Department of Internal Medicine

Michael Grever, MD, Chair

The Department of Internal Medicine comprises 12 divisions, each dedicated to innovations in research, education and patient care. Following are division descriptions and research highlights for 2006:

Division of Cardiovascular Medicine

William Abraham, MD, Director In partnership with patients, researchers and healthcare professionals, Cardiovascular Medicine conducts clinical trials on new cardiovascular drugs, devices and therapies. The Division’s Cardiovascular Clinical Research Unit (CCRU) enables clinical researchers and basic scientists to work together to improve patient care and outcomes. The CCRU manages more than 80 clinical research projects, including investigator-initiated single-site studies, multi-site trials sponsored by the National Institutes of Health, and industry-sponsored trials. Studies span heart failure, interventional cardiology, electrophysiology, pulmonary hypertension, sleep disorders, emergency medicine, and cardiac imaging and genotyping. By linking Ohio State’s Ross Heart Hospital with the University’s Davis Heart and Lung Research Institute, faculty members have advanced patient care through research. Investigators and research staff identify patients who may be candidates for specific protocols, then follow them closely throughout the studies, usually for several years. Results from these studies form the basis for standard-of-care practices and identify additional questions for translational and basic research.

Ongoing Research Programs

Heart failure and a controlled trial investigating outcomes of exercise training (HF-ACTION) PI: William Abraham, MD
Multicenter automatic defibrillator implantation trial II (MADIT II) PI: Charles Love, MD
Implantable cardioverter defibrillator (Chronicle ICD) PI: Garrie Haas, MD
The role of diagnosis and treatment of sleep apnea in the acute exacerbation of heart failure PIs: Rami Khayat, MD, and William Abraham, MD
Trial to assess chelation therapy (TACT) PI: Raymond Magorien, MD

Research Accomplishments of 2006

One major accomplishment has been the development of the Cardiovascular Clinical Research Unit (CCRU) as a model for clinical research at OSUMC and as a national leader in investigating new cardiovascular drug and device therapies. CCRU leaders are working with hospital revenue cycle management to formalize a billing process for clinical research. They also are working with the Medical Center’s Information Warehouse and the Department of Biomedical Informatics to design computer-based research-screening processes.
Physicians at Ohio State’s Ross Heart Hospital use a minimally invasive cardiac catheterization procedure to implant the nation’s first permanent device for monitoring and treating congestive heart failure. This investigational device, called the HeartPod (Savacor, Inc.), allows patients to monitor and change their treatment regimen, if needed, based on specifications pre-set by their physician. Ohio State was the first site in the United States to implant the HeartPod, and it continues to be the highest enrolling site with seven patients. Garrie Haas, MD, is the local principal investigator; Charles Bush, MD, medical director of the Ross Heart Hospital, and Charles Love, MD, director of CV Device Services, conduct the implants; and William Abraham, MD, is the national principal investigator. In 2006, Love was selected as the first electrophysiologist in the world to implant the device using a subclavian approach that allows for easier access through the chest as opposed to implanting through the leg.
The Sleep-Heart Program, a multidisciplinary clinical and research program led by William Abraham, MD, was initiated. Leadership is also provided by Philip Binkley, MD, and Garrie Haas, MD, from Cardiovascular Medicine, and Rami Khayat, MD, from the Division of Pulmonary, Allergy, Critical and Sleep Medicine. The program spans Ohio State’s Ross Heart Hospital, the Sleep Disorders Center at University Hospital East, Ohio State’s School of Public Health, and Ohio State’s Davis Heart and Lung Research Institute. The program examines translational and clinical questions that focus on the relation between respiratory disorders of sleep and cardiovascular diseases. Research tracks include: sleep apnea and autonomic control in patients with heart failure; effects of intermittent hypoxia on the heart; clinical outcomes of treatment of sleep apnea and heart failure; vascular consequences of oxidative stress in sleep apnea; and lipid metabolism in sleep apnea. The program is positioned to study questions about cardiovascular consequences of sleep disorders.
The Division’s Cardiovascular Clinical Research Unit (CCRU) continued to grow through the development of clinical research core lab facilities in cardiac stress testing, cardiac MR/CT and noninvasive imaging. Additionally, the Division and the CCRU experienced unprecedented growth in electrophysiology by adding five physicians who transferred approximately 20 clinical research studies with hundreds of active research subjects. This gives the Division one of the largest clinical research groups at OSUMC.

