine interleukin-6 (IL-6), and in vitro bone diseases associated with abnormal bone resorp- resorption by tumor/osteoclast co-cultures 7,8 tion. Since patients with bone cancers possess while reciprocally up-regulating production of much lower relative survival rates than patients the apoptotic enzyme caspase-3. Suppression 9 with soft tissue cancers, verifying a target such of NF-κB transcription in these breast cancer as NF-κB, governing production of an array of cells also suppressed in vivo tumor-mediated bone destruction after intratibial injection of tumor cells in female immunosuppressed mice. Immunohistochemistry showed the resorptive MMM!f l:H,M lesions formed in bone by MDA-MB-231 cells express both the p65 subunit of NF-κB and IL-6 H!#if' IH at the bone-tumor interface.10 Taken together, Skeletal metastasis, tumor-mediated these fndings demonstrated an essential role osteolys1s for NF-κB signaling in breast cancer-mediated bone destruction. Strong rationale now exists to further investigate genetic and pharmacologic NF-κB inhibitors as standard or adjuvant Adhesion MMP production ,t.. Chemotaxis therapies in these regards. Proliferation .. ■ • REFERENCES: \ :_ _ : •• •••!t Growth factors 1. GUISE TA, MUNDY GR. Cancer and bone. Endocrine Rev, •• • • • ■ • (•-9 - TGF~) and •• ....- P cytokines 1998; 19:18–54. ········· ~ 2. DOMCHEK SM, YOUNGER J, FINKELSTEIN DM, SEIDEN MV. Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer, 2000; 89:363–8. FIGURE 1: THE “VICIOUS CYCLE” OF CANCER-MEDIATED BONE 3. HART IR, FIDLER IJ. DESTRUCTION. Chemical interactions between SDF-1a/CXCL12 and CXCR4 infuence breast cancer Role of organ selectivity in the determination of metastatic patterns of B16 cells to home in on bone, adhere to the bone linings and seed in the bone microenvironment. The tumor melanoma. Cancer Res, 1980; 40:2281–7. cells then secrete cytokines (i.e., PTHrP, TNFa, IL-1, IL-6, and IL-11), many of which are controlled by NF-κB signaling. This stimulates bone resorption by osteoclasts via osteoblast production of RANKL. Matrix 4. PAGET S. The distribution of secondary growths in cancer of the breast. 1889; 1:571-3. metalloproteinase (MMP) production by tumor cells, also controlled by NF-κB signaling, also directly degrades Te Lancet, bone. This bone destruction in turn releases from the bone matrix growth factors capable of stimulating tumor 5. PEDERSON L, WINDING B, FOGED NT, SPELSBERG TC, OURSLER MJ. cells to destroy more bone, creating sustained “vicious” cycles of tumor-mediated bone resorption. Identifcation of breast cancer cell line-derived paracrine factors that stimulate osteoclast activity. 1999; 59:5849–55. biological factors relevant to metastatic progres- Cancer Res, sion in bone, can be of great value. 6. BARNES PJ, KARIN M. Nuclear factor-κ B: a pivotal The bone-seeking MDA-MB-231 transcription factor in chronic infammatory diseases. N Engl J Med, 1997; 336:1066–71. Targeting the NF-κB breast cancer cell line was genetically altered to suppress NF-κB-mediated 7. YAMAMOTO Y, GAYNOR RB. Therapeutic potential of pathway holds signifcant gene expression. In its inactive inhibition of the NF-κ B pathway in the treatment of infammation and cancer. J Clin Invest, 2001; state, NF-κB is bound to an IκB promise in treating var- 107:135–42. protein within the cytoplasm of 8. IOTSOVA V, CAAMANO J, LOY J, YANG Y, LEWIN A, BRAVO R. cells. Phosphorylation of IκB frees ious cancers and diseases Osteopetrosis in mice lacking NF-κ B1 and NF-κ NF-κB to move to the nucleus of cells B2. Nat Med, 1997; 3:1285–9. associated with abnormal to perform NF-κB-mediated gene 9. STORM HH. Survival of adult patients with cancer of transcription.6 A single-point mutation bone resorption.7,8 soft tissues or bone in Europe. Eur J Cancer, 1998; of IκB (replacing one serine amino 34:2212–7. acid for an alanine) was stably infected 10. GORDON AH, O’KEEFE RJ, SCHWARZ EM, ROSIER RN, PUZAS JE. in these breast cancer cells to prevent this Nuclear Factor-κ B–Dependent Mechanisms in 10 phosphorylation and associated gene expression. Breast Cancer Cells Regulate Tumor Burden and Blocking NF-κB signaling in MDA-MB-231 Osteolysis in Bone. Cancer Res, 2005; 65:3209–3217. cells decreased in vitro cell growth, expression

10 Fusion • 2008 Certain Piperazines Mimic Stimulant or Hallucinogenic Effects of Ecstasy Users of 3,4-methylenedioxymethamphetamine hallucinogen-like effects of BZP, MeO-BZP, (MDMA, “ecstasy”) report the drug elicits TFMPP, and m-CPP.6,7 All N-substituted a complex array of subjective effects, some piperazines were tested for locomotor stimulant stimulant-like and others hallucinogen-like.1 effects in a modifed open feld apparatus, and Usage of MDMA has increased worldwide, mice trained to discriminate S(+)-MDMA 2 particularly among young adults. While or R(-)-MDMA from saline were tested for Elyse Katz, MSI regulatory control of MDMA exists in the stimulus generalization to all of the N-substituted Advisor: Bill Fantegrossi, PhD United States, federal law enforcement agents piperazines. Division of Neuroscience, continue to encounter and confscate MDMA The results of the current study indicated Yerkes National Primate across the country.3 In addition to widespread use that BZP, TFMPP, and m-CPP dose dependently Research Center, Emory of MDMA itself, certain “ecstasy” tablets also could fully substitute for S(+)-MDMA, but could University, Atlanta, GA contain N-substituted piperazines which mimic not elicit R(-)-MDMA-like stimulus effects. In the effects of MDMA.4 contrast, m-MeO-BZP dose dependently could This study investigated how certain partially substitute for both enantiomers. BZP N-substituted piperazines, in comparison with profoundly stimulated locomotor activity, but did MDMA enantiomers, may affect classical not elicit a signifcant head twitch response, while stimulant and hallucinogenic FIGURE 1: SUMMARY OF EXPERIMENTAL RESULTS. behaviors in mice trained to Drug Head Twitch Locomotor S(+)-MDMA R(-)-MDMA discriminate either Discrimination Discrimination S(+)-MDMA or

R(-)-MDMA from BZP No Increase Full None saline. Previous MeO-BZP No Decrease Partial Partial studies suggest that the effects of TFMPP Yes Decrease Full None S(+)-MDMA are -CPP No Decrease Full None more stimulant- like than those of R(-)-MDMA, while the actions of R(-)-MDMA TFMPP elicited a dose dependent head twitch are more hallucinogen-like than those of the response but only suppressed locomotor behavior. S(+)- enantiomer.5 Neither m-MeO-BZP nor m-CPP elicited head In a murine model, various N-substituted twitch behavior, as both compounds decreased piperazines were administered and evaluated locomotor activity dose dependently. for head twitch response (a hallucinogen-like Of all the N-substituted piperazines studied, drug effect), increased locomotor activity only BZP exhibited a clear stimulant-like (a stimulant-like drug effect) and MDMA- pattern of behavioral effects, while only TFMPP like discriminative stimulus effects in mice exhibited hallucinogen-like effects in the head (analogous to subjective drug effects in humans). twitch assay. Based on the present fndings, Various doses of l-benzylpiperazine (BZP), m-MeO-BZP and m-CPP cannot be described 1-(3-trifuoromethylphenyl) piperazine (TFMPP), as stimulant-like or hallucinogen-like in the 1-(3-methoxybenzyl) piperazine (m-MeO-BZP) mouse. Still, various N-substituted piperazines or meta-chlorophenyl piperazine (m-CPP) were demonstrate differing ecstasy-like drug effects administered to mice to determine the effects on in a murine model, and warrant further these behavioral endpoints. investigation and monitoring with regard to their The head twitch response is sensitive addiction and abuse potential. to serotonin 5-HT2 agonist activity in the rodent and was therefore used to evaluate the ECSTASY Continued on p. 12

Fusion • 2008 11 ECSTASY Continued from p. 11 4. YAROSH, H., KATZ, E., COOP, A., FANTEGROSSI, W. MDMA-like behavioral effects of N-substituted piperazines in the mouse. Pharmacol Biochem Behav, 2007; 88:18–27. REFERENCES: 5. STEELE TD, NICHOLS DE, YIM GKW. Stereochemical effects of 1. FANTEGROSSI WE, GODLEWSKI T, KARABENICK RL, STEPHENS 3,4- methylenedioxymethamphetamine (MDMA) JM, ULLRICH T, RICE KC, ET AL. Pharmacological and related amphetamine derivatives on inhibition of characterization of the effects of uptake of [3H]monoamines into synaptosomes from 3,4-methylenedioxymethamphetamine (“ecstasy”) different regions of rat brain. Biochem Pharmacol, and its enantiomers on lethality, core temperature, 1987; 36:2297–303. and locomotor activity in singly housed and crowded 6 ORTMANN R, BISCOFF S, RADEKE E, BUECHE O, DELINI-STULA mice. Psychopharmacology, 2003; 166(3):202–11. A. Correlation between different measures 2. FANTEGROSSI WE, KIESSEL CL, DE LA GARZA II R, WOODS JH. of antiserotonin activity of drugs. Naunyn Serotonin synthesis inhibition reveals distinct Schmiedeberg’s, Arch Pharmacol, 1982; 321:265–270. mechanisms of action for MDMA and its 7. PEROUTKA SJ, LEBOVITZ RM, SNYDER SH. Two distinct central enantiomers in the mouse. Psychopharmacology, serotonin receptors with different physiological 2005b; 181:529–36. functions. Science, 1981; 212:827–829. 3. LANDRY MJ. MDMA: a review of epidemiologic data. Journal of Psychoactive Drugs, 2002; 34:163–169. Anatomical Bases for Auditory Projections to Suprasylvian Visual Areas in the Cat Cerebral Cortex A fundamental organizational feature of the they vigorously process sensory information. In mammalian brain is the arrangement of sensory fact, the sensory cortical organization of higher representations in the cerebral cortex. The mammals is one in which primary processing cortical representation of vision is localized areas are typically surrounded by secondary or in the occipital lobe, auditory in the temporal higher-level processing areas. lobe and somatosensory in the parietal lobe. In the cat brain, the lateral suprasylvian Studies of a wide variety of mammals indicate sulcus (LSS) contains representations of the a primary thalamic-recipient area for each visual modality thought to be exclusively sensory modality, designated as the primary populated by visual-specifc neurons.1,2 The Giriraj K. Sharma, MSI sensory cortex. Most textbook depictions of the visual LSS is laterally bordered by the dorsal zone Collaborators: sensory representations show a large gap between of auditory cortex; recent electrophysiological H. Ruth Clemo, PhD; locations of the primary sensory representations. experiments document the presence of auditory/ Brian Allman, PhD; However, these areas are not inactive, but rather visual bimodal cells in what otherwise and, M. Alex Meredith, PhD appears to be the visual Department of Physiology and LSS.3,4 While the sensory Department of Anatomy and function of the LSS Neurobiology, cells has been Virginia Commonwealth expanded with University, Richmond, VA this fnding, the transition/ multisensory zones between auditory and visual regions have not been defned. It FIGURE 1. ORTHOGRADE PROJECTIONS FROM AI TO LSS. Injections of tracer is not known whether result in labeled axons and terminals in the lateral bank of the LSS. Coronal sections are arranged from the left, anterior to posterior. Grey regions indicate location and extent of injection; each black dot represents AUDITORY a single bouton or axon terminal. Inset on left indicates the cortical level from which each coronal section PROJECTIONS originates. Scale bar = 1mm. Continued on p. 13

12 Fusion • 2008 AUDITORY PROJECTIONS transition from auditory to visual sensory Continued from p. 12 modality. Although the LSS has widely been regarded there is a distinct border marking the edge as a visual area of the cat cortex, these results between the two different representations, or if show that multiple auditory cortical projections there is a gradual transition yielding a substantial target the region in a gradated manner. Auditory area in which representations of both modalities projections are quite dense at the external lip of overlap. In the latter case, inputs from different the sulcus and are gradually reduced within the modalities that overlap within a given area depth of the bank of the LSS. Ultimately, the can converge onto individual neurons, thereby broad distribution of auditory input suggests that inducing multisensory properties.5 substantial portions of the visual LSS region may This problem was addressed in our study by be a site of multisensory (visual and auditory) labeling auditory projections to the LSS of the convergence. These overlapped projections may cat using neuroanatomical tract tracing methods. provide the anatomical basis for multisensory Adult cats (n=17) were anesthetized and, properties of neurons in higher mammals. using sterile surgical techniques, biotinylated REFERENCES: dextran amine (BDA) was injected into one of 1. MARSHALL WH, TALBOT SA, ADES HW. Cortical responses of the following auditory cortical areas: anterior the anesthetized cat to gross photic and electrical auditory feld (AAF), primary auditory cortex afferent stimulation. J Neurophysiol, 1943; 6:1–15. (AI) or posterior auditory feld (PAF). Standard 2. PALMER LA, ROSENQUIST AC, TUSA, RJ. The retinotopic cytochemical procedures were used to visualize organization of lateral suprasylvian visual areas in the transported tracer and a computer-based the cat. J. Comp. Neurol, 1978; 177:237–56. digitizing microscope was used to plot the 3. YAKA R, NOTKIN N, YINON U, WOLLBERG Z. Visual, Auditory location of labeled axon terminals. In each and Bimodal Activity in the Banks of the Lateral case, labeled boutons were identifed in the LSS Suprasylvian Sulcus in the Cat. Neurosci and region. Labeled terminal boutons were most Behavioral Phys, 2002; 32:103–08. concentrated at the outer lip of the LSS and the 4. ALLMAN B, MEREDITH MA. Multisensory Processing in label became progressively reduced with depth ‘Unimodal’Neurons: Cross modal Subthreshold along the lateral bank of LSS toward the fundus, Auditory Effects in Cat Extrastriate Visual Cortex. as shown in Figure 1, for AI auditory projections J Neuorphysiol, 2007; 98:545–49. to the LSS (each black dot=1 labeled bouton). 5. MEREDITH MA. Cortico-cortical Connectivity and the This steady decrease in auditory projections Architecture of Cross-modal Circuits. In: Spence C, down the bank of the LSS, as opposed to Calvert G, Stein B (eds.) Handbook of Multisensory an abrupt demarcation, indicates a gradual Processes, 2004; MIT Press:343–55.

