Lisa Crossley, MD, Brigham and Women's Hospital
        Role of CREB and FOXO in the Responses of Neutrophils in Sepsis-Induced Acute Lung Injury
Severe sepsis complicated by acute lung injury/adult respiratory distress syndrome (ARDS) is a condition of uncontrolled inflammation and is associated with significant mortality in elderly patients. Aging may contribute to the risk of developing ARDS. Though current treatment is improving the outcome from ARDS, older individuals (70 years or older) are still twice as likely to die as younger individuals. Accumulating evidence suggests that the apoptosis of neutrophils is a key event that directs the termination of the inflammatory process. Yet in sepsis, neutrophil apoptosis is impaired.

Our hypothesis is that the amplification of key signaling events during sepsis differentially alters the survival of young versus elderly neutrophils. The nuclear transcription factors, cyclic AMP binding protein (CREB) and Forkhead (FOXO) in turn then regulate the expression of genes that effect the survival of these cells. The long-term goal of these studies is to determine how the signaling responses of CREB and FOXO establish the balance between inflammatory mediator production (e.g., IL-1, TNF-?, IL-6) and the factors that terminate the inflammatory response (CD44, IL-10, TGF?. Using biochemical and molecular techniques (e.g., western blotting, PCR, FACS analysis, and immunoprecipitation) these studies will investigate the role of CREB and FOXO in modulating gene transcription of neutrophils. Specific Aims 1 and 2 will be performed using hematopoietic cell lines and ex vivo primary human cells.

These studies will provide crucial insight into the mechanisms through which neutrophils' responses contribute to the inflammatory and infectious diseases that predominately affect the elderly.
Anesthesiology

Jeff J. Ericksen, MD, Virginia Commonwealth University
        Spine Stability Muscle Function in Older Women: Role of Gynecological History
Low back pain (LBP) represents a pervasive source of geriatric disability with estimates of 18-23% prevalence in older adults and nearly 42% in disabled older women. Severe LBP is linked to significant functional impairment. Our understanding of the etiology of most LBP remains imprecise but recent work has focused on spine stability. Stabilization strategies should meet load demands through precise joint compression delivered by coordinated muscle action specific for loads. "Core stabilizer" motor control strategies (MCS) providing postural stability have described specific activation sequences of pelvic, abdominal and spine muscles. These MCS increase the "force closure" stability of spine joints, particularly the sacroiliac joint (SIJ), a frequent contributor to LBP. Rehabilitation interventions based on this model reduced pain and disability in younger adult LBP populations.

Gynecological surgery (GS) may impair lumbopelvic MCS precipitating LBP later in life. The MCS is sensitive to minor injury and spontaneous recovery is not automatic. Population studies associate LBP with pelvic surgeries in older women. Abnormal respiratory function and bladder motion during load challenges in LBP subjects documented altered motor control confirming that maladaptive spine MCS compromises function in those systems. These methods have not been used in older LBP populations to confirm MCS changes manifested as alterations in respiratory function and pelvic floor biomechanics, perhaps involved in incontinence complaints in older women, more common after GS.

Ultrasonography, joint stiffness measures and spirometry will quantify the influence of these prior events on the MCS in older women with LBP and begin a prospective study of women undergoing GS. Later work will apply these methods to research movement therapies (e.g., tai chi, chi gung) for treating LBP in older adults, providing objective assessment tools to confirm subjective improvement and better understand treatment failure.
Physical Medicine & Rehabilitation

Paul Gagne, MD, New York University School of Medicine
        The Effect of Aging on Extracellular Matrix Regulation of Ischemic Limb Vascularization
This proposal describes a 2 year training program through the Dennis W. Jahnigen Career Development Scholars Award focused on The Effects of Aging on the Regulation of Ischemic Leg Revascularization through Collagen-IV and Extracellular Matrix Remodeling. The principal investigator is a board-certified vascular surgeon investigating The Effect of Aging on ExtraCellular Matrix Regulation of Ischemic Limb Revascularization. The impact of these changes specifically on angiogenesis related limb neovascularization will be studied. The central hypothesis is that inadequate ischemic limb revascularization in the elderly is due, in part, to a reduction in the proteolytic exposure of crytic epitopes within collagen type-IV.

