2004 Jahnigen Proposal Abstracts

The 2004 Dennis W. Jahnigen Career Development Scholars Abstracts

Charles Cha, MD, Yale University School of Medicine
	*Effects of Aging on Tumor Angiogenesis in GI Malignancy*
The primary goal of this project is to investigate the effects of aging on tumor angiogenesis and growth. The process of angiogenesis is thought to be blunted with age, but the relationship between aging and tumor angiogenesis is not well understood and potentially could have profound effects on tumor growth and proliferation.

Tumor angiogenesis is a process necessary for cancer to grow beyond a few millimeters in size. To assess the effect of aging on tumor angiogenesis, we plan to design gene silencing small-interfering RNAs (siRNAs) which will silence VEGF and other pro-angiogenic factors. VEGF is one of the most potent pro-angiogenic factors for tumor growth and is secreted by almost all solid cancers. For this reason, VEGF has been one of the primary targets for anti-angiogenic therapy in solid tumors. I hypothesize that the VEGF pathway is altered by the aging process, and this alteration could lead to differences in tumor proliferation and growth when treated by anti-angiogenic therapy.

In our model system, we plan to determine the effects of aging on tumor proliferation in human colorectal cancer cells that are treated with siRNAs targeting vascular endothelial growth factor (VEGF), one of the most potent pro-angiogenic factors for tumor growth. Our goal is to develop VEGF-directed siRNAs as novel agents to inhibit growth and proliferation of human colorectal cancer cells by silencing VEGF gene expression and determine the relative potency of such agents specifically in the elderly population.

It is crucial to understand the effects of aging on tumor angiogenesis. Cancer is the leading cause of death in patients over the age of 65, and anti-angiogenic agents are being tested with increasing frequency in our elderly population. Aging may alter response to these agents, and understanding the mechanisms affecting tumor angiogenesis could improve current treatment regimens for cancer in elderly patients. In addition, these studies are intended to provide a basis for the development of siRNAs as new therapeutic agents to inhibit tumor angiogenesis that are effective in the elderly population.
General Surgery


Joseph C. Cleveland, Jr., MD, University of Colorado Health Sciences Center
	The Effect of Age Upon Myocardial Production
Cardiovascular disease is the leading cause of morbidity and mortality in our aging population. The proportion of elderly patients requiring cardiac surgery continues to exponentially increase. Unfortunately a variety of factors combine to promote an excessive operative risk of morbidity and mortality in older patients undergoing cardiac surgery. Among these factors contributing to higher risk on the elderly is the entity of perioperative myocardial dysfunction.

Cardiac surgical procedures incur an obligatory ischemia-reperfusion (I-R) injury to the myocardium. This myocardial I-R injury is accompanied by a release of pro-inflammatory cytokines. These cytokines, including TNF, IL-1, IL-6, and Il-18, potentially promote myocardial dysfunction, and thereby are associated with increased morbidity and mortality following cardiac surgery.

The cytokine profile of elderly patients undergoing cardiac surgery remains poorly characterized. Further, correlation of cytokine release following cardiac surgery with increasing age may prove valuable in elucidating a mechanism whereby the higher mortality and morbidity following cardiac surgery in the elderly can be explained. Finally, recognized genomic polymorphisms in the TNF gene locus are described. The prevalence of these genetic polymorphisms in the elderly population are ill-defined. Characterization of these polymorphisms in the elderly may shed important insights into the overall response to injury that elderly patients possess.

This project seeks to determine the myocardial production of TNF, Il-1, Il-6, and Il-18 in patients aged 20-90 who undergo elective adult cardiac surgical operations. We also seek to determine the prevalence of the biallellic polymorphisms of the TNF genotype, and to determine whether these polymorphisms affect myocardial levels of cytokines. It is our goal that characterization of these cytokines in the elderly will offer important insights into reducing the current unacceptably high operative mortality in elders undergoing cardiac surgery.
Thoracic Surgery


Edward V. Fehringer, MD, University of Nebraska Medical Center
	Full Thickness Rotator Cuff Tear Prevalence and Correlation with Shoulder Function in Patients 65 Years and Older
The prevalence of full thickness rotator cuff tears in the geriatric population and how those tears affect respective shoulder function are questions that have not been answered. The aims of this study include: 1. To define full thickness cuff tear prevalence in patients 65 and older, 2. To correlate cuff tear presence and size with shoulder function in patients 65 and older, and 3. To correlate several co-morbidities with rotator cuff tear prevalence in patients 65 and older.