Fusion • 2008 13 A Role for Chemokine Gene Variants in Muscle Strength? The overarching goal of the Bone Health volume phenotypes. Although the study cohort Program at Children’s National Medical had not participated in resistance training for Center, in Washington, DC, is to contribute one year, we found that individuals with the answers to the questions, “What makes bone rare alleles consistently had the greatest baseline strong?” and “can we make bones stronger?” muscle strength and lowest subcutaneous fat More specifcally, the program seeks to identify volume. Strikingly, while the presence of the genetic variations that will help individuals rare allele predicted baseline values of muscle better understand their risks for bone health and strength and fat volume, it did not predict disease, while simultaneously providing them signifcantly higher values of muscle hypertrophy Kasra Adham, MSII, with recommendations for healthy behaviors that or gained strength after resistance training. This Research Track can reduce their risks of serious disease. To help achieve this goal, … [I]ndividuals with the rare alleles the Bone Health team partnered with Dr. Eric Hoffman, director consistently had the greatest baseline muscle of the Research Center for Genetic Medicine, to develop a program strength and lowest subcutaneous fat volume. that explores answers to these questions in the clinic, operating room and suggests that the ability of muscle to hypertrophy laboratory. and gain strength are controlled by genes other Our Gill Fellowship summer projects were than CCL2 and CCR2.1,2 devoted to the study of chemokines. Chemokines In addition to providing a research Justin Larkin, MSII are a large group of proteins that act as lures experience, our fellowships also presented the to attract white blood cells and are involved opportunity to observe patient care in the in various disease processes, including acute orthopaedic outpatient clinic and operating and chronic infammation, infectious diseases room. More over, we traveled to the International and cancer. Although primarily associated Conference on Children’s Bone Health in with disease, the infammatory response is also Montreal, Canada, to gain greater exposure to associated with muscle repair, regeneration and international research efforts in bone health. growth.1 Muscle strength, as well as exercise, REFERENCES: contributes to bone strength. The CC family of 1. TIDBALL J. chemokines is the largest of its kind, and one of Infammatory processes in muscle injury and repair. American Journal of Physiology — the most thoroughly characterized chemokines Regulatory Integrative and Comparative Physiology, 1 is CCL2. CCL2 and one of its major receptors, 2005; 288:R345–53. Ronak Patel, MSII CCR2, are encoded by genes CCL2 and CCR2, 2. YU X, DLUZ S, GRAVES D, ZHANG L, ANTONIADES H, HOLLANDER respectively. Given the widespread effects of W, PRUSTY S, VALENTE A, SCHWARTZ C, SONENSHEIN G. Mentors: Joseph Devaney, CCL2 and CCR2, our goal was to investigate Elevated expression of monocyte chemoattractant PhD; Cinzia Brandoli, PhD; whether variants of the genes CCL2 and CCR2 protein 1 by vascular smooth muscle cells in and Laura Tosi, MD infuence skeletal muscle, bone and subcutaneous hypercholesterolemic primates. Proceedings of the Children’s National Medical fat volume at baseline and after resistance National Academy of Sciences of the United States of Center, Washington, DC training in healthy young adults. America, 1992; 89:6953–57. Blood DNA samples and MRI images were obtained from the Functional Polymorphisms Associated with Muscle Size and Strength study of more than 1,200 college students enrolled in a 12-week resistance training program. Investigating the infuence of genetic polymorphisms on bone geometry, fat volume, and skeletal muscle size and strength, variants in CCL2 and CCR2 were found to correlate with specifc skeletal muscle and subcutaneous fat

14 Fusion • 2008 Cloning and Expression of Human Adenovirus Precursor Protein VI and Mature Protein VI There are 47 serotypes of the human adenovirus This experiment established a novel, stepwise that are responsible for a group of respiratory protocol for cloning pVI and VI genes and diseases, including, but not limited to, 30 expressing the proteins in bacterial hosts. The percent of all colds, pneumonia and bronchitis, genes for pVI and VI were successfully amplifed in addition to gastroenteritis, viral pink eye and from genomic adenovirus DNA, digested with 1 cystitis. Epidemiological studies indicate an restriction enzymes, ligated into prepared pET Michelle Louie, MSI adenoviral agent as the cause of 5–10 percent of expression plasmids and transformed into Research Track juvenile pneumonias and respiratory infections bacterial hosts. PCR of the purifed plasmids Advisor: Walter F. Mangel, PhD of children in North America.2 Respiratory verifed successful cloning of the correct gene Brookhaven National infection with adenoviruses is also regularly sequences. Proteins pVI and VI were then Laboratory, NY responsible for a number of infant deaths and expressed in BL21-codon plus(DE3)-RIPL cells considerable morbidity among some adult grown in ZYM-5052 auto-inducing medium. A populations. Serological prevalence studies 15 percent SDS-PAGE and an assay using AVP suggest that the average individual undergoes and Rhodamine fuorogenic substrate confrmed a minimum of two or three clinical episodes successful protein pVI and VI expression. of adenoviral infection during childhood.2 In A supply of purifed recombinant proteins addition, human adenovirus is one of the leading pVI and VI was produced, purifed and stored opportunistic infections that are a major cause for future research. The end of death in patients with Acquired Immune products of this investigation The end products of this Defciency Syndrome (AIDS) and defcient will be signifcant in immune systems.3 developing drug targets for investigation will be signifcant The human adenovirus proteinase (AVP) anti-viral agents and providing is required for the development of infectivity.4 information for the study of in developing drug targets for other viruses with congruent AVP is synthesized by the adenovirus and anti-viral agents … . packaged into nascent virus particles. When activation mechanisms. activated, AVP cleaves virion precursor REFERENCES: proteins, thereby rendering the virus particle 1. BANIECKI M, MCGRATH W, MCWHIRTER M, ET AL. Interaction infectious. AVP requires two viral cofactors for of the human adenovirus proteinase with its maximal activity — adenovirus DNA and an 11-amino acid cofactor pVIc. Biochemistry, 2001; 11-amino-acid peptide, known as pVIc, derived 40:12349–56. from the C-terminus of precursor protein VI 2. SCOTT-TAYLOR T, HAMMOND G. Conserved sequences of (pVI). Protein VI also functions as a precursor the adenovirus genome for detection of all human “scaffolding” protein that plays a critical role adenovirus types by hybridization. J. Clin. Microbiol, in the assembly and maturation of the virus 1992; 30:1703–10. particle.5 3. MANGEL W, MCGRATH W, TOLEDO D, ET AL. Viral DNA and The synthesis and investigation of the a viral peptide can act as cofactors of adenovirus virion proteinase activity. , 1993; 361:274–75. precursor and mature form of protein VI is Nature essential because of its critical role in producing 4. MCGRATH W, ABOLA A, TOLEDO D, ET AL. Characterization of human adenovirus proteinase activity in disrupted the pVIc cofactor required for proteinase virus particles. Virology, 1996; 217:131–38 activation and subsequent viral infection. To characterize the interactions of AVP and DNA 5. MATTHEWS D, RUSSELL W. Adenovirus protein-protein interactions: molecular parameters governing the that render the virus particle infectious, the binding of protein VI to hexon and the activation genes for pVI and VI must be cloned, expressed of the adenovirus 23 K protease. J. Gen Virol, 1995; in bacterial hosts and the resultant recombinant 76:1959–69. proteins purifed. There is no evidence that pVI or VI has been successfully cloned or expressed prior to this experiment.

Fusion • 2008 15 The Role of Retinoic Acid in Neuronal Phenotype Determination An important element of the developing central It is believed that retinoic acid plays a fun- nervous system is the acquisition of specifc neu- damental role in the acquisition and patterning ronal phenotypes. Retinoic acid plays a funda- of GABAergic and glutamatergic phenotypes. mental role in CNS development and is essential Retinoic acid comes from the family of retin- for normal growth of the embryo. The effect oids and has been correlated with causing birth of retinoic acid on neurotransmitter phenotype defects in newborns, both when defcient and determination can be analyzed by examining the when present in excess. These include abnor- expression patterns of specifc molecular markers. malities in facial bone structure, in the ears and The expression of a gamma-aminobutyric eyes, and in brain mass. Retinoic acid acts as a acid (GABA)ergic or glutamatergic neuron can signaling molecule regulating critical processes Negin Daneshpayeh, MSI be examined in a model vertebrate organism during early development, including axial pat- Advisor: Margaret Saha, PhD such as Xenopus laevis, the African clawed terning, cellular differentiation, tissue induction, Department of Biology 5 The College frog. GABAergic neurons release GABA, the proliferation and apoptosis. The natural concen- of William and Mary most abundant inhibitory neurotransmitter in tration of retinoic acid in the body is crucially Williamsburg, VA the CNS, and glutamatergic neurons release important and is constantly regulated. glutamate, the most abundant excitatory In Xenopus development, retinoic acid neurotransmitter in the CNS. In order to becomes important at the beginning of gastrula- visualize the expression patterns, whole- tion (stage 10 of development two). This stage mount in situ hybridization was performed to marks the point at which segregation of body examine the spatial layers begins to take place. It is known that It is believed that retinoic acid plays expression of specifc excess concentrations of retinoic acid in the molecular markers environment affect the formation of the neural a fundamental role in the acquisition during various tube. More specifcally, the effect appears to be a stages of embryo truncated anterior of the CNS. and patterning of GABAergic and development.1,2 The It is hypothesized that the expression patterns xGAT1 and xVGlut1 of the neurotransmitter markers will be altered glutamatergic phenotypes. Retinoic RNA probes allowed by the presence of excess retinoic acid. To test visualization of the this hypothesis, Xenopus embryos were exposed acid comes from the family of retin- expression patterns to various solutions of retinoic acid at different oids and has been correlated with of GABAergic developmental stages.2 In situ hybridizations and glutamatergic were conducted, with xGAT1 and xVGlut1 RNA causing birth defects in newborns, neurons, respectively. probes. Whole mount examination revealed Normal expression obvious malformation in the embryo. The effect both when defcient and when present of xGAT1 is frst on expression patterns of the molecular markers observed at late needs to be further analyzed via histological in excess. neurula stages in the sections. More specifc fndings regarding the anterior portion of role of retinoic acid and its affects on expression the developing spinal cord.3 By tailbud stages, patterns of GABAergic or glutamatergic neurons bilateral xGAT1 expression is apparent in all will help in understanding the acquisition of a regions of the CNS, including distinct regions of specifc neuronal fate. Furthermore, it will help the forebrain, midbrain, hindbrain and olfactory in understanding the development of congenital placodes.3 birth defects in humans. Normal expression of xVGlut1 is frst REFERENCES: detected at late neurula to early tailbud 1. SIVE, HL, GRAINGER, RM, HARLAND, RM. stage embryos with prominent expression in Early Development of Xenopus Laevis: A laboratory Manual. 2000. Cold the developing trigeminal nerve and in the Spring Harbor, New York: Cold Spring Harbor 4 developing spinal cord. By later tailbud stages, Laboratory Press. xVGlut1 mRNA is observed in the pineal gland, the olfactory placodes and more posteriorly in the trigeminal and facial cranial nerves.4 RETINOIC ACID Continued on p. 17

16 Fusion • 2008 RETINOIC ACID Continued from p. 16 4. GLEASON KK, DONDETI VR, HSIA HL, COCHRAN ER, GUMULAK-SMITH J, SAHA MS. The vesicular glutamate transporter 1 2. NIEUWKOOP PD, FABER J. A systematical and chronological (xVGlut1) is expressed in discrete regions of the survey of the development from the fertilized egg till developing Xenopus laevis nervous system. Gene the end of metamorphosis. Normal Table of Xenopus Expr Patterns, 2003; 3:503–07. Laevis (Daudin), 1967. Amsterdam, North-Holland. 5. DEGITZ SJ, HOLCOMBE GW, KOSIAN PA, TIETGE JE, DURHAN EJ, ANKLEY 3. LI M, SIPE CW, HOKE K, AUGUST LL, WRIGHT MA, SAHA MS. The role GT. Comparing the effects of stage and duration of of early lineage in GABAergic and glutamatergic retinoic acid exposure on amphibian limb develop- cell fate determination in xenopus laevis. Journal of ment: chronic exposure results in mortality, not Comparative Neurology, 2006; 495:645–57. limb malformations. Toxicological Sciences, 2003; 74:139–46. A Potential Role for DHEA in Prostate Cancer Dehydroepiandrosterone (DHEA) is the most of these cells to steroid hormones.4 My research abundant endogenous steroid produced by the aimed to determine what specifc factors these adrenals of men and women, although levels stromal cells produced in response to DHEA and decline markedly with age. DHEA is increas- provide insight into how the stromal environ- ingly consumed as a commercial nutritional ment modulates conversion of healthy epithelial supplement for its purported anti-aging effects, cells into malignant prostate cancer. yet its usefulness, long-term safety and effects Prostate epithelial cancer cells were co- 1 remain uncertain. cultured with stromal cells and separated by a Patricia Reutemann, MSII DHEA can be metabolized by the prostate substance called Matrigel, which functioned like Integrative Medicine Track gland and can increase expression of secondary a permeable basement membrane, allowing the Advisor: Julia Arnold, PhD mediators for epithelial growth and differen- passage of soluble stromal mediators to the epi- The National Center for tiation. Furthermore, because it is a precursor thelial cells. After the cells were grown, treated Complementary and Alternative to both estrogens and testosterone, contro- with DHEA and harvested, the co-cultured Medicine Endocrine Section versy exists as to whether DHEA enhances stromal RNA was extracted. Subsequently, National Institutes of Health, or reduces the risk of prostate cancer.2 Since cDNA was synthesized and real-time reverse Bethesda, MD supplements are not regulated by the Food and transcriptase PCR was performed to measure Drug Administration, The National Center expression of 84 genes related to human growth for Complementary and Alternative Medicine factors. (NCCAM) at the National Institutes of Health Results from three separate experiments were (NIH) plays a vital role in researching the effects comparable and showed the up-regulation of of supplements such as DHEA. several specifc genes, including FGF-1 (fbroblast Prostate cancer is the second most common growth factor), IGF-1 (insulin-like growth factor), type of cancer among men in the United States, FGF-7 (fbroblast growth factor) and HPRT-1 and approximately one out of three men will (hypoxanthine phosphoribosyltransferase). While become afficted.3 The prostate epithelium these results are preliminary, they may provide contains glandular cells that synthesize and some insight into what growth factors the stromal secrete products of seminal plasma, including cells produce in response to DHEA and can be prostate-specifc antigen (PSA), the major further explored as targets for stromal regulation diagnostic marker for prostate cancer. These of epithelial cell function. My research experience epithelial cells depend on androgenic stimula- only scratched the surface investigating the role tion for their viability and secretory ability and of DHEA in prostate cancer, but I gained useful become malignant during prostate cancer. They research experience and am optimistic about are surrounded by a fbromuscular stroma that NCCAM’s future efforts on this important topic. not only physically supports the glands, but REFERENCES: also contributes to the endocrine and paracrine 1. ARNOLD, J.T. ET AL. Androgen receptor or estrogen microenvironments of these cancer cells. Thus, receptor-beta blockade alters DHEA-, DHT-, and the stromal cells help control the growth and dif- E(2)-induced proliferation and PSA production in ferentiation of the epithelial cells, as well as play a critical role in mediating the responsiveness DHEA Continued on p. 18