Division of Dermatology

Mark Bechtel, MD, Director

The Division of Dermatology collaborates with the Division of Hematology and Oncology in clinical management, clinical trials and oncologic genetic research focusing on cutaneous lymphoma and cutaneous oncology. Dermatology is also collaborating in a new cutaneous oncology focus group involving dermatology, hematology and oncology, surgical oncology, dermatopathology and cutaneous oncology researchers at Ohio State. A new cutaneous oncology dermatologic surgical facility provides more space for micrographic surgery on cutaneous malignancies. A complex medical dermatology clinic enables dermatology residents to evaluate and manage patients with autoimmune bullous diseases, collagen vascular disease and severe psoriasis. Matthew Zirwas, MD, has joined Dermatology and established the Contact and Occupational Dermatitis Center. Mark Bechtel, MD, was recognized in the 2005-2006 “Best Doctors in America.” He also serves on the American Academy of Dermatology’s Guidelines and Standards of Care Task Force. Zirwas was elected to the board of directors of the American Contact Dermatitis Society.

Ongoing Research Programs

David Lambert, MD, is collaborating with Ronald Glaser, PhD, director of the Institute for Behavioral Medicine Research at Ohio State, in a study funded by the National Institutes of Health on the effects of stress on basal cell carcinoma.
David Lambert, MD, is collaborating with Amanda Tolland, PhD, of Molecular Virology, Immunology and Medical Genetics, in the study of molecular genetics of squamous cell carcinoma.

Division of Digestive Health

Nicholas Verne, MD, Director

After a major recruiting effort throughout 2006, the Department of Internal Medicine selected Nicholas Verne, MD, to direct the Division of Digestive Health. Verne is a nationally known, grant-funded physician scientist who will be responsible for building a comprehensive research program in gastroenterology. Also in this Division during 2006, Sumei Liu, PhD, continued her work with Jackie Wood, PhD, of the Department of Physiology and Cell Biology, to advance understanding of neurophysiologic control of mammalian gastrointestinal functions in health and disease states. John Fromkes, MD, continued his research in conjunction with Gary Stoner, PhD, of the Division of Hematology and Oncology, to examine the cancer-inhibiting properties of black raspberries in people at high risk for esophageal cancer.

Division Accomplishments in 2006

The most significant accomplishment was completing planning and starting construction of office facilities and a state-of-the-art endoscopy unit, both targeted for completion by the end of fiscal year 2007. Additional planning was completed for construction of an outpatient clinic within the new Digestive Health space. These facilities will be a key to faculty recruitment and the growth of a comprehensive research program in gastroenterology.

Division of Endocrinology, Diabetes and Metabolism

Kwame Osei, MD, Director

The Division of Endocrinology, Diabetes and Metabolism continues to excel in research, teaching and patient care. Endocrinology at Ohio State University Hospitals was cited for the 13th time among the Best Divisions in Hormonal Disorders by U.S.News & World Report. The Division will expand its accomplishments through research in diabetes, islet cell transplantation, osteoporosis and bone diseases, thyroid cancer and benign thyroidpituitary disorders.

Ongoing Research Programs

Non-Human Primate Experimental Model of Islet Cell Transplantation (ICTP) (Elizabeth Diakoff, MD)
Women’s Health Initiative (WHI) and Osteoarthritis Initiative (OAI) (Rebecca Jackson, MD)
Diabetes Research Center (DRC) (Kwame Osei, MD)
Thyroid Cancer Program at the Martha Morehouse Medical Plaza (Matthew Ringel, MD)

Research Accomplishments of 2006

In conjunction with the Department of Surgery’s Division of Transplant Surgery, the Division of Endocrinology, Diabetes and Metabolism has established a Non–Human Primate Experimental Model of Islet Cell Transplantation (ICTP). The success of this phase of the program has become the backbone of the human ICTP initiative. Objectives are to develop therapies to ensure long-standing islet cell functional survival in humans by immunoprotection and to promote islet cell growth and anti-apoptosis.
The Division supports two prestigious NIH Centers: the Women’s Health Initiative (WHI) and Osteoarthritis Initiative (OAI). Given the strengths of these centers, the Division has recruited new faculty in bone epidemiology.
The College of Medicine’s Executive Committee approved a business plan to establish a Diabetes Research Center, which will develop treatment strategies for sustaining functional islet cell transplantation (ICTP) and pancreas allograft transplantation (PAT), diabetes and cardiovascular disease, and prevention of type 2 diabetes. A Community Diabetes Program also will be developed.
In conjunction with Ohio State’s Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute, the Division has established a Thyroid Cancer Program at the Martha Morehouse Medical Plaza. This program aims to: define the molecular basis of thyroid cancer growth and metastasis; develop chemotherapies as an adjunct for radioiodine and thyroxine therapy; and develop a translational research program in thyroid cancer.

