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The 2002 Dennis W. Jahnigen Career Development Scholars Abstracts Jonathan Bean MD, MS Deborah J. Culley, MD Alan Dardik MD, PhD David S. Friedman MD, MPH Enrique Garcia-Valenzuela, MD, PhD Kennon Heard, MD Sandhya A. Lagoo-Deenadayalan, MD, PhD Stephen Meldon, MD Larissa V. Rodriguez MD Khaled J. Saleh, MD, MSC, FRSCS Jonathan Bean MD, MS, Harvard Medical School Dr. Bean is an Assistant Professor in the Department of Physical Medicine and Rehabilitation at Harvard Medical School, which is largely based at Spaulding Rehabilitation Hospital. He is the Director of Research Training and Education for the Dept. of PM&R at HMS and Medical Director at the Spaulding Cambridge Outpatient Center. Additionally, Dr. Bean is a consultant with expertise in geriatric PM&R at many of the Harvard Affiliated Hospitals including Massachusetts General Hospital, Brigham and Women's Hospital, and Mount Auburn Hospital. Recognizing the changing demographics of society, Dr. Bean focuses his research on enhancing physical functioning and preventing disability in the elderly. Expanding on an earlier study, Dr. Bean was originally funded for a two-year randomized controlled intervention study, in mobility-limited community dwelling elders. However, with receipt of the Mentored Clinical Scientist Award (K23) from the National Institute on Aging (NIA), the Jahnigen funding was redistributed to serve as ancillary support for an expanded 5-year Randomized Controlled Trial. This study compared a training program known as InVEST (Increased velocity exercise specific to task), which was developed to enhance muscle power and physical performance. The control group participated in the NIA advocated independent exercise program.   Weighted Vest Training in Mobility Limited Elders Mobility limitations affect almost one in 4 individuals over age 65. Limitations with tasks such as rising from a chair, walking across a room and maintaining standing balance are predictive of disability, institutionalization and mortality. Thus, it is not surprising that the need to address exercise interventions in individuals with mobility limitations has been recently emphasized. Although, a large number of studies have established the role of muscle strength as a predictor of mobility in disabled and non-disabled elders, peak muscle power may be a more critical attribute. Muscle power, the ability to perform muscular work per unit time is a variable distinct from strength, declining earlier and more precipitously through the life span. Lower extremity power is associated with fall risk and mobility limitations in institutionalized elders. In recognition, research into exercise interventions enhancing muscular power has been identified as a topic of high priority. Through preliminary work in mobility-limited elders, the investigator has demonstrated that not only is lower extremity muscle power strongly related to performance-based function, but that it likely exerts a greater influence than strength. Machine-based power training in a laboratory was 2-3 fold more potent than classical progressive resistance training performed on the same equipment. Nevertheless, in order for such exercise to be acceptable to community dwelling elders, simple home-based forms of power training must be developed. Therefore, weighted vest exercise has been evaluated. In a study utilizing weighted vests, stair-climbing exercise produced 17% improvements in leg power. This proposal seeks to expand upon this preliminary work. It will be a 2-year randomized controlled gym-based study, in mobility-limited community dwelling elders. It will directly compare a potential form of home-based power training to an established form of home-based strength training. Primary outcomes include the central disablement relationships between impairments in muscle power and measures of function predictive of disability. Physical Medicine and Rehabilitation   Back to the top Deborah J. Culley, MD, Harvard Medical School Dr. Culley is an Assistant Professor at Harvard Medical School. Having long been fascinated with the central nervous system and evidence that surgery and general anesthesia are associated with the development of postoperative cognitive dysfunction she, with significant guidance from her mentor, Dr. Gregory Crosby, developed an animal model of postanesthetic cognitive dysfunction. Dr. Culley speculated that general anesthetics may produce sustained cognitive impairment via further alterations in the glutamate - N-methyl D-aspartate(NMDA) system and that NMDA receptor hypofunction increases susceptibility of aged animals. As a Jahnigen Scholar she investigated this possibility using standard behavioral tests to evaluate cognitive performance in aged rats before and for several weeks after routine general anesthesia. She is presently continuing studies investigating the mechanisms by which general anesthetics adversely effect the aged brain. Additionally, Dr. Culley is working on the development of a rodent model of postoperative delirium with the assistance of her anesthesiology mentor and two geriatrics mentors, Edward Marcantonio and Sharon Inouye, within the Harvard system. She is presently involved in multiple professional societies on geriatric anesthesia and is helping to develop a standardized geriatrics curriculum for anesthesiology residents and fellows.   