Fusion • 2008 17 DHEA Continued from p. 17 3. THE NATIONAL CANCER INSTITUTE. What you need to know about Prostate Cancer, 2005. Retrieved human prostate cancer cells. Te Prostate, 2007; Oct. 20, 2007 from www.cancer.gov/cancertopics/ 67:1152–62. wyntk/prostate. 2. ARNOLD JT, LE H, ET AL. Comparative effects of DHEA 4. ARNOLD JT, ISAACS JT. Mechanisms involved in the pro- vs. testosterone, dihydrotestosterone, and estradiol gression of androgen-independent prostate cancers: it on proliferation and gene expression in human is not only the cancer cell’s fault. Endocrine-Related LNCaP prostate cancer cells. American Journal of Cancer, 2002; 9:61–73. Physiology, Endocrinology, and Metabolism, 2005; 288:E573–E584. Middle Ear Epithelial Cell Secretion of Cytokines with Cigarette Smoke Condensate Exposure Otitis media (OM), an infammation of the organisms and/or their products, leading to middle ear, is a ubiquitous condition of early an increase in restrictive oxygen species (ROS) childhood accounting for 16 million physician and causing activation of the NF-κB complex. offce visits each year. OM is associated with NF-κB translocates to the nucleus and tran- hearing loss, delayed speech development and scribes genes encoding for ICAM-1, TNF-α, the potential for permanent middle ear damage. IL-1β and several secondary pro-infammatory Environmental agents such as tobacco smoke cytokines. have been shown to be a risk factor in the occurrence of OM in early childhood.1 OM can Samaneh Ashktorab, MSII Supervisors: Diego Preciado, be classifed by its associated MD, PhD; and Mary Rose, PhD clinical symptoms, otoscopic Children’s National Medical fndings, complications and Center, Washington, DC, duration. There are two clas- and The George sifcations of OM, acute and Washington University chronic, which differ in dura- tion and result from different etiologies. Acute OM often results from upper respiratory infections; whereas chronic OM is usually non-infectious and thought to be due to chronic infammation and mucous hyper-secretion. Environmental agents Cigarette smoke induces pro-infammatory such as cigarette smoke are highly correlated cytokines in the lower respiratory system, and with the occurrence of chronic OM. Studies exposure of cigarette smoke to the rat lung conducted by different federal agencies suggest induces redox-sensitive transcription factors exposure to tobacco smoke may be a signifcant NF-κB and AP-1, which are linked to the risk factor in the development of chronic OM in transcription of specifc infammatory cytokines early childhood. The direct mechanism by which and chemokines.3 Cigarette smoke also induces cigarette smoke exposure results in OM remains the synthesis of glutathione and gamma- under investigation. glutamylcysteine that is associated with AP-1 or The etiology of OM infammation within an AP-1 like response element.3 In addition to the middle ear mucosa is primarily initiated, increasing transcription of infammatory genes, mediated and regulated by pro-infammatory cigarette smoke also decreases HDAC2 activity cytokines: TNF-α, IL-1β, IL-6 and IL-8.2 The in the rat lung, in turn decreasing histone infammatory cascade is initiated by micro- SMOKE EXPOSURE Continued on p. 19

18 Fusion • 2008 SMOKE EXPOSURE Continued from p. 18 of interest using Enzyme Linked Immunosorbent Assay (ELISA) kits to confrm our fndings. deacetylation, and thus increasing transcription In conclusion, CSC activated pro-infam- of pro-infammatory genes. matory cytokine secretion in mMEEC in vitro. We hypothesized that cigarette smoke These fndings will bring us closer to under- condensate (CSC) stimulation would activate standing the biological mechanism responsible for NF-κB and ultimately increase pro-infammatory the high correlation of OM with young children cytokine secretion in mouse middle ear epithe- exposed to second-hand smoke. lium cells (mMEEC). To investigate our hypothesis, we used a REFERENCES: mouse infammatory antibody array to measure 1. TUTKA P, WIELOSZ M, ZATONSKI W. Exposure to 40 different pro-infammatory cytokines from environmental tobacco smoke and children’s health. CSC stimulated mMEEC. The mMEEC was International Journal of Occupational Medicine and Environmental Health, 2002; 15:325–35. stimulated with 0 micrograms per microliter, 20 2. BARRETT TQ, KRISTIANSEN LH, OVESEN T. NF-κB in cultivated micrograms per microliter and 40 micrograms middle ear epithelium. International Journal of CSC for two, eight and 24 hours, per microliter Pediatric Otorhinolaryngology, 2002; 7:895–903. respectively. The infammatory antibody array 3. HELLERMANN GR, NAGY SB, KONG X, LOCKEY RF, MOHAPATRA SS. was analyzed with chemiluminescence imaging. Mechanism of cigarette smoke condensate-induced We observed a signifcant increase in pro-infam- acute infammatory response in human bronchial matory cytokines IL-6, TNF-α, IFN-γ, IL-4 and epithelial cells. Respiratory Research, 2002. Retrieved IL-13. We plan to further analyze these cytokines May 29, 2007 from: http://respiratory-research.com. Development of an In Vitro Model of Respiratory Tract Submucosal Glands A mucosal layer protects the respiratory tract cells.2,3 The models secrete both MUC5AC epithelium against pathogens and environmental and MUC5B mucins, which are in vivo toxins. Mucin glycoproteins (mucins) are markers for goblet cells and submucosal glands, overproduced in chronic diseases of the respectively.4 However, these cell models do respiratory tract, such as cystic fbrosis (CF) and not develop glands, although they are clearly chronic rhinosinusitis pluripotent and express Sumit Bose, MSII, (CRS), and contribute FIGURE 1: Microscopic view glandular proteins. We Research Track signifcantly to disease of gland-like structure formed hypothesized that HBE Advisors: Mary C. Rose, PhD; morbidity and mortality.1 by H-Tert immortalized tracheal cells would develop and Diego Preciado, MD, PhD bronchial epithelial cells when Mucous hypersecretion glands if grown in the Children’s National Medical grown mixed with Matrigel on predominantly appropriate context. Center, Washington, DC Day 9 after plating. results from goblet Submucosal glands cell hyperplasia and/ are invaginations of or submucosal gland (SMG) hyperplasia. In the epithelium and are composed of ductal and vivo and in vitro model systems are used to secretory cells (both mucous and serous) that investigate mechanisms of mucin hypersecretion secrete mucins and host defense proteins into in the conducting respiratory tract epithelium. the mucosal layer. Cells from various tissues However, there is no established in vitro have already been shown to develop intestinal, glandular model for the submucosa. mammary, salivary, pancreatic or oviduct glands Presently, the standard in vitro models consist when grown on Matrigel, a basement membrane 5,6 of differentiated primary human bronchial complex isolated from murine tumors. The epithelial (HBE) or nasal epithelial cells grown main component of Matrigel is laminin, as on transwell plates coated with collagen at an well as collagen type IV, heparan sulfate and air-liquid interface. Within two weeks, these cells differentiate into a conducting respiratory SUBMUCOSAL GLANDS MODEL tract epithelium with cilia, basal and goblet Continued on p. 20

Fusion • 2008 19 SUBMUCOSAL GLANDS MODEL REFERENCES: Continued from p. 19 1. ROSE MC, VOYNOW JA. Respiratory tract mucin genes and mucin glycoproteins in Health and disease. Physiol 2006; 86:245–78. proteoglycans. At 37° C, Matrigel forms a three- Rev, dimensional gel that supports cell morphogenesis 2. WU R, ZHAO YH, CHANG MMJ. Growth and differentiation and differentiation.7 Currently, there are no of conducting airway epithelial cells in culture. Eur 1997; 10:2398–403. reports of respiratory tract gland (submucosal Respir J, gland) development using Matrigel. 3. BERNACKI SH, NELSON AL, ABDULLAH L, SHEEHAN JK, HARRIS A, Two different approaches were used: DAVIS CW, RANDELL SH. Mucin gene expression during respiratory tract-derived cells were either differentiation of human airway epithelia in vitro. Am J Respir Cell Mol Biol, 1999; 20:595–604. grown on top of, or mixed with, Matrigel. Cell media was changed as required and cells 4. REID C, GOULD S, HARRIS A. Developmental expression of were periodically monitored by microscopy. mucin genes in the human respiratory tract. Am J Respir Cell Mol Biol, 1997; 17:592–98. Experiments were carried out using three different cell lines, including Calu-3 cells (cancer 5. KLEINMAN HK, MCGARVEY ML, HASSELL JR, STAR VL, CANNON FB, cell lines of SMG origin), H-Tert immortalized LAURIE GW, MARTIN GR. Basement membrane complexes with biological activity. Biochemistry, 1986; tracheal bronchial epithelial cells and normal 25:312–18. human bronchial epithelial (HBE) cells. Our preliminary results showed that 6. TERRANOVA VP, AUMAILLEY M, SULTAN LH, MARTIN GR, KLEINMAN HK. Regulation of cell attachment and cell number respiratory tract-derived cells formed glandular- by fbronectin and laminin. J Cell Physiol, 1986; like structures but did not differentiate further 127:473–79. after fve days. A literature review indicates that 7. KLEINMAN HK, MARTIN GR. Matrigel: basement membrane epithelial cells from various tissues require seven matrix with biological activity. Semin Cancer Biol, to 15 days of growth on Matrigel to differentiate 2005; 15:378–86. into glands, with subsequent apoptosis to form 8. DEBNATH J, MUTHUSWAMY SK, BRUGGE JS. Morphogenesis and a glandular lumen.7,8 Our data indicated that oncogenesis of MCF-10A mammary epithelial acini under these conditions, respiratory tract cells do grown in three-dimensional basement membrane not undergo apoptosis to form a lumen. Future cultures. Methods, 2003; 30:256–68. experiments will focus on inducing apoptosis in order to facilitate differentiation of SMG and thus establishment of an in vitro model to investigate SMG development and hyperplasia in respiratory diseases such as CRS and CF.

20 Fusion • 2008 A Three-Dimensional Model of Epicardial Development Development of the epicardium is critical to support the tube scaffold as a viable model for proper heart formation. The epicardium provides epicardial development. all of the precursor cells that form the coronary REFERENCES: system and supplies signals that stimulate cardiac 1. EVANS HJ, SWEET JK, PRICE RL, YOST M, GOODWIN RL. Novel myocyte proliferation. The epicardium forms 3-D culture system for study of cardiac myocyte from mesothelial cells (proepicardial [PE] cells) development. Am J Physiol Heart Circ Physiol, 2003; associated with the developing liver. Here, a 285:H570–H578. model of epicardial development is presented. PE 2. YOST MJ, BAICU CF, STONEROCK CE, GOODWIN RL, PRICE RL, DAVIS Tresa L. Nesbitt, PhD, MSI cells have been isolated from chicken embryos JM, EVANS H, WATSON PD, GORE CM, SWEET J, CREECH L, ZILE MR, Research Track and cultured on a 3-D scaffold. This 3-D model TERRACIO L. A novel tubular scaffold for cardiovascular Advisor: Richard L. Goodwin, PhD, system consists of a tubular scaffold engineered tissue engineering. Tissue Eng, 2004; 10:273–284. University of South Carolina, from type-I collagen and optimized to support 3. GOODWIN RL, NESBITT T, PRICE RL, WELLS JC, YOST MJ, POTTS JD. School of Medicine, Columbia, SC the growth of embryonic cardiac tissues.1,2,3 Three-dimensional model system of valvulogenesis. Using scanning electron microscopy (SEM), Dev Dyn, 2005; 233:122–29. we compared in vivo PEs with PEs cultured on 4. VAN DEN EIJNDE SM, WENINK AC, VERMEIJ-KEERS C. Origin of the tube scaffold for three days. In vivo PE cells subepicardial cells in rat embryos. Anat Rec, 1995; appeared as cobblestone cells covering the AV 242:96–102. sulcus of HH stage-17 chicken hearts as well as 5. NESBITT TL, PATEL PA, YOST MJ, GOODWIN RL, POTTS JD. A the outfow tract of the heart. Cells on the tube 3-D Model of Coronary Vessel Development. In also were observed to migrate as a sheet and vitro animal cellular: developmental biology, 2007; 43:10–16. possessed apical villi characteristic of in vivo PE cells.4 Similarly, PE cells cultured FIGURE 1: COMPARATIVE on the tube scaffold MORPHOGENESIS OF THE displayed a cobblestone PROEPICARDIAL CELLS. A, B, morphology and C, E, G: Representative proepicardium (PE) 5 possess apical villi. morphogenesis in the stage-17 chicken embryo. SEM data also revealed A: Stage-17 chicken embryo showing the PE cells could migrate branchial arches (BA), heart tube (HT) and the in a sheet-like fashion proepicardium (PE). B: Higher magnifcation and inhabit pit-like of (A) showing the PE extending from the areas of the tube liver toward the heart tube (HT). C: PE cells scaffold.5 Moreover, migrate as a sheet from the atrioventricular PE cells cultured on sulcus toward the outfow tract. The dashed the collagen scaffold line indicates the boundary of migrating cells. clearly maintained D, F, H: Representative images of PE cell their morphological morphogenesis on the tubular scaffold. characteristics and D: Chicken PE cells cultured on the collagen tube closely resembled their exhibit a cobblestone appearance. The dashed in vivo counterparts. line identifes the boundary of migrating PE cells Cultured PE cells also on the collagen tube. E: Higher magnifcation expressed markers for of (C) shows that the in vivo cells migrate as a sheet over the HH stage-18 chicken heart. both endothelial and F: PE cells exhibit a cobblestone morphology and smooth muscle cells, are found in pit-like areas of the tube scaffold. bearing a striking G, H: Arrows show the presence of apical villi resemblance to in vivo on the surface of PE cells in vivo and on the cells undergoing collagen scaffold in G and H, respectively (scale vasculogenic bars equal 100 m in A-C and 10 m in D-H). processes.5 Taken μ μ together, these data

Fusion • 2008 21 clinical practice. . . Improving MRI Detection of Creutzfeldt-Jakob Disease Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative prion disease charac- terized by the accu- mulation of abnormal prion protein leading to neuron loss, vacu- olation and/or astro- gliosis. CJD is charac- Andrew Degnan, MSI terized by rapid-onset Research Track dementia, rapid degen- FIGURE 1: DIFFUSION COEFFICIENT (ADC) MAPS OF PATIENTS WITH CJD. Principal Investigator, Mentor: eration and death. In Comparing ADC maps of patients with controls showed more signifcant reductions in ADC within the thalamus Isak Prohovnik, PhD; and striatum using b=2000, suggesting greater sensitivity with high b-value (right). Hedok Lee, PhD, this study, Libyan-born Mount Sinai School Israelis at increased of Medicine, NY risk for the inherited form of CJD were examined a voxel-based statistical software package. at Sheba Medical Center (Tel Hashomer, Israel). Comparisons were examined using Apparent The patients suffered from either familial or spo- Diffusion Coeffcient (ADC) maps, a quantitative radic CJD. Our group previously reported similar measure of proton diffusion capable of providing radiological fndings for familial cases when com- more robust statistical comparison. The compar- pared to the more common sporadic form.1 ison of control subjects to CJD patients showed This study analyzed two diffusion-weighted greater sensitivity to basal ganglia and thalamic (DWI-MRI) sequences to evaluate the sensitivity changes using high-value sequences, while the of higher b-value DWI (b=2000 s/mm2), as lower b-value detected more cortical changes. compared with the more common lower b-value These fndings suggest greater diffusion-weighted sequence (b=1000 s/mm2). DWI-MRI measures MRI sequences may be advantageous in detecting differences in proton movement indicative of CJD-related changes. tissue structure, and it has been demonstrated to REFERENCES: be an early marker of CJD-related pathology with 1. FULBRIGHT RK, KINGSLEY PB, GUO X, HOFFMANN C, KAHANA E, better sensitivity and specifcity than other CJD CHAPMAN JC, PROHOVNIK I. The imaging appearance of criteria such as the cerebrospinal fuid 14-3-3 Creutzfeldt-Jakob disease caused by the E200K muta- 2 protein detection and EEG patterns. DWI-MRI tion. Magnetic Resonance Imaging, 2006; 24:1121–29. patterns in CJD patients typically include hyper- 2. SHIGA Y, MIYAZAWA K, SATO S, FUKUSHIMA R, SHIBUYA S, SATO intensities within the caudate nucleus, putamen, Y, KONNO H, DOH-URA K, MUGIKURA S, TAMURA H, HIGANO S, thalamus and cortical ribbon; these fndings TAKAHASHI S, ITOYAMA Y. Diffusion-weighted MRI abnor- putatively correspond to vacuole formation, the malities as an early diagnostic marker for Creutzfeldt- 3 hallmark histological fnding of prion diseases. Jakob disease. Neurology, 2004; 63:443–49. B-value is a function of diffusion gradient 3. KALLENBERG K, SCHULZ-SCHAEFFER WJ, JASTROW U, POSER S, strength; a higher b-value is thought to be more MEISSNER B, TSCHAMPA HJ, ZERR I, KNAUTH M. Creutzfeldt- sensitive to diffusion and has been used with suc- Jakob disease: comparative analysis of MR imaging 4 cess in detecting other diseases. A high b-value sequences. Am J Neuroradiol, 2006; 27:1459–62. DWI may provide earlier detection of CJD 4. ASSAF Y, MAYZEL-OREG O, GIGI A, BEN-BASHAT D, MORDOHOVITCH M, pathogenesis and improve understanding of the VERCHOVSKY R, REIDER-GROSWASSER II, HENDLER T, GRAIF M, COHEN progression of imaging changes. Y, KORCZYN AD. High b value q-space-analyzed diffu- DWI scans of 10 patients and age- and sion MRI in vascular dementia: a preliminary study. gender-matched controls were analyzed using J Neurol Sci, 2002; 203-204:235–39.