Division of General Internal Medicine

Catherine Lucey, MD, Director

The Division of General Internal Medicine provides comprehensive patient care to an increasingly complex community of patients while educating the next generation of physicians. Division members have achieved local and national recognition for patient care and educational leadership roles. They are also involved in numerous research projects. The Division is strongly focused on medical education. Numerous faculty are recognized as educational leaders in department and college activities. Leadership positions assumed by Division members include directorship of the new Office for Scholarship in Medical Education, chair of the College of Medicine Professionalism Education and Evaluation Committee, co-directorship of the Med 3/4 curriculum, and directorship of the new Meaning in Medicine course for medical students. Division physicians have authored multiple book chapters on topics ranging from physical diagnosis to clinical decision-making, perioperative issues and the educational approach to dealing with problem residents.

Ongoing Research Programs

Point of service testing in diabetes and anti-coagulation management – Mark Wurster, MD
Faculty development of community-based primary care preceptors in underserved communities – Cynthia Ledford, MD
Comparison of medical student and volunteer senior partner expectation for a regional senior partner experience in medical school – Robert Murden, MD

Research Accomplishments of 2006

Cynthia Kreger, MD, continued production of history-taking and physical exam cases for educational CDs. These are used in classes at Ohio State and sold nationwide.
The faculty development proposal by Cynthia Ledford, MD, was funded for more than $200,000, the largest grant ever obtained by a principal investigator in the Division of General Internal Medicine.
Almost half of the faculty was involved in research projects.
Cynthia Ledford, MD, received a Health Resources and Services Administration grant as principal investigator for developing a virtual classroom to help community-based faculty enhance their teaching skills.
Mitchell Medow, MD, was a core participant in a T32 training grant to increase the number of health professionals with formal education in clinical investigation. He also continued his work on the use of decision-making aids by physicians.
Harrison Weed, MD, co-edited a textbook on perioperative medicine.
Mark Wurster, MD, was involved with several projects on point-of-service testing for management of chronic medical conditions.
Cynthia Kreger, MD, Robert Murden, MD, and Mark Wurster, MD, continued to participate in Health Resources and Services Administration grants with colleagues in the Department of Family Medicine.

Division of Hematology and Oncology

Michael Caligiuri, MD, Director

Research in the Division of Hematology and Oncology focuses on developing drug therapies for treating solidtumor and hematologic malignancies, and on cancer prevention through nutrition and natural products. 2006 was productive for the Division as evidenced by the growth in direct research funding. Most notably, Miguel Villalona, MD, was awarded a $3 million phase II clinical trials contract from the National Cancer Institute (NCI), placing Ohio State in a group of only five other cancer institutions in America that have received NCI contracts for both phase I and phase II clinical trials. In addition, Charles Shapiro, MD, was awarded a $1.25 million grant from The Lance Armstrong Foundation to establish a cancer survivorship center at Ohio State that will work to improve the care and quality of life of cancer survivors. These and other grant awards are highlighted below in the Division’s 2006 research accomplishments.

Ongoing Research Programs

Phase I Trials of Anticancer Agents – This program seeks to perform early drug development in solid and hematologic tumors with performance of detailed pharmacokinetic and pharmacodynamic studies – Michael Grever, MD
Early Therapeutics Development with Phase II Emphasis – This program studies National Cancer Institute-sponsored novel anticancer agents in phase II clinical trials – Miguel Villalona, MD
Comprehensive Program for the Prevention, Detection and Treatment of Lung Cancer – This program investigates inhalation programs for the prevention and detection of cancer. Several novel biomarkers for easy detection and innovative imaging modalities have been tested and developed – Gregory Otterson, MD
Experimental Therapeutics in Chronic Lymphocytic Leukemia – This Specialized Center of Research (SCOR) grant is being used to create new and improve current therapies for chronic lymphocytic leukemia – John Byrd, MD
Epigenetic Targeted Therapy for Chronic Lymphocytic Leukemia – This program is developing targeted therapies for chronic lymphocytic leukemia and lymphoproliferative disorders – John Byrd, MD