Mechanisms of Persistent Post-anesthetic Cognitive Impairment with Aging Recent clinical studies demonstrate that anesthesia and surgery are associated with long lasting deterioration in cognitive performance in a substantial percentage of elderly patients. However, the risk factors and mechanisms involved remain unknown. We have demonstrated in the laboratory that that general anesthesia itself could be a factor and that advanced age enhances susceptibility. Although the receptor mechanisms of general anesthesia are complex, many anesthetic agents antagonize N-methyl D-aspartate (NMDA) receptors. This is relevant because activation of NMDA receptors is essential for learning and formation of memory and NMDA receptor hypofunction is a prominent characteristic of the aged brain. Thus, we speculate that general anesthetics may produce sustained cognitive impairment via further alterations in the glutamate – NMDA system and that NMDA receptor hypofunction increases susceptibility of aged animals. To investigate this possibility, we will use standard behavioral tests to evaluate cognitive performance in aged rats before and for several weeks after routine general anesthesia. Results will be compared to those obtained in identically anesthetized young adult rats and unanesthetized control and dizocilipine (a non-competitive NMDA receptor antagonist) treated rats matched for age and baseline cognitive performance. Furthermore, to evaluate potential neurobiological mechanisms, we will examine the brain of behaviorally characterized rats during and at various times after anesthesia for evidence of anesthesia-induced alterations in NMDA receptors, glutamate transporters, and the NMDA-mediated signal transduction cascade involved in learning and memory. Using this combined behavioral and neurochemical approach, we expect these studies to clarify how general anesthesia produces long-lasting cognitive impairment in seniors and to potentially yield methods to mitigate or treat the morbidity associated with it. Anesthesiology   Back to the top Alan Dardik MD, PhD, Yale University School of Medicine Dr. Dardik is an Assistant Professor of Surgery at the Yale University School of Medicine. Prior to joining the faculty in 2001, Dr. Dardik trained in general and vascular surgery at the Johns Hopkins Hospital. As a Vascular surgeon, Dr. Dardik found the majority of patients he was treating were older adults. The 2002 Jahnigen scholar award allowed Dr. Dardik to study the effects of senescence on the endothelial cell response to hemodynamic forces. Results from these studies refocused the Dardik laboratory work to study the effects of aging on vascular responses to intervention and injury. Dr. Dardik currently combines basic science research with clinical patient care with the goal of performing translational research, determining the impact of aging on the vascular system.   Effects of Aging on Endothelial Cell Responses to Hemodynamic Forces Endothelial cell proliferation and migration are central events in normal vascular physiology, such as angiogenesis and vascular graft healing, and abnormal vascular pathophysiology, such as atherosclerosis and neointimal hyperplasia. However, the effects of aging on endothelial cell proliferation and migration, and the vascular system in general, are not well understood.   Although the entire blood vessel is subjected to hemodynamic forces such as blood pressure and cyclic strain, only endothelial cells are uniquely exposed to pulsatile shear stress, the tangential frictional force of the flowing blood on the endothelial cell surface. I hypothesize that shear stress is one of the factors responsible for maintenance of the normally quiescent endothelial cell phenotype in vivo. Conversely, alterations in normal physiological levels or patterns of shear stress, either by injury or by a repair process, or via some other unknown effect of the aging process, lead to changes in endothelial cell structure and function resulting in an activated phenotype, leading to atherosclerosis or neointimal hyperplasia.   The specific aims are: 1) To determine the effects of senescence and aging on shear stress induced endothelial cell activation, that lead to increased intracellular signal transduction, phosporylation of akt, and ultimately, decreased apoptosis and increased cell proliferation. 2) To determine the effects of senescence and aging on shear stress induced transcription and translation of egr-1, leading to increased expression of metalloproteinases such as MT1-MMP, increasing cell migration.   