22 Fusion • 2008 Small Molecules that Induce p53 Signaling in Retinoblastoma Preclinical Animal Models Retinoblastoma is an intraocular malignancy Institute library that were previously shown that occurs in children when a germline to induce p53 in other types of cancer cells, mutation of RB1 is inherited and a somatic we screened and selected small molecules that mutation inactivates the second RB1 allele.1 demonstrated cytotoxic effects in retinoblastoma Common modes of treatment to preserve vision cells. include triple-drug chemotherapy, radiation, One such p53 activator investigated was Audra K. Miller, MSII laser and cryotherapy. When chemotherapy a small molecule that “Reactivates p53 and Advisor: Joan M. O’Brien, MD is combined with focal treatments, up to Induces Tumor cell Apoptosis” (RITA). In UCSF Comprehensive Cancer 40 percent of patients do not respond and previous studies, RITA was shown to suppress Center, San Francisco, CA enucleation of the eye may be required to prevent the growth of osteosarcoma and fbro-sarcoma metastatic retinoblastoma which is often fatal.2 cells.6 By analyzing the effects of RITA in RB1 Current drugs have undesirable side effects, tumor growth assays, RITA demonstrated potent including an increased risk of developing acute cytotoxic effects. We calculated the 50 percent growth inhibitory concentration MS-275 IN OCULAR XENOGRAFT MODEL (GI50) from in vitro

experiments, and VEHICLE correlated growth inhibition with Western Blot analyses. This data demonstrates MS-275 suppression of cell proliferation while up-regulating p53 gene FIGURE 1: Y79-LUC CELLS WERE TRANSPLANTED INTO THE expression. VITREOUS OF DAY-OLD RATS. On day-14 post-transplant the animals were treated To recapitulate by intraperitoneal injection of 20 mg/kg MS-275 or vehicle for 12 days (six treatments total) and the tumorgenicity injected with 150 mg/mL D-Luciferin for imaging with the IVIS Lumina imaging system. properties of RB1 in animals, we used an ocular xenograft myeloblastic leukemia or hearing loss from rat model. Human retinoblastoma cells were ototoxicity.2,3 Since retinoblastoma is a rare transplanted directly into the eyes of newborn disease (300 new cases in the United States each rat pups to establish tumor growth. Using a year), preclinical animal models that recapitulate microscope and the tip of an insulin syringe, the tumorgenicity are important for developing the eyelids of anesthetized rat pups were new chemotherapy treatments.4 surgically opened and the posterior chamber The tumor suppressor RB1 gene is was infused with cultured cells. Tumor growth responsible for regulating cell proliferation, while was established over 14 days and the rats were the p53 gene regulates cell response to stresses treated with drug and a control vehicle. MS-275 such as DNA damage by inducing apoptosis.5 is a histone deacetylase inhibitor and known In retinoblastoma, because the p53 gene is anti-tumor compound previously proven to intact yet suppressed, it is a prime target for suppress retinoblastoma cell growth in vitro. The up-regulation to promote apoptosis and stop rats were treated with either MS-275 or vehicle clonal expansion in tumors. The purpose of every other day for 12 days and were imaged this research is to develop more effective, less using a Luciferin assay every other day. Our toxic novel chemotherapeutic treatments using results indicate statistically signifcant inhibition small molecules that up-regulate p53 to induce of tumor growth with MS-275 treatment when apoptosis in p53-suppressed retinoblastoma cells. By identifying compounds in a National Cancer P53 SIGNALING Continued on p. 24

Fusion • 2008 23 P53 SIGNALING Continued from p. 23 children receiving carboplatin for retinoblastoma. European Journal of Cancer, 2006; 42:492–500. compared to control animals (Figure 1). At the 3. LAURIE NA, GRAY JK, ZHANG J, LEGGAS M, RELLING M, EGORIN end of the treatment period, MS-275 treated M, STEWART C, DYER MA. Topotecan Combination animals had 62 percent tumor growth inhibition Chemotherapy in Two New Rodent Models of when compared to vehicle-only control animals Retinoblastoma. Clin Cancer Res, 2005; 11:7569–78 (p = 0.038). 4. DYER MA, RODRIGUEZ-GALINDO C, WILSON MW. Use of Through the analysis of 140,000 compounds preclinical models to improve treatment of in the NCI library for small molecules that are retinoblastoma. PLoS Med, 2005; 2:e332. good candidates for in vitro and ocular xenograft 5. LAURIE NA, DONOVAN SL, SHIH CS, ZHANG J, MILLS N, FULLER C, model experimentation, we plan to identify novel TEUNISSE A, LAM S, RAMOS Y, MOHAN A, JOHNSON D, WILSON M, antitumor chemotherapies for the treatment of RODRIGUEZ-GALINDO C, QUARTO M, FRANCOZ S, MENDRYSA SM, retinoblastoma. GUY RK, MARINE JC, JOCHEMSEN AG, DYER MA. Inactivation of the p53 pathway in retinoblastoma. Nature, 2006; REFERENCES: 444:61–66. 1. TSAI T, GOMBOS D, FULTON L, CONWAY R, O’BRIEN J, CRONIN J, 6. ISSAEVA N, BOZKO P, ENGE M, PROTOPOPOVA M, VERHOEF L, MASUCCI MUTHIALU A. Retinoblastoma and hypochondroplasia: MARIA, PRAMANIK A, SELIVANOVA G. Small molecule RITA a case report of two germline mutations arising binds to p53, blocks p53 — HDM-2 interaction simultaneously. , 2005; 26;2. Ophthalmic Genetics and activates p53 function in tumors. Nature, 2004; 2. SMITS C, SWEN SJ, GOVERTS ST, MOLL AC, IMHOF SM, SCHOUTEN-VAN 10:1321–28. MEETEREN AYN. Assessment of hearing in very young Surgical Correction of Spinal Deformities after Heart Transplantation: A Case Series Report Several studies have documented an association among the patient population. Two patients had between congenital heart disease and scoliosis congenital heart disease, two had congenital in children.1-4 More recent research has shown cardiomyopathy and one had Marfan syndrome. that children undergoing any type of solid Hospital charts were reviewed to obtain clinical organ transplantation are placed at increased information regarding the heart transplantation, risk for developing a potentially limiting the spinal procedure and the patient’s status spinal curvature.5 Among all solid organ (both cardiac and spinal) at the time of transplantations, heart … spinal deformity surgery can be successfully performed Brian Kaufman, MSII transplantation Advisors: Michael G. Vitale, MD, has been reported in children and adolescents who have undergone heart MPH; and Joshua E Hyman, MD to be a major Morgan Stanley Children’s risk factor for the transplantation. Hospital of New York- development of Presbyterian, NY spinal deformity.5 Armed with this knowledge, scoliosis correction. Diagnostic test results, the pediatric orthopaedic research team at including preoperative cardiac catheterizations, Morgan Stanley Children’s Hospital of New echocardiograms and preoperative Cobb York-Presbyterian Hospital reviewed the cases angles, were obtained from the surgeon’s notes. of patients undergoing scoliosis correction after Intraoperative and follow-up information orthotopic heart transplantation to establish any also was reviewed. Three different procedures necessary changes in their perioperative care to were used to correct the scoliosis in the heart ensure good surgical results. transplant patients. Four patients underwent This study was a retrospective case series a posterior spinal fusion and instrumentation, report of six heart transplant recipients with a one patient underwent a posterior segmental diagnosis of scoliosis, requiring corrective spinal instrumentation without fusion (growing rods), surgery between 1995 and 2007. The causative factor necessitating heart transplantation varied SPINAL DEFORMITIES Continued on p. 25

24 Fusion • 2008 SPINAL DEFORMITIES Continued from p. 24 in congenital heart disease. J Pediatr Orthop, 1991; 11:42–7. and the last patient received an anterior release 3. KAWAKAMI N, MIMATSU K, DEGUCHI M, KATO F, MAKI S. and posterior fusion with instrumentation. Scoliosis and congenital heart disease. Spine, 1995; The average age at time of heart 20:1252–6. transplantation was 7.8 ± 4.5 years. The children then underwent surgical correction for their 4. RECKLES LN, PETERSON HA, WEIDMAN WH, BIANCO AJ. The scoliosis at a mean age of 13.3 ± 5.6 years. association of scoliosis and congenital heart defects. Average length of follow up after the scoliosis J Bone Joint Surg Am, 1975; 57:449–55. surgery was 21.5 ± 14.7 months. Two of the 5. HELENIUS I, ET AL. Scoliosis after solid organ patients in the cohort died as a result of their transplantation in children and adolescents. Am J cardiac condition. Three patients had Transplant, 2006; 6:324–30. complications following the scoliosis procedure. These complications included a fractured single rod construct in one patient, device migration after initial surgery in another patient and one instance of wound infection. None of the complications resulted in adverse sequelae. Appropriate curve correction and control was achieved for all six patients. The mean preoperative major curve was 70.2°. At the time of last follow up, the spinal curvature had corrected to a mean curve of 22.6° (p<0.10). This case report demonstrates how spinal deformity surgery can be successfully performed in children and adolescents who have undergone heart transplantation. Especially with immunosuppressive therapy and numerous comorbid conditions, these patients represent an especially challenging cohort. Adequate surgical correction without serious adverse conditions, therefore, is best accomplished with meticulous preoperative planning and extensive multidisciplinary cooperation both intraoperatively and postoperatively. Despite the risks and challenges, correction of spinal deformity in FIGURE 1: pediatric heart transplant patients can POSTOPERATIVE signifcantly improve quality of life. LATERAL X-RAY OF REFERENCES: A STUDY PATIENT. 1. BEALS RK, KENNEY KH, LEES MH. Congenital heart Note the posterior spinal disease and idiopathic scoliosis. Clin instrumentation inserted during Orthop Relat Res, 1972; 89:112-6. the scoliosis surgery as well as the anterior staples used to 2. FARLEY FA, PHILLIPS WA, HERZENBERG JE, ROSENTHAL fuse the sternum following the A, HENSINGER RN. Natural history of scoliosis heart transplantation.

Fusion • 2008 25 Hip Arthroscopy and the Treatment of Femoroacetabular Impingement This project aimed to assess the long-term performed as an outpatient procedure using fuo- prognosis for patients who presented with femo- roscopy for instrument placement. The proce- roacetabular impingement (FAI) and underwent dure has been slower to evolve than arthroscopy subsequent hip arthroscopy. FAI occurs when of other joints because the hip is much deeper the femoral head does not have its full range of in the body. Furthermore, because the hip is a motion within the pelvic acetabulum. FAI is “ball-and-socket” joint, it is necessary to employ increasingly recognized as a cause of osteoarthritis traction to expose the joint enough to ft the sur- in the hip through dete- gical instruments inside rioration of the labrum without causing further and articular surface. tissue damage. The basic Cory M. Czajka, MSII Impingement itself is the principle of surgical Advisor: Struan H. Coleman, premature and improper treatment of FAI is to MD, PhD, Hospital for Special collision between the restore sphericity to the Surgery, NY head and/or neck of femoral head, thereby the femur and the relieving the impinge- acetabulum. This causes ment. The surgery also a painful and decreased aims to address the range of hip joint pathological changes in motion. FAI commonly the labrum and articular presents as “cam-type” cartilage.1 impingement, a result Studies have shown of excess bone forming FIGURE 1: BALL-AND-SOCKET JOINT. A) Normal that the vast majority of around the head and/ hip; B) Cam impingement; C) Pincer impingement; D) Combination hip arthroscopy patients or neck of the femur; of cam and pincer impingement. return to sports and “pincer-type” impinge- other physical activities ment, an overgrowth of at their peak level of the acetabular rim; or a resulting FAI where the performance prior to the onset of hip pain. The acetabulum is angled in such a way that abnormal majority of patients clearly get better, but it is not impact occurs between the femur and the rim of yet clear to what extent the procedure stops the the acetabulum.1 course of arthritis. Patients who have underlying When the excess bone present on the femoral skeletal deformities or degenerative condi- head and/or neck abuts the rim of the acetab- tions may not experience as much relief from ulum, the cartilage and labrum that line and the procedure as would a patient with simple cushion the acetabulum can be damaged. The impingement. extra bone can appear on X-rays as a small protru- sion. When the protrusion repeatedly rubs against REFERENCES: the cartilage and labrum, such as in athletes who 1. CLOHISY JC, MCCLURE JT. Treatment of anterior femoroac- perform repeated leg fexion and extension, the etabular impingement with combined hip arthros- cartilage and labrum eventually may tear, causing copy and limited anterior decompression. Te Iowa pain. As more tissue tears, the femoral bone will Orthopaedic Journal, 25:164–71. impact with pelvic bone resulting in arthritis. 2. ESPINOSA N, BECK M, ROTHENFLUH DA, GANZ R, LEUNIG M. Treat- Tears of the labrum can also fold into the joint ment of femoro-acetabular impingement: preliminary space, causing a further painful restriction of hip results of labral refxation. Surgical technique. Te motion.2,3 Journal of Bone and Joint Surgery, 2006; 88:925–35. Arthroscopy of the hip has become an accepted surgical procedure with well-defned 3. SHUGARS RA, MORE RC. Arthroscopic hip surgery. Te indications and expected outcomes, primarily Association of Perioperative Registered Nurses Journal, due to recent advances in surgical instrumen- 2006; 82:975–98. tation and techniques.3 Hip arthroscopy is