Research Accomplishments of 2006

Miguel Villalona, MD, received a $3 million phase II contract in early therapeutics development from the National Cancer Institute.
Charles Shapiro, MD, was awarded a $1.25 million grant from The Lance Armstrong Foundation to establish a cancer survivors center at Ohio State that will improve the care and quality of life of cancer survivors.
Michael Grever, MD, is co-principal investigator (PI) for an $11.84 million program project grant awarded by the National Cancer Institute for “DNA methylation & chromatin modifications: mechanisms & applications in cancer therapy.” PI for this grant is Samson Jacob, PhD, of Molecular and Cellular Biochemistry.
Robert Baiocchi, MD, PhD, received a V Foundation Scholar Award to study Epstein-Barr virus-associated malignancies.
Kristie Blum, MD, was awarded a National Cancer Institute grant targeting transcriptional repression in chronic lymphocytic leukemia.
William Blum, MD, received a National Cancer Institute grant to help develop experimental therapeutics in adult leukemia.
Steven Clinton, MD, PhD, landed a National Cancer Institute grant to study the effects of tomato-soy juice on prostate cancer.
Thomas Lin, MD, PhD, was awarded a National Cancer Institute grant to study the efficacy of Flavopiridol in treating B-cell non-Hodgkin lymphoma.
Guido Marcucci, MD, received a National Cancer Institute grant to research the pharmacologic modulation of chromatin remodeling in leukemia.
Manisha Shah, MD, was awarded a National Cancer Institute grant for focusing on targeting RAF and VEGF signaling in thyroid cancer.
Clara D. Bloomfield, MD, received the Distinguished Service Award for Scientific Achievement from the American Society of Clinical Oncology. She also was elected president of the Association for Patient Oriented Research and was named a Distinguished University Professor, Ohio State’s top faculty award.
John Byrd, MD, was one of five researchers selected to receive the Leukemia & Lymphoma Society’s Stohlman Scholar Award for outstanding contributions in blood cancer research.

Division of Human Genetics

Albert de la Chapelle, MD, PhD, Interim Director

The Division of Human Genetics (HG) serves as a single platform for translational and clinical research, clinical activities, and education and outreach. Its goals are to enhance The Ohio State University Medical Center as a leader in gene discovery/characterization and molecular epidemiology, to set standards for the clinical management of patients with genetic predisposition, and to set guidelines for society regarding the research and clinical usage of genetic information. Its clinical responsibilities are to provide genetic counseling to patients and families, and expert consultations to physicians and other professionals. HG not only provides adult medical genetics care to residents of central Ohio and beyond, but it also gives patients and physicians in the community free access to HG research protocols. HG coordinates clinical-genomic databases, specimen repositories and the use of both inhouse and referral diagnostic facilities to support clinical research in human genetics.

Ongoing Research Programs

Columbus-area HNPCC (hereditary nonpolyposis colon cancer) study – Albert de la Chapelle, MD, PhD
Variants in high-risk breast cancer genes and contribution to cancer risk – Amanda Toland, PhD
Frequency and clinical spectrum of germline PTEN mutations in a population-based series of incident breast cancer cases in central Ohio – Charles Shapiro, MD
Study to identify multiple human low penetrance genes that control genetic susceptibility and resistance to cancer – Kevin Sweet, MS, CGC, and Amanda Toland, PhD