It is crucial to understand the effects of senescence and aging on the blood vessel response to hemodynamic forces. An ability to modulate these pathways may lead to improved treatments for atherosclerosis, as well as the creation of bypass grafts resistant to neointimal hyperplasia. Different therapeutic strategies are necessary for elderly patients, basing therapy on pathways that are physiologically relevant for them and not based on pathways relevant for younger patients. General Surgery   Back to the top David S. Friedman MD, MPH, Johns Hopkins University Dr. Friedman is an Associate Professor at the Wilmer Eye Institute of Johns Hopkins University School of Medicine, and Associate Professor in the Department of International Health at Johns Hopkins Bloomberg School of Public Health. Dr. Friedman received his medical degree from Harvard Medical School, completed his residency at Wills Eye Hospital and served as a glaucoma fellow with Dr. Harry Quigley. A recipient of a master's degree in public health and a doctorate in chronic disease epidemiology from Johns Hopkins, Dr. Friedman was the recipient of a Clinician Scientist Award from the National Eye Institute in which he studied vision rehabilitation in nursing homes. He is a recipient of the Douglas Jahnigen Award from the American Geriatrics Society and has consistently carried out research on elderly populations, particularly as related to the impact of glaucoma on these individuals.   Vision Restoration in Assisted Living Residents Admission to an assisted living (AL) facility is often the first step in a downward spiral. AL residents suffer from disabilities, both physical and mental, and further decline often leads to nursing home admission, hospitalization, or death. This study hopes to assess vision restoration as a means of preventing further decline in function among AL residents.   About 1.3 million elderly Americans reside in AL facilities at present, with the number projected to double in the next 10-15 years, and to reach 3.9 million by 2025. Vision impairment is common among the institutionalized elderly, with rates of vision loss estimated to be close to 30%. Over half of those with vision loss would benefit from glasses or cataract surgery, while others might benefit from low vision training and aids. Vision loss is documented to cause declines in physical and neuropsychiatric function.   The proposed randomized clinical trial will determine whether or not intensive efforts to rehabilitate vision in AL residents can help preserve the physical and emotional well being among these frail individuals. Specifically, we will evaluate whether or not interventions to improve access to and use of vision services can decrease the rate of nursing home admissions, hospitalizations and death. Furthermore, we will evaluate the cost-effectiveness of the rehabilitation program to allow a more complete understanding of the practicality of carrying out this intervention on a larger scale. Finally, we will look cross-sectionally at the differences in function between those with and those without a visual impairment at baseline. Ophthalmology   Back to the top Enrique Garcia-Valenzuela, MD, PhD, Emory University Dr. Garcia-Valenzuela is an Assistant Professor at the Emory University Eye Center. Throughout his medical training he was interested in two areas of biology, neurosciences and aging. He decided to become a Clinician-Scientist in Retina, a subspecialty of Ophthalmology to pursue these interests. Dr. Garcia-Valenzuela was drawn to studying the elderly population because of their particular vulnerability to retinal blindness. In his Jahnigen study, Dr. Garcia-Valenzuela searched for retinal stem cells, seeking to characterize certain retinal stem cells to open the door for further experimentation.   Stem Cell Therapy for Age-related Retinal Disease Age-related retinal diseases remain the most prevalent blinding problem in the elderly. There is great potential to develop new treatments for these diseases using stem or progenitor cells. Recent evidence points to the existence of retinal stem cells in the mammalian adult eye, including the human. We intend to search for retinal stem cells in Eye Bank postmortem eyes from subjects of different ages, with particular attention to those from old and very old donors. Stem cells will be looked for in various ocular tissues, particularly in the retinal peripheral margin, the pars plana and the pars plicata. Comparisons of the in vitro survival, numbers present in situ, and differentiation potential into mature retinal cells will be made among stem cells derived from different donor ages. Stem cells will be transfected in vitro with green fluorescent protein for identification in transplantation experiments. These human derived cells will be transplanted into the subretinal space of adult rat retinas, both undamaged and damaged. Host animals will belong to two groups: young adult and old. One of the blinding retinal diseases affecting the elderly is retinal detachment. A rat model of this type of photoreceptor loss has been devised and will be used in these transplantation experiments. Immunocytochemical techniques will be used to assess differentiation. Microscopy will be used to determine synaptic connectivity by grafted cells. Comparisons among young and old donors and hosts will be made. Having a stem cell of adult human origin would set research much closer to clinical application. Their most significant potential is that they are probably located in an ocular