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The 2002 Dennis W. Jahnigen Career Development Scholars Abstracts
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Jonathan Bean MD, MS, Harvard Medical School
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Weighted Vest Training in Mobility Limited Elders
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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.
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Physical Medicine and Rehabilitation
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Deborah J. Culley, MD, Harvard Medical School
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Mechanisms of Persistent Post-anesthetic Cognitive Impairment with Aging
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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.
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Anesthesiology
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Alan Dardik MD, PhD, Yale University School of Medicine
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Effects of Aging on Endothelial Cell Responses to Hemodynamic Forces
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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.
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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.
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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.
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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.
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General Surgery
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David S. Friedman MD, MPH, Johns Hopkins University
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Vision Restoration in Assisted Living Residents
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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.
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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.
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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.
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Ophthalmology
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Enrique Garcia-Valenzuela, MD, PhD, Emory University
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Stem Cell Therapy for Age-related Retinal Disease
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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.
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Ophthalmology
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Kennon Heard, MD, University of Colorado Health Sciences Center
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Acute Drug Toxicity in Elderly Patients: A National Study of Overdoses,
Adverse -Drug Reactions and Poisoning
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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.
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Emergency Medicine
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Sandhya A. Lagoo-Deenadayalan, MD, PhD, Duke University Medical Center
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Aging and the Immune Response to Surgical Stress
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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.
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The
SPECIFIC AIMS of my proposed study are as follows:
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1.
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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.
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2.
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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.
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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.
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General Surgery
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Stephen Meldon, MD, Case Western Reserve University
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An ED-Based Falls Prevention Screening and Referral Program
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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.
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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.
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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.
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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.
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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.
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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.
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Emergency Medicine
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Larissa V. Rodriguez MD, UCLA School of Medicine
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Autologous Adipose Derived Stem Cells for the Reconstruction of the Atrophic
Aging Female Urethra: Tissue-Engineering Techniques for the Treatment
for Stress Urinary Incontinence
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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.
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Urology
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Khaled J. Saleh, MD, MSC, FRSCS, University of Minnesota
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Effectiveness of Revision Knee Arthroplasty: A Multicenter Study
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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.
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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).
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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.
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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.
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Orthopaedic Surgery
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