Research Accomplishments of 2006

Heather Hampel, MS, CGC, and Albert de la Chapelle, MD, PhD, along with other members of the Human Genetics (HG) staff, published the findings of the Columbus-area HNPCC study with regard to the screening of 543 newly diagnosed endometrial cancer patients in the journal Cancer Research in August 2006. As a result of this study, the Ohio State University Pathology Department and Gynecologic Oncology Division, in conjunction with the Division of HG, has begun performing immunohistochemistry staining for the four mismatch repair proteins on all newly diagnosed endometrial cancer patients at Ohio State University Medical Center as a clinical billable service.
Rebecca Nagy, MS, CGC, is collaborating with Gail Herman, MD, PhD, (Columbus Children’s Hospital) on her Ohio Department of Health Services grant titled Regional Genetics Center at Children’s Hospital. Nagy participates in a statewide directory and speaker’s bureau giving presentations on cancer genetics.
Kimberly Kelly, PhD, received funding from the Tzagournis Endowment Trust Fund to support a Cancer Family History Public Health Campaign ($99,996). Judith Westman, MD, along with Amy Sturm, MS, CGC, and Kevin Sweet, MS, CGC, are also involved in this project. This campaign promotes awareness of the importance of family history of cancer and gives the public tools to gather, evaluate and use family history to learn more about their cancer risk.

Division of Immunology

Ronald Whisler, MD, Director

The Division of Immunology makes advances in academic excellence and research while serving the University and the community in the clinical setting. The Division’s publications and peer-reviewed grants demonstrate considerable strength, with Kevin Hackshaw, MD, and Clark Anderson, MD, participating as co-investigators on program project grants. Anderson furthered his National Institutes of Health (NIH)-supported studies of Fc receptors. Kevin Hackshaw and Ronald Whisler, MD, serve as co-principal investigators with Rebecca Jackson, MD, on the Osteoarthritis Initiative funded by NIH. Division members also have been conducting clinical investigations into more efficacious treatment regimens for rheumatoid arthritis, systemic lupus erythematous, fibromyalgia, osteoporosis and osteoarthritis.

Ongoing Research Programs and Research Accomplishments of 2006

FcRn Binds and Transports Albumin – Clark Anderson, MD
Clinical Centers for the Osteoarthritis Initiative – Kevin Hackshaw, MD and Ronald Whisler, MD
Phase III randomized, double-blind, placebo-controlled, multicenter study of retreatment with rituximab in subjects with rheumatoid arthritis receiving background methotrexate – Kevin Hackshaw, MD
A randomized, phase 3, controlled, double-blind, parallel group, multicenter study to evaluate the safety and efficacy of rituximab in combination with methotrexate (mtx) compared to mtx alone in methotrexate-naive patients with active rheumatoid arthritis - Ronald Whisler, MD and Kevin Hackshaw, MD

Division of Infectious Diseases

Larry Schlesinger, MD, Director Faculty in the Division of Infectious Diseases (ID) continued their commitment to research in 2006 by submitting 27 grants. Active funding included $13.97 million from the National Institutes of Health (NIH), the Health Resources and Services Administration (HRSA), and the Department of Health and Human Services to support research for patients with HIV/AIDS. The Division’s NIH-awarded AIDS Clinical Trials Unit (ACTU) ranked highly among research awards across the University in 2006, and its HRSA AIDS Education and Training Center continued to thrive. The Center for Microbial Interface Biology (CMIB) was awarded Center status by the Ohio State University Board of Trustees. The CMIB’s multidisciplinary educational and research programs explore fundamental questions about infectious diseases, microbial pathogenesis, bioterrorism and disaster preparedness. Research awards for core CMIB members totaled $5.55 million. Major research areas within the Division include HIV/AIDS, fungal infections, infections in the immunocompromised host, tuberculosis, parasitic infections, epidemiology and food-borne infections.

Ongoing Research Programs

Adult AIDS Clinical Trials Unit (ACTU) – Led by Susan Koletar, MD, this unit is part of a national and international multicenter group that conducts clinical trials to increase knowledge about the pathogenesis, prevention, course and treatment of HIV infection and associated complications.
Epi-Centers for Prevention of Healthcare Related Infections, Ohio State Health Network Infection Control Collaborative – Under the leadership of Kurt Stevenson, MD, MPH, this collaborative includes Ohio State and 14 outreach sites that optimize electronic health information systems to improve surveillance for healthcare-associated infections, antimicrobial resistance and other adverse biological events.
Great Lakes Regional Center of Excellence in Biodefense and Emerging Infectious Disease Research – This program, funded by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases, awarded Ohio State a grant titled “Lung innate immune responses to Francisella tularensis: a central role for the macrophage.” The grant, led by Larry Schlesinger, MD, includes four projects conducted by investigators in the Center for Microbial Interface Biology at Ohio State and by Ohio State’s Davis Heart and Lung Research Institute. The researchers are exploring lung immune responses to these bacteria – especially as they relate to interactions with macrophages – to identify molecular targets for new diagnostic strategies as well as targeted immune therapies aimed at enhancing host immunity.
CD8 T Cells and Immunity to Tuberculosis in Old Mice – Joanne Turner, PhD. This study, funded by the National Institute of Allergy and Infectious Diseases, explores how the aging immune system response differs from that of younger individuals when it encounters a pathogen. This knowledge will help design a vaccine or post-exposure therapy to protect the elderly from infectious disease.