region that is not typically affected by most retinal diseases, and it is a location easily accessible for their surgical retrieval. Stem cells from individual patients could be expanded and manipulated in vitro to be used later in transplantation therapy in the same patient. Retinal stem cells of this origin would avoid two major problems for other stem cells: 1) immunological rejection, 2) ethical controversy regarding their origin. It is important to establish the cellular behavior that retinal stem cells derived from elderly individuals may have, as these subjects have the highest prevalence of retinal blindness and would likely be the first human subjects in any experimental trial. Characterization of such retinal stem cells would open the doors to further experimentation, including genetic manipulation, extracellular guidance of differentiation both in vitro and during retinal transplantation as photoreceptor replacement therapy to retinal blindness affecting the elderly. Ophthalmology   Back to the top Kennon Heard, MD, University of Colorado Health Sciences Center Dr. Heard is an Associate Professor in the Division of Emergency Medicine at the University of Colorado School of Medicine and Director of the Medical Toxicology Fellowship at the Rocky Mountain Poison and Drug Center. Dr. Heard's interest in Geriatric Toxicology started during his fellowship and quickly became a research focus. After his training, his Jahnigen Award study was to describe the epidemiology of drug overdoses and poisonings among elderly Emergency Department (ED) patients using three national data sets and to develop guidelines for the management of these patients. He also was awarded a Geriatric Education for Specialty Residents award that focused on methods to improve ED prescribing for elderly patients. His current geriatric research continues to evaluate ways to improve medication selection for elderly ED patients.   Acute Drug Toxicity in Elderly Patients: A National Study of Overdoses, Adverse -Drug Reactions and Poisoning While the area of geriatric poisoning may seem limited, poisoning is the result of many clinical scenarios. Poisoning may result from suicide attempt, drug interactions, and medication errors, all of which are important issues for older patients. The objective of this study is to describe the epidemiology of drug overdoses and poisonings among elderly Emergency Department (ED) patients using three national data sets and to develop guidelines for the management of these patients. The first database is the American Association of Poison Control Centers/Toxic Exposure Surveillance System. The information in this database is gathered from the over 2 million annual calls to Poison Centers. The other databases are collected by the National Center for Health Statistics and include a statistically valid nationwide sample of patients seen in Emergency Departments and discharged from short stay hospitals in the U.S. The analysis will provide a description of geriatric poisoning patients, compare younger poisoning patients to older poisoning patients with regard to demographics, agents involved and outcome, and finally use univariate and multivariate analysis to develop a clinical prediction model to assist clinicians providing bedside care to older poisoning patients. This research project will provide me with the basis of a strong academic career and help our institution continue to develop as a center of excellence in Geriatric Emergency Medicine. Emergency Medicine   Back to the top Sandhya A. Lagoo-Deenadayalan, MD, PhD, Duke University Medical Center Dr. Lagoo-Deenadayalan is an Assistant Professor in the Department of Surgery and a Senior Fellow at the Center for Aging and Human Development at Duke University. Her professional and personal experiences have given her a sense of urgency for improving and expanding the scope of surgical care for older patients. She has worked toward this goal by pursuing research in basic science, studying the effect of aging on immune responses to endotoxin. Her study under the Jahnigen program aimed to explore age-related differences in immune responses to surgical stress and sepsis in a rodent model of aging.   Aging and the Immune Response to Surgical Stress The goal of this research is to understand age-related differences in local and systemic immune responses elicited by the surgical stress of minimally invasive surgery (MIS). Minimally invasive procedures have increased in all age groups due to numerous advantages of MIS over conventional open surgery. However, in older patients, there is an increased likelihood of untoward effects due to hemodynamic instability, especially in the presence of sepsis. The mechanisms underlying these insalubrious events in elderly patients during laparoscopic surgery are not completely understood. My hypothesis is that age-related changes in the response of peritoneal macrophages to endotoxin (lipopolysaccharide, LPS) lead to an exaggerated peritoneal inflammatory response during abdominal surgery, which in turn increases the elderly patient’s susceptibility to adverse systemic inflammatory responses. I further hypothesize that such local and/or systemic inflammatory responses (SIR) are accentuated by carbon dioxide pneumoperitoneum (CO2-P) used in laparoscopic surgery leading to adverse hemodynamic consequences. To test this hypothesis, I propose to compare the subsets of peritoneal and peripheral blood cells, the levels of LPS binding molecules on these cells, the chemokines and cytokines produced locally and systemically during surgery, and the in-vitro response of these cells to LPS in young and old patients undergoing laparoscopic surgery. These results will be correlated with the patient’s cardiovascular and respiratory responses recorded during surgery.   