26 Fusion • 2008 Novel “Non-Fusion” Technologies May Help Patients with Spinal Stenosis Technological advances, especially spanning indications and contraindications for each the last two decades, have greatly advanced the device. Of these patients, 22 percent were eligible feld of spinal surgery. Many of these advances to receive an interspinous spacer, 30 percent focused on creating alternatives to spinal fusion. were eligible to undergo facet replacement and Historically, spinal fusion has been widely 34 percent were eligible to receive posterior used to treat degenerative pathologies in the dynamic stabilization. Twenty-three percent of David Goodwin, MSII spine. However, eliminating vertebral motion patients were eligible to receive all three devices, Advisor: Warren Yu, MD and placing greater stress on adjacent spinal while 65 percent were not eligible to receive The George Washington segments limits the effectiveness of these fusions. any device. Reviewing 100 patients who had a University, Washington, DC As a result, new classes of non-fusion surgical lumbar surgery other than fusion, 25 percent of devices have emerged, including interspinous patients were eligible to receive an interspinous spacers, facet replacement systems and posterior spacer, 26 percent were eligible to undergo facet dynamic stabilization systems. These devices replacement and 27 percent were eligible to offer innovative, as well as minimally invasive, receive posterior dynamic stabilization. Twenty- approaches to spinal surgery. The interspinous fve percent of patients were eligible to receive all spacer, facet replacement system and posterior three devices and 73 percent were not eligible to dynamic stabilization are each indicated to treat receive any of the devices. spinal stenosis.1,2 Interspinous spacers, facet replacement and This retrospective study evaluated the posterior dynamic stabilization, therefore, stand percentage of patients who would be eligible to impact 20–30 percent of lumbar surgeries. to receive one of these non-fusion devices. As future research and technology expand the indications or eliminate Eligibility was defned as matching at least one the contraindications for these devices, the number of patients eligible to indication but none of the receive these devices may increase signifcantly. contraindications for each device. There have been no published studies investigating the percentage of As future research and technology expand the patients who may potentially beneft from any of indications or eliminate the contraindications for these devices. these devices, the number of patients eligible to Patients were divided in two groups, the frst receive these devices may increase signifcantly. including patients who had a lumbar fusion We predict that these devices will have a and the second consisting of patients who had signifcant impact on spine surgery. any other lumbar surgery. Indications and REFERENCES: contraindications in this study were adapted 1. HANLEY E. The indications for lumbar spinal fusion from IDE clinical trials for interspinous spacers, with and without instrumentation. Spine, 1995; facet replacement and posterior dynamic 20:143S–153S. stabilization. We evaluated the inclusion/ 2. ESSES S, HULER R. Indications for Lumbar fusion in the exclusion criteria for multiple models in each Adult. Clinical Orthopedics and Related Research, category and selected the most stringent criteria. 1992; 279:87–100. As a result, indications and contraindications were based on the inclusion/exclusion criteria for the IDE clinical trials of X Stop interspinous spacer, Anatomic Facet Replacement System and Stabilimax posterior dynamic stabilization. Medical records of 100 patients who had lumbar fusions were cross-referenced with

Fusion • 2008 27 Effect of Bone Density on Mechanical Properties after Percutaneous Vertebroplasty Vertebral compression fractures are the most Bone mineral density of 13 vertebral columns common injuries resulting from osteoporosis, from adult Caucasian female cadavers was mea- with an estimated incidence of 700,000 per year sured with a dual-energy X-ray absorptiometry in the United States.1 Among persons over 65, (DEXA) scanner. Vertebral bodies (n=126) were 33 percent of women have sustained a vertebral assigned to fve groups based on cement treat- compression fracture, and this fracture rate is ment: intact, untreated, 4 percent fll, 12 percent three times higher in women than in men. These fll and 24 percent fll. Non-intact specimens fractures cause acute and chronic back pain, were compressed asymmetrically to simulate a disability and increased mortality risk.2 One wedge compression fracture before treatment treatment option is percutaneous vertebroplasty with PMMA cement. Strength and stiffness were Nabila Hai, MSII or injection of cement, typically polymethyl measured in axial compression. Research Track methacrylate (PMMA) acrylic bone cement, into The two most signifcant fndings of the Advisor: Jove Graham, PhD the vertebral body. However, previous studies study suggest that: (1) the improvements in US Food and Drug have shown that injecting an excessive amount stiffness and strength resulting from vertebro- Administration, Center for Devices and Radiological Health, of cement can increase the risk of both cement plasty depend signifcantly on bone density, and 2 Silver Spring, MD leakage and secondary adjacent fractures. While (2) only the highest cement dose in the study the primary purpose of the surgery is to eliminate (24 percent vertebral body fll, average of 7 mL) back pain, patients and practitioners expect other had an appreciable effect on either mechanical benefts, including mechanical reinforcement property. Regarding strength, only the 24 per- of the vertebra as well the prevention of adverse cent fll group improved strength over untreated effects. levels, and greater improvements in strength The primary objective of this study was to were seen in patients with higher bone density. determine how bone mineral density (BMD) Unlike stiffness, however, the strength of the 24 affects mechanical stiffness and strength of the percent fll group not only improved relative to vertebral body after vertebroplasty. A secondary the untreated group but was enhanced beyond objective was to determine how the relation- the intact levels. The greatest improvements ships between mechanical properties and BMD in stiffness would be expected in patients with vary with the amount of cement injected. The higher bone density (who are the least likely to clinical goal of this research was to help physi- suffer a fracture or need vertebroplasty). Results cians understand how BMD can identify a dose suggest that highly osteoporotic patients may of cement that can restore mechanical properties receive the least amount of improvement in to the greatest extent possible for a specifc patient without increasing the risk of complications. BONE DENSITY Continued on p. 29 FIGURE 1: X-RAYS VERIFYING CONSISTENT VERTEBROPLASTY. All cement was injected using a transpedicular approach through the left pedicle with the needle tip in the anterior third of the vertebral body near the axial midplane. (A) L3 vertebra injected with 4 percent volume of cement. (B) T12 vertebra injected with 12 percent volume of cement. (C) L2 vertebra injected with 24 percent volume of cement. A B C

28 Fusion • 2008 BONE DENSITY Continued from p. 28 2. SILVERMAN S, MINSHALL M, SHEN W, ET AL. The relationship of health-related quality of life to prevalent and incident mechanical properties from vertebroplasty. For vertebral fractures in postmenopausal women with these patients, it may be advisable for clinicians osteoporosis. Arthritis Rheum, 2001; 44:2611–19. to limit their expectations of vertebroplasty to pain relief but not mechanical beneft and to *This study was published in the August 2007 select a cement volume that will minimize risks issue of Spine: Graham J, Ahn C, Hai N, Buch B. of adverse events. Effect of bone density on vertebral strength and REFERENCES: stiffness after percutaneous vertebroplasty,” Spine, 1. RIGGS B, MELTON LR. Involutional osteoporosis. New 2007; 32:E505–E511. England Journal of Medicine, 1986; 314:1676–86. Identifying the Correlation between Pseudo-bulbar and Cognitive Impairment in Primary Lateral Sclerosis Primary Lateral Sclerosis (PLS) and Amyotrophic in the PLS population. Fifteen PLS patients and Lateral Sclerosis (ALS) both involve degenera- six age-matched, healthy volunteers participated tion of neurons. In PLS, loss of corticospinal in the study. The full battery of bulbar function tract Upper Motor Neurons (UMN) results in measures were carried out on 14 of the patients stiffness and brisk refexes. In ALS, there is loss and two of the volunteers. This work up included of UMN and Lower Motor Neurons (LMN); clinical examination measures for hyperrefexia Kimberly N. Capers, MS, MSII as a result, one fnds atrophy, fasciculation in addition to two speech measures: the rate of Advisor: Mary Kay Floeter, MD, and diminished refexes in addition to UMN speech and the Assessment of Intelligibility of PhD, National Institutes of fndings. Dysarthric Speech test. The measures of the rate Health, National Institute of Although Pringle et al have developed a clas- of speech and clarity of enunciation declined in Neurological Disorders and sifcation scheme for PLS, there still remains a parallel; as speech became slower it also became Stroke, Bethesda, MD question as to whether PLS and ALS are indeed more diffcult to understand. Rate of speech separate disease entities.1 A previous study found also refected the presence of hyperrefexia; brisk that stiffness and spasticity are more commonly jaw jerks and gag refex were associated with seen at the initial presentation of PLS and that slow rates of speech as well. The rate of speech wasting of the limb is rare, and concluded, “a was thereafter used as the primary measure of patient presenting with spasticity who does not bulbar function for comparison with the Mattis develop wasting within three years most likely DRS-2 dementia score. The psychologist in our has PLS.”2 group obtained the dementia scores for 14 of the ALS patients often manifest cognitive patients and six of the volunteers. changes of frontal lobe executive dysfunction to Preliminary analysis of the correlation varying degrees, in some cases leading to fronto- between rate of speech and scores on the Mattis temporal dementia (FTD). These impairments dementia scale does not suggest a correlation at are most commonly seen in those ALS patients this time. Regression analysis with a straight line with bulbar impairment. Schreiber et al found, ft was performed in an attempt to elucidate this “there is a fronto-temporal pattern of cognitive relationship. We concluded that the relationship dysfunction in ALS expressing itself early in the between cognitive function and bulbar dysfunc- course of the disease and mainly with bulbar tion should be studied in a larger population of forms.”3 Furthermore, Lomen-Hoerth found in patients with PLS and compared to patients with her study that half of patients showed executive ALS to better understand the common features function defcits.4 of these disorders. Furthermore, understanding To further elucidate whether there is a dis- the underlying cortical pathology by imaging tinction between ALS and PLS, our study aimed measures of atrophy as well as pathologic studies to determine if a correlation exists between bulbar dysfunction and cognitive impairment COGNITIVE IMPAIRMENT Continued on p. 30

Fusion • 2008 29 COGNITIVE IMPAIRMENT Continued from p. 29 sclerosis. A longitudinal study in 52 patients. Journal of Neurology, 2005; 252:772–81. in PLS may further help explain the disease pro- 4. LOMEN-HOERTH C. Characterization of amyotrophic lat- cess itself. eral sclerosis and frontotemporal dementia. Dementia 2004; 17:337–41. REFERENCES: and Geriatric Cognitive Disorders, 5. MURPHY J, HENRY R, ET AL. “Establishing subtypes of the 1. PRINGLE CE, HUDSON AJ, ET AL. Primary lateral sclerosis. continuum of frontal lobe impairment in amyo- Clinical features, neuropathology and diagnostic trophic lateral sclerosis.” Archives of Neurology, 2007; criteria. Brain, 1992; 115:495–520. 64:330–34. 2. TARTAGLIA MC, ROWE A, ET AL. Differentiation between 6. ZHAI P, PAGAN F, ET AL. Primary lateral sclerosis: A hetero- primary lateral sclerosis and amyotrophic lateral scle- geneous disorder composed of different subtypes? rosis: examination of symptoms and signs at disease Neurology, 2003; 60:1258–65. onset and during follow-up. Archives of Neurology, 2007; 64:232–36. 7. KUNCL RW. Motor Neuron Disease, 2002. 3. SCHREIBER H, GAIGALAT T, ET AL. Cognitive function in bulbar- and spinal-onset amyotrophic lateral Clopidogrel in a Pediatric Population: Safety and Effcacy Results from a Single Center Although thrombotic diseases are less prevalent with clopidogrel in a larger pediatric popula- in children than in adults, complex pediatric tion. Patients (≤ 18 years) who were prescribed patients, such as those with congenital heart dis- clopidogrel between March 2002 and August ease, remain at risk for clot formation. Few guide- 2005 were retrospectively identifed at Children’s lines exist for treatment of pediatric patients, Hospital, Boston, MA. Data from the time of leading pediatric practitioners to prescribe the frst documented clopidogrel use to the most drugs, such as clopidogrel, off-label based upon recent follow-up were collected and adverse events extrapolation from adult experience and perceived were classifed according to seriousness and rela- clinical need. tionship to clopidogrel. Evidence-based information on clopidogrel, a Among 90 patients, 53 percent were male, the Lily A. Maltz, MSI, thienopyridine derivative and potent antiplatelet, median age was 6.7 years and the median weight Research Track is limited to adults at risk for, or with a history was 23.6 kg at frst clopidogrel use. Prescriptions Advisors: Kathy J. Jenkins, MD, MPH; Kimberlee Gauvreau, ScD; of, ischemic stroke, acute coronary syndrome, were mostly for cardiac indications (96 percent) and Jean A. Connor, DNSc, RN, peripheral arterial disease or are at risk of death with the remainder for neurological indica- 1 CPNP, Department of Cardiology, from vascular disease. Several large, randomized tions (4 percent). Common cardiac indications Children’s Hospital, Boston, MA trials have evaluated the safety and effcacy of included history of thrombosis involving a con- clopidogrel in adults using pre-determined dosing duit or shunt, abnormal vasculature with poten- criteria, and generally found the drug to be safe tial for low fow and device placement. Median and effcacious.2,3,4 total dose was 1.3 mg/kg/day and duration of Published material supporting the safety and therapy varied greatly (median 45 days, < one effcacy of off-label use of clopidogrel in the pedi- day – four years). Minor bleeding occurred in atric population remains scarce. Several pediatric three patients, all on concomitant acetylsalicylic studies of clopidogrel performed outside of the acid (ASA). One patient experienced catastrophic United States are underpowered by small sample bleeding after a vessel tear during catheteriza- sizes. Two such studies performed at the Hospital tion. Another patient with poor ventricular for Sick Children in Toronto, Canada had cohorts function and a fenestrated Fontan (an operation of only 15–17 patients. Overall, both studies performed on children with complex congenital found clopidogrel to be well tolerated in children heart defects) had baffe thrombosis and subse- with minimal adverse events, the majority due to quent stroke while on clopidogrel and ASA. minor bleeding.5,6 We performed a study to provide descriptive CLOPIDOGREL IN PEDIATRICS information about off-label treatment practice Continued on p. 31

30 Fusion • 2008 CLOPIDOGREL IN PEDIATRICS 2. YUSUF S, ZHAO F, MEHTA SR, CHROLAVICIUS S, TOGNONI G, FOX Continued from p. 30 KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med, 2001; In conclusion, our study demonstrated that 345:494–502. clopidogrel prescribed for children of all ages 3. CAPRIE STEERING COMMITTEE. A randomised, blinded, was well tolerated. Most prescriptions were for trial of clopidogrel versus aspirin in patients at thrombosis prevention in patients with cardiac risk of ischaemic events (CAPRIE). Lancet, 1996; disease. Bruising and minor bleeding events 348:1329–39. occurred rarely. While various trials demonstrate 4. DIENER HC, BOGOUSSLAVSKY J, BRASS LM, CIMMINIELLO C, CSIBA the benefts of treatment with clopidogrel to pre- L, KASTE M, ET AL. Aspirin and clopidogrel compared vent thrombotic events in adults, a need remains with clopidogrel alone after recent ischaemic stroke for further clinical trials examining the safety and or transient ischaemic attack in high-risk patients effcacy of clopidogrel in children.2,3,4 A qualita- (MATCH): randomised, double-blind, placebo- tive prospective study would provide additional controlled trial. Lancet, 2004; 364:331–37. information about the burden of drug use on 6. SOMAN T, RAFAY MF, HUNE S, ALLEN A, MACGREGOR D, DEVEBER G. families, and could capture additional informa- The risks and afety of clopidogrel in pediatric arterial ischemic stroke. , 2006; 37:1120–22. tion about dosing, safety and effcacy that can Stroke improve the application of this drug in children. 5. FINKELSTEIN Y, NURMOHAMED L, AVNER M, BENSON LN, KOREN G. REFERENCES: Clopidogrel use in children. J Pediatr, 2005; 147:657–61. 1. Physicians’ Desk Reference. 60 ed. Montvale, NJ: Thomson; 2006. Funding for this study provided by Bristol-Myers Squibb. Development of Class I HLA Typing Assay for HIV Clinical Trials in East Africa Highly polymorphic human leukocyte antigen chain reactions (PCR) which incorporate (HLA) class I and II genes are important host sequence-specifc primers (SSP), sequence genetic factors whose encoded molecules form specifc oligonucleotide probes (SSOP/SSO) or intracellular complexes with pathogen-derived sequence-based typing (SBT).6 Real time PCR peptides and migrate to surfaces of infected cells uses primer-probe combinations to distinguish and mediate adaptive immune responses. This HLA alleles based on fuorescence emissions Olalesi Osunsade, MSI, process is fundamental to HIV infection and and melting curve profles, which are cheaper Advisors: Francine McCutchan, AIDS progression. While many relationships than SBT and do not require loading agarose PhD; and Gustavo Kijak, between HLA genotypes and HIV/AIDS are gels which are prone to contamination. Many PharmD, PhD, U.S. Military well established, scientists emphasize the need real-time PCR systems also use 384-well reaction HIV Research Program, Henry to study the infuence of HLA alleles on the plates, which produce large amounts of data in a M. Jackson Foundation for effcacy of HIV drugs.1,2,3 This need is apparent short period of time. Such advantages have made the Advancement of Military in the development of a global HIV vaccine that it a popular method of HLA typing.7 Medicine, Rockville, MD targets the diverse populations of Sub-Saharan I was part of a team developing an SSP- Africa, where an estimated 25 million people are real time PCR assay for HLA class I typing to infected with HIV.4 support ongoing HIV vaccine clinical trials in These HIV vaccine clinical trial participants East Africa. During my time there, we developed are ideal candidates for studying HLA an assay capable of distinguishing among 14 genotypes. Subsequent identifcation of these alleles of the HLA-A locus of HLA class I known genotypes can in turn be used to interpret to be predominant in 80–90 percent of East drug effcacy in participants.1,5 “HLA typing” African populations. The completed system, describes methods used to identify HLA alleles which also will type the remaining HLA-B and based on HLA gene sequences. Techniques usually involve conventional polymerase HLA TYPING Continued on p. 32