Research Accomplishments of 2006

The AIDS Clinical Trials Unit (ACTU) at Ohio State advances AIDS care via research on the pathogenesis, prevention, course and treatment of HIV infection and associated complications through affiliation with the national and international AIDS Clinical Trials Group (ACTG). The ACTU was refunded in December 2006 for $11.9 million over seven years. By playing leadership roles for protocol development and administration of the ACTG, Ohio State participates in the design and implementation of clinical trials that seek to optimize clinical management of HIV and related complications, evaluate agents with novel mechanisms or improved toxicity profiles for treating HIV and/or major co-pathogens (e.g., tuberculosis and hepatitis), evaluate the safety, immunogenicity and efficacy of multiple candidate HIV vaccines and adjuvants, develop means of reducing HIV transmission, and minimize the risk of vertical transmission by maximizing care of HIV-infected women during child-bearing years.
The national Centers for Disease Control designated Ohio State as one of five (in the country) Epi-Centers for Prevention of Healthcare-Related Infections, a five-year project funded at $1.97 million. This Ohio State Health Network Infection Control Collaborative includes the University and 14 outreach sites that improve surveillance for healthcare-associated infections, antimicrobial resistance and other adverse biological events by optimizing available electronic health information systems. This enables facilities to focus less on data collection and more on improving processes and outcomes, particularly in small community hospitals where staffing and other resources are limited. Through the Ohio State University Health System, the Ohio State Health Network and the Ohio State University Information Warehouse, health information will be surveyed for targeted events, retrospective comparison of electronic with traditional surveillance, and prospective validation of surveillance methodology for accuracy and cost efficiency.
OSU Center for Microbial Interface Biology (CMIB) – In 2006 the CMIB (which includes leadership from the Division of Infectious Diseases) grew to 55 faculty campuswide and nearly 50 core personnel in the Biomedical Research Tower (BRT), and was awarded University Center status by the Board of Trustees. Research funding for core CMIB members in the BRT totaled $5.55 million, with $10.55 million in review.The CMIB is a member of the Great Lakes Regional Center of Excellence in biodefense and emerging infectious disease research. It also serves as a centerpiece for collaborations in research and education with units/departments across the University. A Provost Targeted Investment in Excellence program was awarded in Public Health Preparedness for Infectious Diseases to Larry Schlesinger, MD, College of Medicine, in conjunction with the colleges of Public Health, Veterinary Medicine, Biological Sciences, Pharmacy, and Food, Agriculture and Environmental Sciences. The award totals $979,068 to the College of Medicine/Division of Infectious Diseases. Also in 2006, CMIB faculty in the BRT had 20 papers published or in press, along with numerous published abstracts, invited lectureships and review panel appointments, both nationally and internationally.
Great Lakes Regional Center of Excellence (GLRCE) in Biodefense and Emerging Infectious Diseases Research – Investigators in Ohio State’s Center for Microbial Interface Biology (CMIB) and the Division of Infectious Diseases received a fiveyear grant totaling $546,877 from the GLRCE to study lung innate immune responses to Francisella tularensis, the causative bacterium of tularemia and a targeted agent of bioterrorism. The most worrisome infectious agents of bioterrorism would be artificially disseminated as aerosols to the lungs. Thus, a clearer understanding of lung immune responses to these bacteria, especially as they relate to interactions with macrophages, is essential for identifying molecular targets for new diagnostic strategies and targeted immune therapies aimed at enhancing host immunity. This project involves investigators in both the CMIB and Ohio State’s Davis Heart and Lung Research Institute.
CD8 T Cells and Immunity to Tuberculosis in Old Mice – The elderly are more susceptible to infectious diseases, but vaccinating them is less effective when using vaccines designed for young individuals. To design a vaccine or post-exposure therapy that can protect the elderly, it is necessary to understand how the aging immune response reacts to pathogens. Using an aging mouse model of tuberculosis, researchers have found that old mice express a transient early resistance to infection that correlates with the presence of CD8 T cells within the lungs – a previously unrecognized immune mechanism that is absent from the lungs of young mice. Joanne Turner, PhD, will use a low-dose aerosol infection model of tuberculosis to further characterize this CD8 T cell population and determine when CD8 T cells become more active in the lungs of old mice, as well as the mechanism by which CD8 T cells mediate early resistance.