The SPECIFIC AIMS of my proposed study are as follows: 1. To study age-related differences in peritoneal cells - “the local factors”: (A) characterize the peritoneal cell subsets at the beginning and end of laparoscopic procedures; (B) determine the baseline and induced expression of LPS receptors- CD14 and Toll like receptors, TLR2 and TLR4, on the peritoneal cell subsets; and (C) examine LPS-induced gene expression of chemokines (e.g. IL-8), proinflammatory cytokines (e.g. IL-6) and nuclear factor κ–B (NFκ-B) by peritoneal macrophages. 2. To study age-related differences in peripheral blood during surgical stress – “the systemic factors”: (A) study changes in peripheral blood mononuclear cell subsets (PBMs) obtained before and after surgery and their responsiveness to LPS – (gene expression of cytokines, NFκ-B, and expression of LPS receptors); and (B) measure plasma chemokines and cytokines levels (IL-6, IL-8, IFN-, IL-10, TNF-) before and after surgery.   I expect that this information will help identify elderly surgical patients at increased risk for developing complications and devise strategies to prevent such complications, thus improving the standards of geriatric care. General Surgery   Back to the top Stephen Meldon, MD, Case Western Reserve University Dr. Meldon is an Emergency Medicine physician in Cleveland Ohio. After taking an instructor course developed by the Society for Academic Emergency Medicine and the John A. Hartford Foundation, Dr. Meldon became interested in geriatric emergency medicine. He has since increasingly focused his teaching and research efforts on the emergency care of the older person. Dr. Heard tested his hypothesis that an ED-based falls prevention program, consisting of identification and assessment of older patients at risk for falling, with direct linkage to a mobility evaluation and training program will be effective in decreasing the incidence of subsequent falls.   An ED-Based Falls Prevention Screening and Referral Program BACKGROUND: Falls are a leading cause of accidental death, morbidity and hospital admission among those aged 65 years and older. Physiologic and environmental risk factors for falls serve as the basis for potential fall-prevention interventions. Fall prevention programs that include exercise and balance training appear to be effective. Emergency departments (ED) are an important point of entry into the healthcare systems for older patients at risk for falls, and ED-based screening and intervention programs may be particularly effective.   HYPOTHESIS: An ED-based falls prevention program, consisting of identification and assessment of older patients at risk for falling, with direct linkage to a mobility evaluation and training program will be effective in decreasing the incidence of subsequent falls.   METHODS: Randomized clinical trial of an ED-based screening and direct-referral falls prevention program. Participants will be randomized to usual care or to an intervention group, who will enroll in an exercise and balance evaluation/training program.   PARTICIPANTS: ED patients aged 75 years or greater who present to the ED with complaint of fall or have a history of falls within the preceding 3 months. Patients would be excluded if they are admitted to the hospital, critically ill or significantly injured, cognitively impaired without proxy or are nursing home residents.   INTERVENTIONS: Intervention will consist of enrollment in an existing mobility program, consisting of a thorough, multifactorial evaluation and a goal oriented, individually tailored physical training rehabilitative phase.   MAIN OUTCOME MEASUREMENTS: Main outcome measurement will be incidence of falls in a subsequent 12-month follow-up period. Secondary outcomes will include correlation of brief ED mobility/balance screens with the in-depth mobility assessment and the predictability of the ED screens for subsequent falls. Additional outcomes will include measurements of functional assessment and independence, healthcare utilization, and compliance with the exercise program. Emergency Medicine   Back to the top Larissa V. Rodriguez MD, UCLA School of Medicine Dr. Rodriguez is an Associate Professor of Urology and Co-Director of the Division of Female Urology, Reconstructive Surgery and Urodynamics at the University of California, Los Angeles. Part of her professional interest is research into incontinence and prolapse disorders, which are most prevalent in the elderly. She began to develop tools to evaluate female patients who undergo treatment for incontinence. The aim of her research was to apply tissue-engineering techniques to discover cures for stress urinary incontinence (SUI) in the elderly population. The hypothesis was that the aging female urethra can be reconstructed by providing a gel matrix with all the necessary cellular, growth factor and scaffold elements for formation of functional urethral smooth musculature for the treatment of SUI.   