Once IRB approval has been obtained, Dr. Fehringer will recruit patients aged 65 and older that have not undergone previous shoulder surgery from the University of Nebraska Medical Center geriatric clinics. Patients will be asked to assess their shoulder’s function as part of two shoulder functional assessment metrics: The Simple Shoulder Test and the Constant-Murley score. The Simple Shoulder Test is a patient-directed questionnaire that involves simple ‘yes-no’ answers to twelve questions about a shoulder’s function. This twelve item functional inventory has been demonstrated to have discriminate and construct validity, to be reproducible, and to be responsive to changes in shoulder function resulting from therapeutic interventions.^1,2,14 The Constant-Murley score is frequently used as a clinical shoulder metric and requires both patient and examiner input to assess function.^22,23 Bilateral shoulders may be included if neither shoulder has undergone previous surgical intervention. If bilateral shoulders are included, patients will be assessed with both metrics for each shoulder.

Following the questionnaires, Dr. Fehringer will examine the respective shoulder(s) of patients with an ultrasound probe. The procedure is safe, painless, and requires approximately seven to ten minutes to examine both shoulders. All abnormalities will be noted and recorded. Full-thickness rotator cuff tears, when present, will be measured. 200 shoulders will be examined. The prevalence of full thickness cuff tears will be calculated. Correlations between tear presence and shoulder function as well as tear size and shoulder function will be made. Age will be correlated with tear presence and size as well as with function. Co-morbidity and cuff tear correlations will be determined. Data analysis will be performed with the aid of a biostatistician, Julie Stoner, Ph.D., of the University of Nebraska Medical Center Department of Preventive and Societal Medicine.
Orthopaedic Surgery


Lisa J Gould, MD, PhD, University of Texas Medical Branch
	Mechanisms of Impaired Wound Healing in the Elderly
Treatment of chronic, non-healing wounds is a major public health issue that is growing as our population ages. It is estimated that 5 million Americans suffer from chronic wounds, costing the US health system $20 to $25 billion a year. Chronic wounds currently affect about 15% of older Americans. This figure is expected to steadily increase as the number of individuals 65 and older rises. In addition, the incidence of chronic conditions that predispose the elderly to wounds is increasing. For example, diabetes is increasing at a rate of 14 percent per year and accounts for 80 percent of all chronic wound costs (1). Diabetes and the other major causes of chronic wounds, venous and arterial insufficiency and pressure ulcers, are all conditions that produce tissue ischemia. Because a common denominator of chronic wounds is tissue ischemia, the elderly are at high risk for developing wounds that won’t heal.

The long-term goal of my research is to improve wound healing in the elderly. Oxidative stress and reactive oxygen species (ROS) are known to be important factors in aging and age related diseases. Although recent studies support the concept that numerous aspects of wound healing are under redox control, the impact of oxidative stress on wound healing in the elderly has not been explored. In this study, I will test the hypothesis that there is an imbalance between ROS and the antioxidant defense systems in the aged animal that contributes to impaired healing. This will be accomplished by examining the role of oxygen, oxidants and anti-oxidants on wound healing in young and old rats.

This research will improve our understanding of the cellular and molecular mechanisms behind delayed healing in the elderly. With this insight we will be better equipped to develop rational and effective treatments, resulting in decreased cost and morbidity.
General Surgery


Leanne Groban, MD, Wake Forest University
	*The Role of GH/IGF-1 in Diastolic Heart Failure of Aging*
Aging is associated with diminished cardiac performance characterized by impaired relaxation. The age-related cellular and molecular changes contributing to diastolic impairment may represent adaptive, physiologic dysfunction or the other end of the clinical disease spectrum, diastolic heart failure. Diastolic heart failure accounts for more than 50% of the hospital admissions in older patients. Given the growing proportion of elderly persons in the US, the greatest opportunity for reducing death from heart failure lies in our understanding of the age-related phenomena that contribute to the disease progression of diastolic dysfunction so that preventive treatment strategies can be established.

One age-related physiologic change that has been associated with an increased risk of clinical heart failure is a decline in GH secretion or Insulin-like Growth Factor-1 (IGF-1). Correspondingly, a beneficial effect of low-dose GH administration to aged animals has been shown to improve myocardial structure and function. Preliminary Doppler echo data from our adult-onset GH deficient rat suggest that an age-related decline in GH and IGF-1 could contribute to early diastolic dysfunction, however its significance with respect to lowering the threshold for the development of diastolic heart failure is unclear.