Fusion • 2008 31 HLA TYPING Continued from p. 31 REFERENCES: 1. CARRINGTON M, O’BRIEN SJ. The infuence of HLA HLA-C loci of HLA class I, will perform HLA genotype on AIDS. Annu Rev Med, 2003; class I typing for four individuals in less than 54:535–51. two hours at a third the cost of SBT. Through 2. NOLAN D, GAUDIERI S, JOHN M, MALLAL S. Impact of host such effciency, our assay also can be performed genetics on HIV disease progression and treatment: in East African clinical trial feld labs where new conficts on an ancient battleground. AIDS, other laboratory tests are performed at low costs. 2004; 18:1231–40. Besides studying the effcacy of drugs in these 3. MCNICHOLL JM, DOWNER MV, UDHAYAKUMAR V, ALPER CA, settings, HLA genotyping data generated by our SWERDLOW DL. Host-pathogen interactions in emerging assay can be combined with HIV sequencing and re-emerging infectious disease: a genomic and epidemiological data from patients — perspective of tuberculosis, Malaria, Human using bioinformatics tools — to study the Immunodefciency Virus Infection, Hepatitis B, and emerging selective pressures created by the AIDS Cholera. Annual Rev Public Health, 2000; 21:15–46. epidemic.8 Such premises were behind recently 4. EDITORS HOFFMANN C, ROCKSTROH JK, KAMPS BS, EDS. HIV demonstrated “HLA footprints,” which show Medicine, 2006. 14th edition. how HIV viruses mutate and escape immunity 5. VARDAS E, BUTTÒ S, GLASHOFF R, MALNATI MS, POLI G, CLERICI M. in response to particular HLA types within a Preparing for phase II/III HIV vaccine trials in population.9 This is just another suggestion for Africa. Microbes Infect, 2005; 7:1436–44. how large-scale HLA genotyping data can be 6. ADAMS SD, KRAUSA P, MCGINNIS M, SIMONIS TB, STEIN J, MARINCOLA used effectively. FM. Practicality of High Throughput HLA Sequence- Overall, through its ability to support the Based Typing. ASHI Quarterly, 2001;25. large-scale and cost-effective HLA genotyping 7. FANER R, CASAMITJANA N, COLL J, CARO P, PUJOL-BORRELL R, needed for studying the effcacy of HIV vaccine PALOU E, JUAN M. Real-Time PCR Using Fluorescent candidates in East African clinical trials, this Resonance Emission Transfer Probes for HLA-B Typing. Hum Immunol, 2006; 67:374–85. assay could be an important component in the design of a global HIV vaccine. 8. CAO K, MOORMANN, AM, LYKE KE, ET AL. Differentiation between African populations is evidenced by the diversity of alleles and haplotypes of HLA class I loci. Tissue Antigens, 2004; 63:293–325. 9. KLENERMAN P, MCMICHAEL A. “Finding Footprints among the Trees.” Science, 2007; 315:1505–07.

32 Fusion • 2008 Gastric Stimulation for Vomiting, Nausea and Related Symptoms Associated with Gastroparesis Using Enterra™ System Gastroparesis is a stomach disorder character- the electrical stimulation begins at the time of ized by delayed gastric emptying. Patients with surgery. After six weeks, patients are randomized gastroparesis suffer from a number of gastrointes- to either the “On” or “Off” position for three tinal (GI) symptoms, including bloating, nausea, months, then set to the opposite group for three vomiting, early satiety, postprandial fullness, additional months. Patients are required to attend epigastric pain and heartburn. Gastroparesis scheduled follow-up appointments at three, six, has become an increasingly common medical nine and 12 months post-implantation and annu- condition among the United States population, ally thereafter until the study is closed. At each affecting more than 1.5 million people. No cure follow-up appointment, subjects are assessed for for this disorder currently exists. symptom severity, frequency, complications and Ricky Singh Harika, MSII Non-operative therapies for patients with adverse events, health status, quality of life and Advisors: Fredrick Brody, MD; gastroparesis include diet modifcation, drug normal daily activities. The following symptoms Christine Carter, PhD, therapy (including Prokinetics and Anti-emetics) are assessed using a Likert scale of zero (absent) GW Medical Faculty Associates, and nutritional feeding via gastric or jejunal to four (extremely severe): vomiting, nausea, early Department of Surgery, feeding tubes. However, these approaches can satiety, bloating, postprandial fullness, epigas- Washington, DC negatively affect the patient’s quality of life. tric pain, epigastric burning, chest pain, chest Surgical procedures include gastrectomy, pyloro- burning and other symptoms. plasty and gastrojejunostomy. However, these The results from baseline to 12 months noted procedures have provided limited success and are a decrease in the frequency of vomiting, nausea, prone to complications. early satiety, bloating, postprandial fullness, epi- The George Washington University Medical gastric pain, epigastric burning, chest pain, chest Center is one of 10 clinical sites in the U.S. par- burning and other symptoms. Secondly, there was ticipating in a novel treatment study for patients a signifcant decrease in vomiting at each follow with gastroparesis. Currently, 50 patients are up appointment: three, six, nine and 12 months. enrolled in the study, with plans to enroll more Lastly, there was a signifcant decrease in the total patients in the future. This clinical trial is a severity scores and frequency scores at each three double-blinded, randomized study to evaluate month interval up to 12 months. the safety and effectiveness of gastric stimula- This study demonstrated that Enterra™ tion on the frequency of nausea and vomiting gastric stimulation is an effective and safe treat- in patients with gastroparesis. The procedure ment option for the reduction of the severity involves a surgical implant of an Enterra™ elec- and frequency of symptoms associated with trical stimulator, provided by Medtronic, Inc., gastroparesis. This treatment has improved the onto the body of the stomach. Interim results of quality of life for many people and has allowed the clinical trial, organized by Medtronic, show them to carry out a normal lifestyle and feel in control of their symptoms. Results of this study that gastric stimulation reduces symptoms of will be used to support a pre-market approval nausea and vomiting in patients for whom drug application (PMA) to the U.S. Food and Drug therapy was unsuccessful. The goal of this study Administration. is to induce a sustained reduction in the often debilitating symptoms of this disease. REFERENCES: Patients were asked to fll out a monthly 1. MEDTRONIC. Gastroparesis Fact Sheet. 2007; Retrieved diary of their symptoms prior to surgery to assess July 14, 2007 from http://wwwp.medtronic.com/News- their baseline frequency of nausea and vomiting, room/LinkedItemDetails.do?itemId=1101836121811&i . early satiety, bloating, postprandial fullness, temType=fact_sheet&lang=en_US 2. FOX J, FOXX-ORENSTEIN A. . 2006; Retrieved epigastric pain, epigastric burning, chest pain Gastroparesis July 14, 2007 from http://www.gi.org/patients/ and chest burning. Several study-related tests gihealth/gastroparesis.asp are performed to determine if the patient quali- 3. MEDTRONIC. Enterra™ Terapy: Gastric Electrical Stimu- fes for the study. An implant is placed inside lation (GES). 2007; Retrieved July 14, 2007 from the abdomen onto the body of the stomach and http://www.medtronic.com/neuro/enterra/.

Fusion • 2008 33 Breast-Specifc Gamma Imaging as an Adjunct Modality for the Diagnosis of Invasive Breast Cancer Mammography has remained the modality noted and compared to the laterality and location of choice for breast cancer screening with a of the biopsy proven invasive cancer. The clinical sensitivity of 78-85 percent.1-4 However, this report in the patient’s record was used for BSGI percentage declines signifcantly for women interpretation and cases were not reinterpreted for with dense breasts and sub-centimeter cancers. the study. Limitations such as these have resulted in the Out of the 149 invasive cancers identifed, 146 development of adjunct imaging modalities to were recognized with BSGI, totaling a sensitivity improve breast cancer detection. of 98 percent for the BSGI detection of invasive One such method involves nuclear medicine breast cancers. There were three cancers unidenti- techniques, in which physiological properties fed by BSGI, each being of grade 1 histology and Rigved V. Tadwalkar, MSII of tumors are utilized to effectively make a Research Track sub-centimeter lesion size. One explanation for diagnosis. Most common among these is the Advisor: Rachel F. Brem, MD the inability of BSGI to fnd these three patho- use of 99mTc-Sestamibi with a general purpose Breast Imaging and Intervention logically proven invasive cancers may be due to gamma camera. Although Center, GW Medical Faculty the posterior and otherwise this modality has improved Associates, Washington, DC FIGURE 1: BREAST SPECIFIC diffcult to image area of breast cancer detection by GAMMA IMAGING. Patient the breast. In the case of a large margin, it has been with a multifocal infltrating ductal one patient, the small size found to be inadequate in carcinoma of the left breast seen of the breast along with the discovery of non-palpable as separate areas of increased a posterior location may lesions and those less than radiotracer uptake in the craniocaudal be the cause for the non- one centimeter in size view. visualization of the lesion. due to intrinsic resolution Despite these limitations, 5–8 limitations. BSGI was still able to To resolve these diffculties, a small feld- identify 40 percent (2/5) sub-centimeter, grade 1 of-view camera was developed that allows tumors. Moreover, our study showed four out of 9 high-resolution detection of breast lesions. This 149 infltrating ductal carcinoma cases that were technique, Breast Specifc Gamma Imaging pathologically categorized as multifocal. BSGI (BSGI), is a substantial improvement over the was able to correctly identify the multifocality in general purpose gamma camera model. The all instances. design of BSGI allows one to reliably image sub- Our results demonstrate that BSGI is a highly centimeter lesions due to its improved resolution sensitive method of diagnosing invasive breast and shape which is optimized for breast imaging. cancer. This study, using the largest sample size of Furthermore, images acquired from the device are invasive cancers studied with BSGI to date, along in projections correlated to the medial-lateral and with data in the literature, also suggests that craniocaudal views of traditional mammography, BSGI is a reliable adjunct imaging modality. allowing images to be interpreted in a straightfor- ward manner. Until now, there have been limited REFERENCES: studies defning the sensitivity of this emerging 1. ROSENBERG ED, HUNT WC, WILLIAMSON MR, ET AL. Effects of age, modality. This study is the largest to date, deter- breast density, ethnicity and estrogen replacement mining the sensitivity of BSGI for the diagnosis therapy on screening mammographic sensitivity and of invasive breast cancer. cancer stage at diagnosis: review of 183,134 screening Our project was a retrospective review of 139 mammograms in Albuquerque, NM. Radiology, consecutive women with biopsy-proven invasive 1998. 209:511–18. carcinoma from November 2004 to June 2007. 2. KOLB TM, LICHY J, NEWHOUSE JH. Comparison of the The images acquired from the BSGI were sub- performance of screening mammography, physical jectively categorized based on the degree of focal examination and breast US and evaluation of factors radiotracer uptake. Lateralization and region of the focal area of increased radiotracer uptake were GAMMA IMAGING Continued on p. 35

34 Fusion • 2008 GAMMA IMAGING Continued from p. 34 mammography and histopathological diagnosis. Nuc Med Commun, 1999; 20:317–25. that infuence them: an analysis of 27, 825 patient 7. FENLON HM, PHELAN NC, O’SULLIVAN P, ET AL. Benign versus evaluations. Radiology, 2002; 225:165–75. malignant breast disease: comparison of contrast- 3. KHALKHALI I, MENA I, JOUANNE E, ET AL. Prone scintimam- enhanced MR imaging and Tc-99m tetrofosmin mography in patients with suspicion of carcinoma of scintimammography. Radiology, 1997; 205:214–20. the breast. J Am Coll Surg, 1994; 178:491–97. 8. PALMEDO H, BENDER H, GRUNWALD F, ET AL. Comparison of 4. KHALKHALI I, CUTRONE JA, MENA IG, ET AL. Scintimammog- fuorine-18 fuorodeoxyglucose positron emission raphy: the complementary role of Tc-99m sestamibi tomography and technetium-99m methoxyisobu- prone breast imaging for the diagnosis of breast carci- tylisonitrile scintimammography in the detection of noma. Radiology, 1995; 196:421–26. breast tumours. Eur J Nucl Med, 1997; 24:1138–45. 5. MEKHMANDAROV S, SANDBANK J, COHEN M, ET AL. Technetium 9. MAJEWSKI S, KIEPER D, KEPPEL C. Optimization of dedicated 99-m MIBI scintimammography in palpable and scintimammography procedure using small detector nonpalpable breast lesions. J Nucl Med, 1998; prototypes and compressible breast phantoms (abstr). 39:86–91. Presented at the IEEE Medical Imaging Conference, 6. ARSLAN N, OZTURK E, ILGAN S, ET AL. Tc-99m MIBI scinti- Lyon, France. October 2000. mammography in the evaluation of breast lesions and axillary involvement: a comparison with