Autologous Adipose Derived Stem Cells for the Reconstruction of the Atrophic Aging Female Urethra: Tissue-Engineering Techniques for the Treatment for Stress Urinary Incontinence The main aim of our research is to apply tissue-engineering techniques to discover cures for stress urinary incontinence (SUI) in the elderly population. We plan to test the hypothesis that the aging female urethra can be reconstructed by providing a gel matrix with all the necessary cellular, growth factor and scaffold elements for formation of functional urethral smooth musculature for the treatment of SUI. The goal is to develop a cost effective, minimally invasive, and durable treatment of stress urinary incontinence (SUI) based on adipose derived stem cells (ADSC). We are investigating a system by which autologous adipose derived stem cells can be harvested from a patient, differentiated into viable adipose cells, then injected into the urethral sphincter of incontinent patients, providing a vascularized, long-lived bulking agent for the treatment of SUI. Additionally, our laboratory currently is evaluating the capacity of stem cells to differentiate into functional smooth muscle cells that could then be used to reconstruct functional normal urethras. This research involves studies in the feasibility and optimal techniques of differentiation of adipose derived stem cells into adipose and smooth muscle cells. It also involves a search for an injectable biocompatible matrix containing both growth and angiogenic factors to enhance the differentiation and long-term viability of these cells. We are also evaluating the efficacy of this system as a treatment for stress urinary incontinence in an animal model. Urology   Back to the top Khaled J. Saleh, MD, MSC, FRSCS, University of Minnesota Dr. Saleh is a Professor in the Department of Orthopaedic Surgery and Public Health Sciences at the University of Virginia. During his residency, Dr. Saleh began to appreciate the significance of lower extremity problems for mobility and function in the elderly. He has devoted his research to the field of geriatric orthopaedics, combining his medical and public health background for a unique perspective. He designed several multicenter studies to prospectively document functional outcome following knee arthroplasty procedures. Study results will help physicians map out the ideal surgical reconstruction for various severities of a failed knee replacement, and will help predict outcomes as measured by function and disability at one year.   Effectiveness of Revision Knee Arthroplasty: A Multicenter Study In 1995, 243,919 total knee arthroplasties (TKA) were performed in the United States; this number will double by 2030 as the population ages. There has been a concomitant increase in the number of TKA revisions (TKAR) performed. Revision surgery, generally, is technically more difficult than primary replacement and entails much higher cost. The outcomes of revision surgery have been poorly documented and their correlates poorly understood. Given the increasing demands on limited healthcare resources, it is important to document patient outcome following this procedure and to establish best-practice guidelines for it.   The proposed study poses the fundamental question: for a given severity of deterioration, how do patient factors and surgical reconstruction affect outcome in TKAR? We theorize that increased severity of TKA failure will be associated with a greater TKAR preoperative physical disability, will require a more complex reconstruction, and will relate to less satisfactory outcomes (as measured by functional ability, complication rates, and length of convalescence).   We propose a fourteen-center prospective cohort study to document functional outcome following revision knee arthroplasty procedures. We will enroll patients in need of TKAR who meet specified inclusion/exclusion criteria. The dependent variable, outcome will be monitored preoperatively and at six and twelve months postoperatively using validated Health Related Quality of Life instruments. The independent variables in the study include subject factors, preoperative TKA deterioration severity, and surgeon-reported reconstruction deterioration severity. We will also monitor changes in physical function, course of recovery, and complication rates. For the primary analysis, scores on the WOMAC Function sub-scales assessed at 6 and 12 months will be used as repeated dependent variables, in repeated measures ANCOVA.   Study results will help physicians map out the ideal surgical reconstruction for various severities of a failed knee replacement. They will help predict outcome as measured by function and disability at one year. Orthopaedic Surgery Back to the top