To evaluate the role of GH/IGF-1 “senescence” in the pathogenesis of diastolic dysfunction to diastolic heart failure, the adult-onset GH deficient dwarf model will be studied pre and post thoracic aortic constriction (pressure-overload failure). Dwarf rats treated and subsequently withdrawn from GH (adult-onset GH deficiency) will be compared to dwarfs continuously repleted with GH and to heterozygous, saline-treated dwarfs [wild-type] in order to assess in vivo diastolic function (Doppler; Conductance) and ex vivo myocyte mechanics and extracellular maladaptations (fibrosis). We hypothesize that GH replacement given to adult dwarfs will prevent or delay age-associated diastolic dysfunction and raise the threshold for development of diastolic heart failure through IGF-1 mediated alterations in calcium homeostasis and ventricular remodeling.
Anesthesiology


Badrinath Konety, MD, University of Iowa
	Profiling post-operative risk in elderly patients undergoing surgical intervention for bladder and other urologic cancers
A large portion of national health expenditure for cancer care is for prostate and bladder cancer. Among all cancers, bladder cancer patients incur the most costs from diagnosis to death. A large proportion of patients with bladder cancer are > 65 years of age. While a majority of bladder cancer patients develop recurrent superficial disease, about 25% have muscle invasive disease requiring radical surgical therapy and/or radiation and chemotherapy. Approximately --% of patients who undergo radical surgery such as removal of the entire bladder (radical cystectomy) for bladder cancer are >70 years of age. There is evidence that increased age and co-morbidity can increase the likelihood of adverse post-surgical events such as death. Hence appropriate patient selection would be important in reducing the risk of mortality and morbidity from aggressive therapy for bladder cancer. Current methods of assessing the risk of a negative post surgical outcome, be it death or complications relies on determining the performance status and co-morbidity level. There are very few models specifically designed to predict peri-operative risk and almost all the models currently available are neither population, age or disease specific. Previous studies have also demonstrated that risk assessment models developed for the general population lose their discriminatory power when applied to the elderly since age itself is one of the tools used for risk discrimination. It is also becoming increasingly evident that several other factors such as functional level (dependency for ADL, IADL) serum cytokine profile, cognitive status and caregiver levels can be independent predictors of mortality and outcome from illness in older patients. We propose to conduct a prospective pilot study in a small cohort of elderly (>70 years) bladder cancer patients undergoing radical cystectomy to determine the correlation between various functional, cognitive, physiologic, disease related and caregiver related parameters and outcome after radical cystectomy. We will compare the utility and accuracy of standard statistical methods such as regression modeling and a computerized data mining algorithm to predict outcomes. The data mining approach will allow us to predict outcomes from surgery on an individual basis for each patient. We feel that being able to better predict outcomes from surgery would allow us to make better decisions regarding the best treatment approach for each individual patient. Accurate risk profiling would help ensure the most cost-effective and clinically beneficial method.
Urology


Patrick Kortebein, MD, University of Arkansas for Medical Sciences
	*Resistance Exercise & Prostate Cancer: Effects on Muscle & Quality of Life*
In elderly men, sarcopenia is associated with decreased muscle mass, strength and functional capacity, and hypogonadism can be a primary contributing factor to this process. Hypogonadism, by pharmacological or surgical means, is the desired effect of androgen deprivation therapy in the treatment of prostate cancer in order to slow tumor growth. This type of treatment intervention is a common primary, or adjunctive, treatment for prostate cancer and has been demonstrated to improve survival. However, this treatment also results in impotence, decreased muscle mass and increased fat mass. Preliminary data from our laboratory has shown that men with extreme hypogonadism, due to the use of megestrol acetate, lose strength and muscle mass if they do not exercise. However, a similar group of men that completed a resistance exercise training program maintained fat free mass and muscle size in spite of castrate levels of circulating testosterone levels. We propose to examine the effects of resistance exercise training in elderly men receiving androgen deprivation therapy for prostate cancer as a means of preserving or increasing skeletal muscle mass as well as improving strength, fatigue and quality of life. Specifically, we will examine a group of sedentary elderly men with prostate cancer that have received combined radiation and androgen deprivation (ADT) therapy; half of the subjects will complete a 12 week progressive resistance exercise training (high-intensity) program, while the other half will perform a low-intensity non-progressive resistance exercise program (low-intensity). We will comprehensively examine the effects of the loss of testosterone, with high- and low-intensity resistance exercise on body composition, strength, fatigue, and quality of life in men with prostate cancer. We will also test the hypotheses that androgen deprivation therapy decreases the fractional rate of muscle protein synthesis (FSR), that resistance exercise training will increase muscle FSR, and that high-intensity resistance exercise will increase strength and prevent loss of muscle mass in elderly men with prostate cancer. In this way, we will determine the effectiveness of resistance exercise as a potential treatment for the accelerated sarcopenia, weakness, and fatigue that is attendant to androgen deprivation therapy for prostate cancer.
Physical Medicine & Rehabilitation


Karen L. Miller, MD, University of Utah
	*Gynecologic Surgery, Fall Risk, and Functional Outcomes in Older Women*
Deconditioning, functional decline, and falls are potential adverse consequences of surgery in older persons. Other than traditional surgical outcomes, such as mortality or wound infection, gynecologists are uninformed about risks to health and function faced by older women after hospital discharge from gynecologic surgery. This is due both to a lack of short-term outcome data, and to a failure of non-geriatricians to consider frailty and functional issues in older women. This proposal seeks to address the knowledge deficit in this area for purposes of improved education, clinical care, and future research. We postulate that major gynecologic surgery has an adverse impact on balance in the first postoperative week, which implies a fall risk; that activities of daily living decline measurable in the postoperative period; and that baseline factors such as age and impaired function correlate with an increased risk of postoperative balance and functional decline.

