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The 2004 Dennis W. Jahnigen Career Development Scholars Abstracts
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Charles Cha, MD, Yale University School of Medicine
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Effects of Aging on Tumor Angiogenesis in GI Malignancy
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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.
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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.
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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.
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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.
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General Surgery
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Joseph C. Cleveland, Jr., MD, University of Colorado Health Sciences Center
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The Effect of Age Upon Myocardial Production
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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.
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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.
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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.
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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.
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Thoracic Surgery
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Edward V. Fehringer, MD, University of Nebraska Medical Center
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Full
Thickness Rotator Cuff Tear Prevalence and Correlation with Shoulder
Function in Patients 65 Years and Older
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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.
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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.
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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.
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Orthopaedic Surgery
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Lisa J Gould, MD, PhD, University of Texas Medical Branch
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Mechanisms of Impaired Wound Healing in the Elderly
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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.
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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.
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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.
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General Surgery
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Leanne Groban, MD, Wake Forest University
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The Role of GH/IGF-1 in Diastolic Heart Failure of Aging
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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.
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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.
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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.
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Anesthesiology
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Badrinath Konety, MD, University of Iowa
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Profiling post-operative risk in elderly patients undergoing surgical
intervention for bladder and other urologic cancers
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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.
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Urology
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Patrick Kortebein, MD, University of Arkansas for Medical Sciences
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Resistance Exercise & Prostate Cancer: Effects on Muscle & Quality of Life
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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.
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Physical Medicine & Rehabilitation
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Karen L. Miller, MD, University of Utah
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Gynecologic Surgery, Fall Risk, and Functional Outcomes in Older Women
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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.
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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.
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Gynecology
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Kevin Terrell, DO, Indiana University School of Medicine
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Computer-Assisted Decision Support to Increase the Safety of Prescribing to Older
Adults in the Emergency Department
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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…”
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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.
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The specific aims of this proposal are to:
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Reduce prescribing of potentially inappropriate medications
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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.
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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.
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Emergency Medicine
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Stephen Tsang, MD, PhD, Columbia University
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A Genetic Dissection of Age-Related Macular Degeneration
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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.
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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.
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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.
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Ophthalmology
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