Religious Experience in Epilepsy The ancient association between epilepsy and than other epileptics. We hypothesized that TLE having a concurrent religious/spiritual experience predisposes individuals to a heightened sense of has persisted through the ages and remains religiousness/spirituality, also associated with to the present day. People with epilepsy have neuroplastic changes, the net effect of which is to been reported to have heightened religious enhance sensory activation of the limbic system. experiences and spiritual orientations from A systematic survey of religious experience in a clinical perspective. In particular, people epilepsy, with a focus on TLE, was conducted with temporal lobe epilepsy (TLE) have been with a more comprehensive questionnaire Shivani M. Bhatt, MSII, described as intensely religious, preoccupied with on spirituality/religion than previously Research Track the study and practice of spirituality/religion administered. Advisor: Laura S. Boylan, MD and frequently report intense spiritual/religious Data for this study was collected from Department of Neurology, NYU experiences. Waxman and Geschwind (1975) adults admitted to the New York University School of Medicine, NY proposed an Interictal TLE Personality citing Comprehensive Epilepsy Center inpatient “hyperreligosity,” an excessive preoccupation video-EEG monitoring unit between April 16, with religion/spirituality, as a distinct behavioral 2001 and Sept. 16, 2002. The study population trait among its probable characteristics.1 consisted of 151 patients with various types The TLE Interictal Personality was further of epilepsy. The Brief Multi-Dimensional investigated by Bear and Fedio (1977) using Measure of Religion/Spirituality for use in a structured personality inventory and hyper- Health Research (BMMRS) was used to assess religiousness was among the set of 18 personality individual religiousness/spirituality.3 The traits consistently observed in TLE patients.2 BMMRS is a 39-item questionnaire developed The proposition of an interictal TLE Personality by the Fetzer Institute in association with has been controversial and our attempt to verify the National Institute on Aging (1999) that this syndrome, in addition to other studies, have examines 11 different domains of religiousness/ been met with mixed results. spirituality which have been identifed as related Our study evaluated the religiousness/ to physical and mental health. spirituality of TLE patients as compared with We found TLE patients are no more patients with primary generalized epilepsy religious/spiritual than other epilepsy patients and other types of focal epilepsy to determine whether TLE patients are more religious/spiritual RELIGION AND EPILEPSY Continued on p. 36

Fusion • 2008 35 FIGURE 1: BMMRS DOMAIN SCORES TLE Study Population vs . National Means REPRESENTED

BY OUR STUDY 70 POPULATION

(TLE SUBJECTS) 60 VS. THE GENERAL POPULATION (GSS 50 SAMPLE). Scores are scaled from 0-100 with higher 40 scores indicating experiences with a greater degree of 30 religiousness/spirituality. 20 *Signifcant Differences (p value < .05) in the BMMRS 10 mean scores of TLE subjects vs. the general population (GSS 0 Sample) were found in nine out of the 11 BMMRS domains: Daily Spiritual Experiences (p < .0001); Religious/ Spiritual Values and Beliefs (p < .0001); Forgiveness ■ GSS Sample (p < .0001); Private Religious/ □ TLE Subjects Spiritual Practices (p < .0001); ■ PGE Subjects Positive Religious/Spiritual BMMRS Domain □ Non-TLE Subjects Coping (p = .0010); Positive ■ All Religious/Spiritual Support (p < .0001); Organizational RELIGION AND EPILEPSY Continued from p. 35 REFERENCES: Religiousness (p = .0017); 1) GESCHWIND N, WAXMAN SG. The interictal behavior Negative Religious/Spiritual and report fewer religious conversion experiences. syndrome of temporal lobe epilepsy. Archives of Support (p = .0430); Overall Upon comparison of the study population with General Psychiatry, 1975; 32: 1580–86. Self-Ranking (p < .0001). the BMMRS normative population distribution 2) BEAR DM, FEDIO P. Quantitative analysis of interictal There were no signifcant data from the 1998 General Social Survey, we behavior in temporal lobe epilepsy. Archives of differences in Religious/Spiritual found epilepsy patients as a whole are more Neurology, 1977; 8:454–67. History and Negative Religious/ religious/spiritual than the general population.4 3) FETZER INSTITUTE/NATIONAL INSTITUTE ON AGING WORKING GROUP. Spiritual Coping domains. Our fndings refute the purported Multidimensional Measurement of Religiousness/ “hyperreligiosity” associated with TLE. No Spirituality for Use in Health Research: a report direct causal relationship can be established of the Fetzer Institute/National Institute on Aging between seizure discharges in the temporal lobe Work Group, 1999; Kalamazoo, MI: John E. Fetzer Institute. and deepened religiousness/spirituality. The religious/spiritual preoccupation and intense 4) DAVIS JA, ET AL. General Social Survey. The National Data Program for Social Sciences, 1998; National religious conversion experiences proposed as Opinion Research Center, University of Chicago. part of the constellation of TLE personality traits is not supported by our data. Heightened religiousness/spirituality may be a trait common among all epileptics, regardless of epilepsy type and seizure origin.

36 Fusion • 2008 A Geometrical Forefoot Model: Relationship to Foot Function In collaboration with the Motion Analysis where P is the pressure, F is the focus and D Laboratory of Leon Root, MD, biomechanical is the distance from the center to a vertex. We foot function was studied using a geometrical hypothesized that feet with normal rectus align- forefoot model designed to assess and treat pedal ment and function had a hyperbolic conic curve pathology. Malleolar valgus index (MVI) and describing their MTPJ relationships with an center of pressure excursion index (CPEI) were eccentricity greater than one.4,5 developed to measure static and dynamic foot Barefoot plantar pressures were measured function.1 Many sophisticated and complex foot during one’s comfortable walking speed with models have been created, however, none have the Novel emed X system. The plantar loading been used for clinical decision making.2,3 A sim- parameters (peak pressure, peak force, pressure- Steven V. Kardos, MSII plifed mathematical approach was developed by time integral) were measured in each anatomical Research Track Demp to model metatarsal length patterns from region of the foot (hallux, frst–ffth MTPJs, Advisor: Howard J. Hillstrom, PhD dorsoplantar X-rays by unique conic curves and medial arch, lateral arch, medial heel and lateral Hospital for Special Surgery, NY, their eccen- heel) using a masking algorithm. In Figure 2, the Temple University tricities.4,5 Our maximum pressure throughout the stance phase FIGURE 1 School of Podiatric Medicine, study explores y of a healthy asymptomatic person ( ) and a right Philadelphia, PA the association person with diabetes and HV (left) is illustrated. between these The areas of high pressure are indicated by the X model param- arrows. Note that eters and the the subject with biomechanical diabetes and HV has foot function higher plantar pres- in healthy sures and a reduced asymptomatic CPEI indicative of individuals. overpronation as The Demp compared with the forefoot model healthy individual. (Figure 1) Using our simplifed constructs a conic curve through the meta- geometric forefoot tarsophalangeal joint (MTPJ) centers. Five model, conserva- MTPJ x,y coordinates are used to solve the FIGURE 2 tive or surgical equation for a unique conic curve: treatments may be AX2 + BX + CXY + DY + EY2 = 0 modifed to optimally convert a pathological foot to a healthy asymptomatic foot with improved where A, B, C, D and E are the resulting biomechanical function. fve coeffcients. In this study, medial and lateral aspects of each MTPJ were calculated with a 3-D REFERENCES : digital pointer. The midpoint of each medial and 1. SONG J, ET AL Foot type biomechanics: comparison lateral MTPJ joint space was considered to be of planus and rectus foot types. JAPMA, 1996; the MTPJ center. A forefoot coordinate system 86:16–23. was generated such that the x-axis projected from 2. CAMACHO DL, ET AL A three-dimensional, anatomically the ffth MTPJ to the frst MTPJ, the y-axis detailed foot model: A foundation for a fnite ele- ment simulation and means of quantifying foot-bone was perpendicular to that vector, and the origin position. J Rehab Res Dev, 2002; 39:401–10. was at the ffth MTPJ. Using Maple software, conic curves were created and the possible curve 3. GILCHRIST LA, WINTER DA A two-part, viscoelastic foot model for use in gait simulations. 1996; types were: ellipse, parabola and hyperbola. J. Biomech, 29:795–8. FIGURE 1: CONIC Eccentricity, which is a constant that describes CURVE MODEL. the shape of a conic curve, was calculated as 4. DEMP PH A mathematical model for the study of meta- tarsal length patterns. JAPMA, 1964; 54:107–110. FIGURE 2: follows: PEAK PLANTAR 5. DEMP PH Geometric Models that Classify Stuctural PRESSURES: healthy E = (P x F1)/(P x D1) = (P x F2)/(P x D2) Variations of the Foot. JAPMA, 1998; 88:437–41. (right), HV (left).

Fusion • 2008 37 public health issues. . . Barriers to Therapeutic Cancer Vaccine Development Therapeutic cancer vaccine development is that inhibit T-cell responses and tumor escape an exciting and rapidly evolving discipline of mechanisms.7 biotechnology. However, it is undoubtedly bur- While scientifc innovation remains the prin- dened by a variety of obstacles that need to be cipal factor for determining success, a paradigm addressed before success can be achieved. shift in three regulatory factors could greatly Therapeutic vaccines energize the body’s facilitate the development process. immune system to recognize and attack estab- First, the current regulatory system is geared lished tumors that are otherwise ignored by to support single-agent drug approvals, yet normal physiologic immune surveillance.1 combinations may be necessary. There is an Prophylactic vaccines, on the other hand, are increasing trend in therapeutic vaccine develop- Robert C. Ward, MSII administered to healthy individuals and are ment toward the use of multiple antigens and Health Policy Track designed to prevent infection from cancer- adjuvants. Attacking cancers from several angles Advisor: John E. Calfee, PhD causing viruses.2 may yield synergistic and clinically signifcant American Enterprise Institute, As of August 2007, two prophylactic cancer results.1 Washington, DC vaccines had been approved by the Food Second, traditional effcacy endpoints, which and Drug Administration (FDA). In 2000, are based on quantitative tumor assessments, ENGERIX-B was approved to prevent While a variety of tumor-associated antigens have been primary liver cancer as a result of chronic identifed and many immunotherapeutic strategies hepatitis B infection. In 2006, Gardasil was have been tested, objectively defned clinical responses approved to prevent infection from some of are rare. the most common strains of human papillomavirus that cause cervical may not always adequately assess clinical beneft cancer.2 Currently, the scope for cancer prophy- (i.e., survival and quality of life). Tumor response laxis is limited because few cancers are caused by and patient response are not necessarily mutually viruses.3 inclusive.8 Thus, when a candidate vaccine meets Therapeutic cancer vaccines, however, have specifed safety standards, various effcacy criteria the potential to combat nearly any type of estab- should be considered to account for this potential lished tumor. Yet, so far none have reached the discrepancy. market by earning FDA approval.4,5 This lack of And third, current designs of clinical trials success can be attributed to both scientifc and can be made more effcient and effective. The regulatory barriers. adaptive clinical trial approach, which employs As a collection of altered self cells, tumors Bayesian statistical methods, offers a scientif- contain many of the same identifcation markers cally rigorous alternative to the classic design.9 as normal cells of that tissue. That, in part, This approach is suitable in studies as informa- makes it diffcult to convince the immune system tion accrues during a trial, potentially allowing to attack and eradicate tumors.6 While a variety for smaller and more informative trials and of tumor-associated antigens have been identifed enabling patients to receive better treatments. and many immunotherapeutic strategies have Furthermore, this approach better handles com- been tested, objectively defned clinical responses bination therapies and multiple endpoints.10 are rare. The reasons for this include the inability Implementing these changes may help of current approaches to generate effcient bring quicker approvals of safe and effcacious T-cell responses, the presence of regulatory cells VACCINE BARRIERS Continued on p. 39

38 Fusion • 2008 VACCINE BARRIERS Continued from p. 38 4. EASTMAN P. FDA Commissioner pledges help in bringing new immunotherapies to cancer patients. therapeutic cancer vaccines. That, in turn, Oncology Times, 2007; 29:29–30. would encourage further innovation, leading to 5. FOX JL. Uncertainty surrounds cancer vaccine review improved treatments that can increase the dura- at FDA. Nat Biotechnol, 2007; 25:827–28. tion and improve the quality of life. 6. PARDOLL D. Does the immune system see tumors as for- REFERENCES: eign or self? Annu Rev Immunol, 2003; 21:807–39. 7. WARD RC, KAUFMAN HL. 1. PARDOLL D, ALLISON J. Cancer immunotherapy: breaking Targeting costimulatory pathways for tumor immunotherapy. , 2007; the barriers to harvest the crop. Nat Med, 2004; Int Rev Immunol 10:887–92. 26:161–96. 8. SCHLOM J, ARLEN PM, GULLEY JL. 2. SOBOL RE. The rationale for prophylactic cancer vac- Cancer vaccines: moving beyond current paradigms. , 2007; cines and need for a paradigm shift. Cancer Gene Clin Cancer Res 13:3776–82. Ter, 2006; 13:725–31. 9. GOTTLIEB S. 3. PBR STAFF. Can therapeutic vaccines fulfll their 2006 Conference on adaptive trial design, Washington, DC. U.S. Food and Drug Administra- promise? Pharmaceutical Business Review. Jan. 24, tion. July 10, 2006. Retrieved from 2006. http://www.pharmaceutical-business-review. http://www.fda. . com/article_feature.asp?guid=6A311756-BFD0-4F94- gov/oc/speeches/2006/trialdesign0710.html 9D6B-7F3F514275A9. 10. BERRY DA. Bayesian clinical trials. Nat Rev Drug Discov, 2006; 5:27–36. Increasing Awareness and Access to Emergency Contraception Each year, approximately 750,000 to 850,000 In 2006, the Harlem Health Promotion adolescent women become pregnant in the Center (HHPC) began developing an United States, and of these pregnancies, 74 to 95 Emergency Contraception (EC) awareness percent are unintended or unwanted.1 Teenage campaign to address the dire need for enhanced mothers are less likely to receive timely prenatal contraception options amongst its high-risk care and are more likely to smoke during Black and Latino patient populations. To pregnancy. Babies born to teenage mothers are date, there is a defciency in culturally specifc at increased risk of low birth weight, pre-term and tailored intervention materials for this birth, serious chronic illnesses or developmental population, and research indicates high rates of delays.2 Due in part to these signifcant teen pregnancy coupled with a lack of awareness Jalan Washington, MPH, MSI outcomes, understanding teen pregnancy and about EC.6 This project titled “EC as 1, 2, 3” Advisor: Alwyn Cohall, MD assisting teens who wish to delay childbearing is utilizes community-based participatory research Columbia University Mailman an issue of increasing public health and medical and social marketing techniques. School of Public Health: Harlem importance. This model relied on a youth development Health Promotion Center, New Recent estimates suggest that approximately theory, and allowed youth to actively participate. York City Department of Health 46 percent of high school students and 80 For the summer of 2006, a group of 10 Black and Mental Hygiene, NY percent of college students between 18 and 24 and Latino “youth experts” between the ages have had sex.3 The National Longitudinal Study of 15 and 20 were selected to participate. These of Adolescent Health found that sexual activity “experts” assisted with major tasks, including during adolescence is associated with inconsistent incorporating the fndings of formative research or no use of contraception.4 Marginalized with experiential knowledge. The participants youth, including youth of color, youth in foster also worked with a Harlem-based flmmaker care, and low-income youth are more likely and design students from Parsons New School to be confronted with fnancial, cultural and of Design. Additionally, as the Youth Advisory institutional barriers to obtaining health care Board Coordinator, I developed and coordinated which may contribute to their increased risk of a comprehensive youth development curriculum negative sexual outcomes.5 Developing health which included leadership and professional programs to address teen pregnancy, especially among high-risk populations, is a major EMERGENCY CONTRACEPTION challenge requiring multi-level approaches. Continued on p. 40

Fusion • 2008 39 EMERGENCY CONTRACEPTION 4. MANLOVE J, RYAN S, FRANZETTA K. Contraceptive use and Continued from p. 39 consistency in U.S. teenagers’ most recent sexual relationships. Perspect Sex Reprod Health, 2004; development, critical social analysis and media 36:265–75. training for the affliated youth. 5. AUGUSTINE J, ALFORD S, DEAS N. Youth of color: at In May 2007, the project materials, which disproportionate risk of negative sexual health included an educational DVD, brochure, outcomes. Advocates for Youth, 2004. posters and Web site were launched for use with 6. COHALL AT, GUPTARAK M, BADI A. EC as 1, 2, 3 project the Center’s Mobile Health Team outreach to proposal. Harlem, NYC: Harlem Health Promotion high-risk youth and for use Center, 2005; 32. in training and educational sessions with medical, nursing, and public health students and clinical providers. The overall project succeeded in producing outstanding educational materials for youths. As one youth stated, “they were ready to hear our voice and make it an echo for change.” REFERENCES: 1. ABMA J, CHANDRA A, MOSHER WD, PETERSON L, PICCININO L. Fertility, family planning, and women’s health: new data from the 1995 national survey of family growth. Hyattsville, MD: National Center for Health Statistics; 1997. 2. VENTURA SJ, MATHEWS TJ, HAMILTON BE, VENTURA SJ, MATHEWS TJ, HAMILTON BE. Births to teenagers in the United States, 1940–2000. Natl Vital Stat Rep, 2001; 49:1–23. : For more information about Emergency Contraception, / Call 1-646-123-4567 or visitwww.ec123.org { 3. GRUNBAUM JA, KANN L, KINCHEN SA, ET AL. ~{:.._.... -·-.· . ·.. ·... :.__\j Youth risk behavior surveillance: United States, 2001. J School FIGURE 1: ADVERTISEMENT FOR “EC AS 1,2,3” CAMPAIGN Health, 2006; 72:313–28. FOR EMERGENCY CONTRACEPTION.