The specific aims of the study are to quantify the extent of balance impairment that occurs in women aged 65 and older at one postoperative week using validated measures; to establish age-specific norms for the anticipated extent and range of balance and functional decline among older women; and to define baseline and perioperative predictors of such. The primary outcome will compare a subjective and objective balance assessment at the first postoperative week to baseline. We will also query both balance and functional status using subjective measures at several time points in the first two postoperative weeks and assess physical performance at weeks one and two. We will repeat major outcome measures at six postoperative weeks. We will correlate baseline and perioperative factors with the extent of decline. The primary outcome will be statistically analyzed using a paired t-test. Secondary outcomes will be analyzed using univariate and bivariate statistical methods.
Gynecology


Kevin Terrell, DO, Indiana University School of Medicine
	Computer-Assisted Decision Support to Increase the Safety of Prescribing to Older Adults in the Emergency Department
As defined by Beers criteria, 6% of older emergency department patients receive one or more prescriptions for medications considered potentially inappropriate for older adults. In collaboration with the American Geriatrics Society, leaders in Emergency Medicine recently defined a research agenda for Geriatric Emergency Medicine. The panel recommended: “Interventional trials of methods to reduce prescription of potentially inappropriate medications, such as … computer-assisted decision support systems integrated into discharge instructions…”

The central hypothesis for the proposed research is that computer-assisted prescribing will reduce the number of potentially inappropriate medications prescribed to older emergency department patients. We also hypothesize that this system can improve prescribing in terms of medication dosage.
The specific aims of this proposal are to:
Reduce prescribing of potentially inappropriate medications
Reduce prescribing of appropriate medications at inappropriate doses, by providing emergency physicians with computer-assisted decision support at the time they are writing discharge prescriptions for older adults.

Physicians will be randomized to computer-assisted decision support or to the control group. Physicians randomized to the intervention group will receive patient-specific electronic reminders about choice or dose of drug when writing emergency department release orders that include the targeted medications. “Hot buttons” and fixed choice menus will facilitate decision-support by providing suggestions for suitable alternative therapies based on the physician’s indication for the drug. Physicians in usual care will not receive the reminders but the computer will track their practice patterns. The technology needed to conduct this study already exists at our health care system. This system has already been used to improve prescribing in the hospital and ambulatory settings. We seek to employ the potential of this system in the practice environment of the emergency department which presents unique challenges to quality improvement. We expect to find that computer-assisted decision support improves emergency department prescribing to older adults.
Emergency Medicine


Stephen Tsang, MD, PhD, Columbia University
	A Genetic Dissection of Age-Related Macular Degeneration
This proposal is designed to provide a diverse and extensive experience in genetics, pathology and geriatrics that will allow the applicant to develop into a mature scientist-clinician with an outstanding potential to contribute to aging research. The proposed project will focus on the generation of mouse models to study features of age-related macular degeneration (AMD). Not only is AMD a common disorder, it is also untreatable. The recent identification of CAG16,263CGG allele of Hemicentin-1 as the genetic defect in ARMD1 locus opened the window into the early events leading to AMD. Knock-out of Hemicentin-1 should reveal its function in development and formation of the Bruch membrane. Additionally, knock-in of CAG16,263CGG allele into the mouse germ-line should generate an animal model so that efficacious treatments for this common disorder can be tested.

Dr. Ronald Liem is well known for biochemical and molecular biological studies of the aging intermediate filaments (cytoskeleton) in neurons. Drs. Liem and Peter Gouras will serve as co-mentors for the PI's postdoctoral studies. In addition, Columbia has an outstanding panel of faculty members, many of whom have professional relationships with Dr. Liem and can serve as scientific consultants to the PI. The proposed project will be at the cutting edge and is an ideal area with which to launch a career in aging research.
The proposed program also incorporates clinical training to understand how AMD predisposes the elderly to other medical and psycho-social complications. Dr. Rafael Lantigua, who is nationally recognized for expertise in measurement of geriatric health outcomes, will be a co-mentor for this clinical aspect of the program. This intense program provides vast clinical experience in diagnosis and treatment of the complete scope of aging problems as well as a number of didactic activities including lectures, special seminars, and attendance at clinical research meetings.
Ophthalmology