Division of Nephrology

Brad Rovin, MD, Director

Investigators collaborating on the Nephrology Program Project on SLE nephritis – Lee Hebert, MD, Brad Rovin, MD, Dan Birmingham, PhD, and Chack- Yung Yu, PhD – were invited to resubmit a competitive renewal to the National Institute of Diabetes and Digestive and Kidney Diseases. They have now published more than 40 original papers and review articles on lupus nephritis and placed four abstracts at the 8th International Congress on Systemic Lupus Erythematosus (SLE) in Shanghai, China. Rovin and Hebert are participating in four clinical trials of novel therapeutic agents for the treatment of SLE and are active members of the Lupus Clinical Trials Consortium. Clinical trials run by Anil Agarwal, MD, Nabil Haddad, MD, Hebert, Dan Spetie, MD, Ganesh Shidham, MD, Rovin, Todd Pesavento, MD, and Jon Von Visger, MD, PhD, brought more than $1.5 million in research funding to the Division.

Ongoing Research Programs

SLE Program Project in Human Lupus Nephritis – This work examines clinical, genetic and novel biochemical risk factors for the onset, severity and prognosis of lupus nephritis flare.
The African-American Study of Kidney Disease and Hypertension (AASK) – This is an NIH-sponsored clinical trial of risk factors for kidney disease and hypertension in African-Americans.
The Lupus Clinical Trials Consortium (LCTC): Through this consortium, the Division of Nephrology participates in multicenter, international trials of new therapeutics for lupus and lupus nephritis.
Clinical Research in Transplantation – The Transplant Center has initiated two large prospective clinical trials. One looks at reducing complications of steroid therapy in renal transplant recipients, and the other examines homocysteine as a cardiovascular risk factor for renal transplant patients.
Clinical Anemia Program: The Nephrology clinical trials unit is involved in studies to define the best approaches to anemia management in patients with chronic kidney disease.

Research Accomplishments of 2006

The Program Project in Lupus Nephritis has provided novel insights into human SLE. Studies on the role of the complement system in the pathogenesis of lupus have revealed four important findings. First, variability in gene copy number of the fourth complement component (C4) is an important risk factor for onset of SLE. Specifically, low C4 gene copy number predisposes to lupus onset, while high copy number provides protection. Second, genetically determined low copy number of erythrocyte complement receptor-1 (ECR1), which interacts with complement-coated immune complexes in circulation, is associated with onset of renal manifestations of lupus. Third, E-CR1 function during SLE flare protects the kidney from damage mediated by immune complexes and complement. Fourth, the pattern of complement activation prior to and at the onset of SLE flare suggests the involvement of two complement activation pathways: the classical pathway during renal flare initiation, and the alternative pathway driving actual renal tissue damage. These data underscore the importance of the complement system, both in protecting against the onset of SLE and its manifestations, and in driving the tissue damage that defines the clinical presentation of SLE nephritis.
Adiponectin, an adipocyte-derived cytokine thought to play a role in metabolic disorders such as obesity and diabetes, has been identified as a potential biomarker of lupus nephritis. To understand the relationship between this novel cytokine and lupus, scientists launched studies to determine its potential as a modulator of inflammation. Although existing literature suggests that adiponectin may have anti-inflammatory properties, Ohio State scientists have shown that this adipokine can induce the expression of proinflammatory chemokines by endothelial cells and monocytes. They also have shown that adiponectin is present in the kidneys of patients with lupus nephritis, and that its RNA expression is upregulated compared with control renal tissue. In addition, a known adiponectin receptor is present on glomerular podocytes. These findings demonstrate that adiponectin can be made in organs other than adipose tissue, and that the expression of ligand and receptor in the glomerulus suggests a role for adiponectin in modulating glomerular function. A potential effect of adiponectin in lupus may be to augment inflammation through induction of proinflammatory cytokines. This remains to be demonstrated and is part of an ongoing effort to define the role of adiponectin in lupus nephritis.
Clinical studies of extended dosing of darbopoietin showed that it is possible to increase the dosing interval of this drug to once a month. This finding is likely to impact the care and quality of life of patients with chronic kidney disease and anemia who are not yet on dialysis. Darbopoietin was effective at extended dosing intervals in adults and older patients with anemia of chronic kidney disease. Less frequent dosing has the potential to decrease resource utilization and medication errors while enhancing patient comfort and convenience.
The Transplant Center has initiated a prospective trial to eliminate steroids as a chronic maintenance agent for renal transplant recipients. This study could help minimize steroid complications, which are a major source of morbidity in the renal transplant population. The Transplant Center is also one of the largest enrolling centers in a National Institutes of Health-sponsored clinical trial to determine if homocysteine reduction will attenuate cardiovascular events and improve the survival of transplant recipients.
The Interventional Nephrology Group examined central vein stenosis in association with internal jugular dialysis catheters and demonstrated a high incidence of this problem. This finding has generally gone unrecognized but could change the approach to temporary dialysis catheters in patients with chronic kidney disease, because central vein stenosis impairs the ability to successfully create permanent dialysis access.