The principal investigator also proposes to pursue didactic training in geriatric medicine through courses on aging, conferences, journal clubs and research meetings within the New York University. The investigator will be mentored in Geriatrics by Dr. Michael Freedman, the Head of the Division of Geriatrics and Dr. Terry Fulmer, Head, Division of Nursing, NYU School of Education. Dr. Thomas Riles, Chairman of Surgery, is his vascular surgery mentor. Dr. Peter Brooks, Director of Angiogenesis Research at NYU is the basic science mentor.

Improved care of elderly vascular patients, and improved insight into the effects of aging on translational opportunities (i.e therapeutic angiogenesis) related to the investigator's research will be gained. Education of other vascular surgery faculty, surgery residents, vascular fellows and medical students on the geriatric aspects of the treatment of vascular patients will also be accomplished. Geriatric fellows and residents will likewise benefit from joint conferences with vascular surgery and through research positions in the principle investigators laboratory.
General Surgery

Ula Hwang, MD, MPH, Mount Sinai School of Medicine
        Geriatric Pain Management in the Emergency Department (ED) Setting
The emergency department (ED) is a unique environment in which highly specialized care is delivered to the acutely ill and injured, and safety net care is provided to disenfranchised and vulnerable populations. Both of these missions are increasingly threatened by the phenomenon of ED crowding. Atypical presentations, cognitive impairments, co-morbidities, and polypharmacy serve to make the elderly population particularly vulnerable to the adverse effects of a crowded ED. Given the rapidly increasing volume of emergency department visits by persons aged 65,6 it is imperative to understand the impact of ED crowding on the care of the older adult. Pain management has been identified as an issue for quality of care improvements in older adults11 and serves as a useful model to explore ED care in the geriatric population.

We propose a prospective observational study of geriatric pain management in the emergency department of a single institution, the Mount Sinai Medical Center. The specific aims of this one-year study are: 1) to identify patient-related risk factors for under-assessment and under-treatment of geriatric ED pain; 2) to identify ED environmental risk factors (i.e., crowding) associated with under-assessment and under-treatment of geriatric ED pain; and 3) to gather descriptive data on the current practice of pain management for older adults in the ED. We hypothesize that compared to younger patients, those 65 years old will be under-assessed and under-treated; among those 65 years old, age 85 years, comorbidities, cognitive impairments, and frailty will increase the risk of under-assessment and under-treatment. We further hypothesize that ED crowding will increase the risk that older patients will be under-assessed and under-treated for pain. ED crowding measures include patient-specific means for number of patients, triage scores, ED lengths of stay, number of inpatient boarders, physician:patient and nurse:patient ratios.
Emergency Medicine

Michael Johns. MD, Emory University Voice Center
        Efficacy of Treatment for Age-Related Dysphonia
Changes in voice are commonly associated with aging. While these changes can be mild, severe vocal difficulties resulting from vocal fold atrophy occur regularly. Age-related vocal changes (presbylaryngis) significantly impair elderly individuals' ability to communicate meaningfully with others and frequently impair their quality of life. With changing age demographics in our society and increasing emphasis on quality of life, demand for treatment of presbylaryngis is becoming more paramount. The efficacy of the current treatment modalities for presbylaryngis is unknown. Most of the current evidence is anecdotal or case series reports. In order to effectively counsel patients, understanding treatment outcomes is important. The aim of this proposal is to conduct a randomized prospective study to determine the efficacy of the primary treatment modalities for presbylarnygis. Enrolled patients will be randomized to one of three treatment arms: observation, voice therapy, or vocal fold augmentation plus voice therapy. Patients will undergo the respective treatment arm for two months with a comprehensive pre and post treatment outcomes battery. Target enrollment is 100 patients, with complete data on at least 63 patients, over the two-year funding period. The results of this study will yield a clear understanding of the efficacy of major treatment modalities for presbylaryngis, will direct future research into age-related vocal disability, and will serve as a platform for a career of geriatric otolaryngology research.
Otolaryngology