40 Fusion • 2008 travel abroad. . . Medical Relief Efforts in Jammu, India Since India attained independence in 1947, that approximately 25 percent of their monthly Jammu and Kashmir have been in a state of polit- income went toward diabetes medications and ical and social turmoil due to tensions between blood sugar testing for one person. Hindus and Muslims. In 1990, tensions between More valuable was learning about the lifestyle the groups peaked and many families had no changes each family made upon migration. Each choice but to leave their homes and start fresh. family was given a 10' by 15' room in which to Seventeen years later, Kashmiris are still trying live in. A group of about 10 families was expected to use one communal bathroom, one water pump and to live without Cherie-Priya Dhar, MSII privacy from their neigh- Global Health Track bors. In that one room, Advisor: K.L Chowdhury, MD children would sleep, Shriya Bhat Mission Hospital, play and study while Jammu, India their parents cooked and washed clothes. Health care was also a luxury. I remember coming across a man lying on the dirt foor in front of his quarter with a measured hemoglobin of 3 and fever of 104 degrees. His children, ages 10 and 8, stood above his head, his wife FIGURE 1: MOTHER BATHING HER DAUGHTER AT A WATER PUMP IN and mother pressing A MIGRANT CAMP IN JAMMU. his feet and legs. His elder brother stared at to get their lives back together and move on from him with fear in his eyes. His pale skin and weak, the terror they experienced. unmoving body made me think he was going to In the summer of 2007, I traveled with sup- pass away before me. The nearest hospital was port from the American Association of Physicians 20 miles away, and there was no ambulance to of Indian Origin to Jammu, India. Under the take him, nor were the funds available to pay for guidance of Dr. K.L. Chowdhury and his staff, his care. A previous doctor had recommended a I worked inside migrant camps and at the Shirya blood transfusion, but there was no Type A blood Bhatt Charitable Hospital in Jammu, India. type match in his family. Diabetes has increased in prevalence within As a medical student, I was unable to help. I the Kashmiri migrant community. About 25 could not offer any physical comfort. Instead, he percent of the adult population aged 18 and over gave something to me. He reaffrmed my reasons suffers from diabetes, and nearly 33 percent from for aspiring to become a physician: to provide hypertension. The clinic suggested gathering relief and support. I want to work in this type information on the management costs of dia- of community: where resources are sparse, and betes in terms of medications and monitoring, the need is great. Dr. Chowdhury and his staff as well as the type of diet and the current blood amazed me with their tireless efforts to aid this glucose levels. I prepared a survey and went to community and demonstrated how effort and the “quarters” of about 80 families and found passion can create positive change.

Fusion • 2008 41 A Place of Learning: The Mondaña Clinic, Ecuador During the three-hour canoe ride to Mondaña, these illnesses are being addressed and treated. the sun pierces through the dense foliage of the For example, because many of these communities Ecuadorian rain forest as the canopy rises and have no running or potable water, the Yachana falls along the river’s shore. My goals while in Foundation developed a cheap water fltration this beautiful setting were to involve myself in system to improve community sanitation the community healthcare system and patient and thereby reduced parasitic and bacterial population through education, conversation infections. To address insuffcient health and treatment. In the education, I spent quiet of the headwind, time teaching and I wondered what interacting with the M. Matthew Neimat, MSI challenges lay ahead. students from the local Global Health Track Advisor: Robert Morrow, The Mondaña Yachana High School. MD, MPH Clinic was started in I had the opportunity Mondaña Clinic, Yachana 1995 by The Yachana to discuss health and Foundation, Ecuador Foundation to address hygiene and to design the needs of a large, ✶ and implement a frst medically underserved responder and sex- population. The education course. Clinic, located along The Yachana the Upper Napo River Foundation was in the Ecuadorian started to address rain forest, now \ the health care needs serves local Mondaña Ecuador of the underserved

and 25 surrounding -•- P'OIW:lllleunclarr communities along --* --NtlionllCIPll;ol communities, with _ • ....., Pfow'QQP!al the Upper Napo a patient population --- River and has now ..,,... ___N of more than 10,000. broadened its focus These communities FIGURE 1: APPROXIMATE LOCATION OF THE to include education, are spread over a wide MONDAÑA CLINIC IN ECUADOR. eco-tourism, rain forest geographic area, many conservation, micro accessible only by canoe or long hikes, making enterprise and micro lending. The Foundation is access to health care diffcult. Nonetheless, the so deeply involved in the lives of the surrounding clinical staff makes regular visits. I traveled on communities that it has become an integral such a visit and was privileged to share meals part of health, education and preservation with families where I learned about the local of the Upper Napo River. This was a unique history, culture and health. The Mondaña opportunity for me to learn about and make Clinic is the cornerstone of health care in the an impact on the health care and education of area, and visits are a critical part of the Clinic’s a large, underserved community. I observed, responsibilities. They represent the beginnings frsthand, what one organization is doing to of a growing effort to provide for marginalized preserve one of the world’s richest biological populations within remote regions of Ecuador. resources and improve the lives of its inhabitants. In the Clinic, the lack of modern diagnostic It came as no surprise to me when I discovered technology forces doctors to rely on signs and that, in the indigenous Quichua language, the symptoms to differentiate diagnoses and treat word Yachana means, “a place of learning.” patients. I was challenged to learn these practical REFERENCES: skills promptly. During my time in the rain 1. Foundation for Integrated Education and forest, I saw a variety of illnesses, the most Development: Community Healthcare in the common of which were parasitic infections, Amazon Rain Forest. Retrieved from http://www. the common cold or gripe, and malnutrition. funedesin.org/html/health-care.htm. Accessed Oct. 8, I learned a great deal about the ways in which 2007.

42 Fusion • 2008 other abstracts. . . Development of a Longitudinal Genetics Curriculum Genetics is an ancient science. Yet, recently, with test were administered to third-year students the description of the DNA molecular structure during their OB/GYN clerkship. The curriculum and the completion of the sequencing of the in genetics reinforced genetic concepts learned human genome, much more information relevant in the frst two years of medical school and to the practice of medicine is being revealed. The introduced their clinical application. The cur- evolution of the feld from a basic descriptive riculum, administered through Blackboard®, was science of Mendelian genetics, drosophila and case-based using an organ-system approach, and other organisms, to cancer biology, molecular introduced students to relevant online genetics immunology, cardiovascular genomics and resources. Students were presented clinical pharmacogenomics has made the management vignettes on genetic diseases and answered clini- Nisha Chadha, MSII of curricula change in U.S. medical schools seem cally relevant questions about these disorders. Medical Education Track slow and fragmented. The ensuing gap between The curriculum was designed with principles Advisors: Karen Lewis, PhD; available information and knowledge of medical of adult learning theory to emphasize skills in Lisa Freese, MS; Charles self-directed learning. After com- J. Macri, MD; The George Pre-curriculum medical student surveys indi- pleting the curriculum, students Washington University, took a post-test and their scores Washington, DC cated defcient knowledge and comfort with were compared to their pre-test genetics. Ninty-seven percent of the students were scores. Students then completed an exit survey. In the pilot study, comfortable speaking with patients about family 17 students completed the needs assessment, and pre- and post-test. history, but 31 percent did not feel comfortable Twelve of 17 students showed improved scores, with a mean discussing a diagnosis of a genetic disease. increase of 11.5 percent. Five of 17 failed to demonstrate improvement, students, residents and practitioners, poses a chal- with a mean decline of 4.5 percent. lenge for teaching and the dissemination of this Pre-curriculum medical student surveys vital information. indicated defcient knowledge and comfort with Although most medical schools have devel- genetics. Ninety-seven percent of the students oped genetics courses for frst- and second-year were comfortable speaking with patients about medical students, the integration of basic science family history, but 31 percent did not feel com- and clinical medicine has lagged. In addition, fortable speaking about a diagnosis of a genetic exposure to genetics in the early years of medical disease. In the exit survey, students expressed the school and having to recall and apply it in the need for a more robust genetics education cur- clinical years is a diffcult task for most students. riculum beginning in the second year. They indi- This educational shortcoming calls for the imple- cated overall satisfaction with our experimental mentation of a genetics curriculum for medical curriculum, particularly the online resources, and students in their clinical years. Addressing this recommended its future use. disparity in genetics education during the med- The addition of this curriculum into the cur- ical school years can improve the knowledge base of future clinicians in these regards. rent GW SMHS curriculum would make medical In recognition of this educational defcit, genetics education more longitudinal, reinforce researchers at The George Washington University genetics concepts in a clinical setting, and assist School of Medicine and Health Sciences (SMHS) students in developing self-directed learning skills designed a genetics curriculum for third-year to be better equipped to fnd genetics information medical students. A needs assessment, and throughout their careers. The curriculum will pre- and post-test about medical genetics was be administered to 180 GW medical students developed. As a pilot study, the survey and pre- between July 2007 and June 2008.

Fusion • 2008 43 index. . .

BASIC SCIENCE ABSTRACTS Hip Arthroscopy and the Treatment of Femoroacetabular What Role Do Androgens Play in Bone Growth? Impingement, Cory M. Czajka, MSII ...... 26 Adrian A. Woo, MSI ...... 6 Novel “Non-Fusion” Technologies May Help Patients with Anti-Proliferative Properties of Tymosin Fraction 5 Spinal Stenosis, David Goodwin, MSII ...... 27 in HL-60 Human Promyelocytic Leukemia Cells, Efect of Bone Density on Mechanical Properties after Ali A. Damavandy, MSI ...... 7 Percutaneous Vertebroplasty, Nabila Hai, MSII ...... 28 ER-targeted Bcl-2 Mitigates Ethanol Toxicity More Identifying the Correlation between Pseudo-bulbar and Signifcantly than Wildtype or Mitochondria-targeted Bcl-2, Cognitive Impairment in Primary Lateral Sclerosis, Andreea G. Balan, MSI ...... 8 Kimberly N. Capers, MSII ...... 29 A New Focus in Breast Cancer Bone Metastasis: NF-κB Gene Clopidogrel in a Pediatric Population: Safety and Efcacy Suppression, Andrew H. Gordon, PhD, MSII ...... 9 Results from a Single Center, Lily A. Maltz, MSI ...... 30 Certain Piperazines Mimic Stimulant or Hallucinogenic Development of Class I HLA Typing Assay for HIV Clinical Efects of Ecstasy, Elyse Katz, MSI...... 11 Trials in East Africa, Olalesi Osunsade, MSI ...... 31 Anatomical Bases for Auditory Projections Gastric Stimulation for Vomiting, Nausea and Related to Suprasylvian Visual Areas in the Cat Cerebral Cortex, Symptoms Associated with Gastroparesis Using Giriraj K. Sharma, MSI...... 12 Enterra™ Gastric Stimulation System, A Role for Chemokine Gene Variants in Muscle Strength?, Ricky Singh Harika, MSII ...... 33 Kasra Adham, MSII; Justin Larkin, MSII; Breast-Specifc Gamma Imaging as an Adjunct and Ronak Patel, MSII ...... 14 Modality for the Diagnosis of Invasive Breast Cancer, Cloning and Expression of Human Adenovirus Precursor Rigved V. Tadwalkar, MSII ...... 34 Protein VI and Mature Protein VI, Michelle Louie, MSI .15 Religious Experience in Epilepsy, Te Role of Retinoic Acid in Neuronal Phenotype Shivani M. Bhatt, MSII...... 35 Determination, Negin Daneshpayeh, MSI ...... 16 A Geometrical Forefoot Model: Relationship to Foot Function, A Potential Role for DHEA in Prostate Cancer, Steven V. Kardos, MSII ...... 37 Patricia Reutemann, MSII ...... 17 Middle Ear Epithelial Cell Secretion of Cytokines with PUBLIC HEALTH ABSTRACTS Cigarette Smoke Condensate Exposure, Samaneh Ashktorab, MSII ...... 18 Barriers to Terapeutic Cancer Vaccine Development, Robert C. Ward, MSII ...... 38 Development of an In Vitro Model of Respiratory Tract Increasing Awareness and Access to Emergency Contraception, Submucosal Glands, Sumit Bose, MSII ...... 19 Jalan Washington, MPH, MSI ...... 39 A Tree-Dimensional Model of Epicardial Development, Tresa L. Nesbitt, PhD, MSI ...... 21 TRAVEL EXPERIEINCES CLINICAL RESEARCH ABSTRACTS Medical Relief Eforts in Jammu, India, Cherie-Priya Dhar, MSII ...... 41 Improving MRI Detection of Creutzfeldt-Jakob Disease, Andrew Degnan, MSI ...... 22 A Place of Learning: Te Mondaña Clinic, Ecuador, M. Matthew Neimat, MSI ...... 42 Small Molecules that Induce p53 Signaling in Retinoblastoma Preclinical Animal Models, Audra K. Miller, MSII . . . . 23 OTHER ABSTRACTS Surgical Correction of Spinal Deformities after Heart Transplantation: A Case Series Report, Development of a Longitudinal Genetics Curriculum, Brian Kaufman, MSII ...... 24 Nisha Chadha, MSII ...... 43

44 Fusion • 2008 Fusion is the annual student-run scientific iournal of the GW William H. The Beaumont Medical Research Society created to showcase student achievements in basic science and clinical research, public health, medical edu­ cation and international health-related travel experiences. Submissions for next year's issue of the iournal will be accepted beginning September 2008 from the Class of 2011 as well as the incoming Class of 2012. More information about the submission process will be provided during the summer of 2008. If students have any questions or comments, please contact the Beaumont Society at [email protected]. Contributions to the publishing costs of this iournal are appreciated. If you would like to make a donation, please con- tact us at [email protected]. All proceeds will go toward the publishing costs for next year's iournal. FUSi ON 13THANNUAL GWUMC RESEARCH DAY, MARCH 12, 2008

THE GEORGE WASHINGTON UNIVERSITY MEDICAL CENTE R

WASH IN GTON DC 2300 Eye Street, NW Ross Hall, Suite 713 -W Wash ington, DC 20037