Division of Pulmonary, Allergy, Critical Care and Sleep Medicine

Clay Marsh, MD, Director

The Division has joined the Center for Critical Care and continues building along specialtybased product lines and analytical programs to “create the future of medicine to improve people’s lives.” The goal is to be a leader in personalized health care focusing on translational research. Progress is evidenced by recognition in U.S.News & World Report as the 24th best respiratory program in the country, and by having 10 faculty recognized among the Best Doctors in America.® New initiatives, current research and ongoing projects include:

Sepsis registry in the ICU with biobanking capability
Stress and depression in advanced lung disease
Pulmonary interventional procedures
Growth of the Asthma Research Center
Mechanistic work in defining biomarkers in patients with sepsis
Mechanistic programs in antibody-directed therapies in cancer, sepsis, cell life and cell death, oxidant imaging and function, cell signaling, angiogenesis, mitochondrial biology, regulation of cystic fibrosis transmembrane regulator protein (CFTR), glucocorticoid receptor biology, infectious disease and inflammation

Ongoing Research Programs

Translational research in critical care, asthma, ILD, emphysema, lung cancer, sleep medicine, pulmonary hypertension, and allergy
Translational research in acute lung injury in the ICU that focuses on quality improvement, execution of evidence-based pathways and structure/function relationships in clinical delivery
Translational research in pulmonary hypertension
Collaboration with Ohio State’s Davis Heart and Lung Research Institute in lung remodeling and repair, sepsis and mitochondrial biology
Studying the role of inflammatory cells in lung complications of bone marrow transplantation
Studying tissue microenvironment and human disease, along with the role of genetics in lung and critical care disease
Fibrosis, remodeling, lung injury and cancer – Clay Marsh, MD, Philip Diaz, MD, Jeanette Marketon, PhD, Estelle Boyaka, PhD, John Mastronarde, MD, Patrick Nana-Sinkam, MD, Karen Wood, MD
Innate immune system function, sepsis and infectious disease – Mark Wewers, MD, Susheela Tridandapani, PhD, Andrea Doseff, PhD, Daren Knoell, PharmD, Karen Wood, MD, Amal Amer, PhD
Mitochondria biology and critical care disease – Elliott Crouser, MD, Douglas Pfeiffer, PhD, Ruairi Fahy, MD
Process-based research and decision making – James O’Brien, MD, Naeem Ali, MD, Scott Aberegg, MD, Stephen Hoffmann, MD, Virginia Nivar, PhD
Redox biology of the lung and muscle and sleep medicine – Thomas Clanton, PhD, Ulysses Magalang, MD, Valery Khramtsov, PhD, Narasimham Parinandi, PhD, Rami Khayat, MD

Research Accomplishments of 2006

Creation of a critical care and lung genetics program focusing on microRNA expression in health and disease
Creation of a sepsis registry and biobanking program
Named as a center for the National Institutes of Health-sponsored LOTT (Long-term oxygen treatment trial)
Creation of a chronic stress and depression program in advanced lung disease