Martin Makary, MD, Johns Hopkins University
        Frailty as a Predictor of Surgical Outcome
Background
The long-term goal of this research project is to improve care of elderly patients undergoing surgery by identifying factors that predict postoperative complications and ultimately, implementing interventions to reduce those complications. Surgical decision-making in the elderly is often complicated by poorly understood confounding variables and a crude estimate of operative risk. The only objective estimates of operative risk are based on cardiopulmonary status (American Heart Association /American College of Cardiology (AHA/ACC) criteria) or a sum of comorbidities (American Society of Anesthesiology (ASA) score).
Hypothesis
We hypothesize that a frailty score predicts clinical and economic outcomes in elderly patients undergoing surgery. Operative risk in the elderly may correlate with a measurable physiologic reserve and provide useful information in surgical decision-making.
Specific Aims

1. To identify the prevalence of frailty among patients presenting for general and vascular surgery.
2. To measure frailty as a predictor of postoperative outcome (morbidity, mortality, recovery, disposition to home or a transitional or long-term care facility, and resource utilization), and to compare the outcomes of frail patients by surgical approach (open versus laparoscopic).
3. To compare the use of a frailty assessment to other currently used pre-operative predictors of outcome to see if frailty contributes to the risk stratification either independently or in conjunction with other currently used methods.

1. Apply a validated frailty assessment to all patients presenting for general, vascular, or orthopedic surgery at our institution. Postoperative outcome data will be collected.
2. Develop regression models to identify the correlation between frailty, pre-operative characteristics, surgical approach, and post-operative outcome.
3. Simultaneously collect an ASA score and AHA/ACC pre-operative risk score and analyze their relative positive predictive value compared to and in conjunction with a frailty score.

Simon Mears, MD, Johns Hopkins Bayview Medical Center
        Osteoporotic Pelvic Fractures: Biomechanics and Sacroplasty
Recently, sacroplasty has been introduced as a possible treatment for painful pelvic fractures, but little basic information is known about the procedure. Sacroplasty involves the injection of bone cement into the fractured sacrum to give immediate support to the broken pelvis. The technique is a variant of vertebroplasty, which is used to treat osteoporotic vertebral body compression fractures. I propose to refine sacroplasty by determining the method of cement delivery, the safest anatomical approach, the amount and placement of cement, and the risk of cement extravasation and subsequent nerve injury.

To test the augmentation of the fractured pelvis, more information is needed about the basics of the injury. In the geriatric patient, two types of injury patterns predominate, and these patterns often are confused. The osteoporotic pelvic fracture is an injury caused by minimal or moderate trauma, such as a fall from standing height or less. It is hypothesized that the fall delivers a lateral compression force through the iliac crest, causing the pubic rami and sacrum to fracture. On the other hand, there is no discernable trauma associated with the sacral insufficiency fracture. One possible etiology is a physiologically normal force, such as that from stepping off of a curb, applied to pathologically weak bone. I propose to develop a simulated sacral insufficiency model in the human cadaver. Resulting sacral fractures then will be augmented by sacroplasty, and the strength of the augmented bone will be tested biomechanically to determine the optimal placement and volume of cement needed to restore sacral strength.
Orthopaedic Surgery

Nancy Perrier, MD, University of Texas/MD Anderson Cancer Center
        The Effect of Parathyroidectomy on Cognition and Function in the Elderly
Primary hyperparathyroidism (PHPT) is a complex endocrinopathy involving calcium metabolism and parathyroid hormone. Approximately 100,000 new cases of PHPT are diagnosed each year in the United States, and approximately 80% of patients exhibit nonclassical symptoms such as cognitive dysfunction, psychological or psychiatric symptoms, low energy, physical pain, sleep disorders, decreased ability to complete daily tasks at home or work, and decreased social interaction. The debate regarding whether parathyroidectomy should be performed early in the disease process when patients are "asymptomatic," or wait until they exhibit classical symptoms of nephrolithiasis, pancreatitis, and osteoporosis remains unresolved. The National Institutes of Health has called for controlled studies to shed light on the nonclassical symptoms of PHPT. It is our hypothesis that earlier surgical treatment of PHPT in older adults is a safe approach to reducing the burden of cognitive, neurobehavioral, and physical function decline associated with the disease. Our specific aims are: (1) quantify longitudinal differences in neuropsychological function of patients treated surgically versus those observed medically according to current community standards; (2) evaluate longitudinal impact of earlier surgery on the functional performance; and (3) identify areas of the brain affected by subclinical PHPT. Functional magnetic resonance imaging, combined with biochemical markers, a neuropsychological battery, a functional performance battery, and health related quality of life instruments will all be implemented. Twelve patients will be randomized into either the surgical or nonsurgical group. Results of this study may provide the basis for future work educating surgeons and primary care physicians on the functional benefit of earlier intervention of this disease. The significance of this study is to encourage early detection and referral for definitive treatment in older adults who are at risk for adverse symptom progression that may not be initially recognized by primary care physicians as being caused by this electrolyte and hormonal imbalance.
General Surgery

John A. Taylor, III, MD, University of Connecticut School of Medicine
        Pathogenesis of Chronic Urinary Retention
Urinary retention (UR) presents a major challenge in the care of older adults. Chronic UR is especially common, often remaining undiagnosed until it progresses to complete UR, urosepsis, renal failure or overflow incontinence. Although bladder outlet obstruction (BOO) is common among elderly men, impaired detrusor contractility (IDC) can also impede normal bladder emptying in both men and women. IDC is closely associated with degeneration of muscle cells and axons, as well as with increased deposition of debris and collagen (fibrosis) in widened intercellular spaces. The development of effective interventions for the prevention, treatment and management of this common geriatric condition has been hindered by an incomplete understanding of its pathophysiology.

The goal of this application is to leverage unique institutional resources together with critical new preliminary data to implicate a single molecule and signaling pathway in the pathogenesis of both detrusor fibrosis and muscle loss - key features of IDC. Our central hypothesis is that a potent pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF) and MIF-mediated cyclooxygenase (COX-2) induction play a central role in detrusor decompensation by promoting detrusor fibrosis and smooth muscle death following BOO.

We propose to examine the role of MIF and COX-2 in mediating detrusor muscle loss and fibrosis following partial BOO in mice bred to lack both gene copies for mif and mice lacking both copies for cox-2. Acute and chronic obstruction models will be studied. Qualitative and quantitative structural changes as well as expression of both mif and cox-2
Urology

Edward Uchio, MD, Yale University School of Medicine
        Aging Effects on the VHL Tumor Suppressor Pathway in the Development of Renal Carcinoma
Renal cancer is a disease of the elderly, with most presenting in the sixth and seventh decades of life. There is however a less common hereditary disorder, von Hippel Lindau (VHL) disease, in which a known genetic defect results in renal cancer development at an early age (<50yrs). The underlying defect is a mutation in the VHL tumor suppressor gene which leads to the formation of an abnormal or non-functioning protein. This protein is very important in how our normal cells sense the presence of oxygen, such that in VHL disease the cells respond as though there is a lack of oxygen and produce various factors to stimulate their growth and well being. These factors (PDGF, TGF-æ, TGF-B1, Glut1, EPO, VEGF, etc.) have been implicated in the development of renal cancer and tumor growth. We have a novel opportunity in which a rare hereditary cancer syndrome (< 4% of all renal cancers) may give us insight into the possible mechanisms of tumor development in the elderly. In fact, studies of the more common renal cancer seen in the elderly (96%) have shown aberrations in the same VHL tumor suppressor gene pathway. We hypothesize that the development of renal cancer in the elderly is due to changes in tumor promoting factors caused by VHL tumor suppressor pathway inactivation that occurs with aging.

We propose the use of gene silencing by small interfering RNAs (siRNAs) to inhibit the VHL tumor suppressor pathway to simulate aging in the normal kidney. We plan to characterize the effect of these changes on tumor development, growth, and behavior. Since cancer is a leading cause of death in the elderly, an understanding of the molecular basis of its development will allow us to develop cancer specific therapies with improved efficacy and less toxicity which is especially important in the elderly population.
Urology