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Your path: Jahnigen Program > Jahnigen Career Development Scholars Awards > 2008 Dennis W. Jahnigen Career Development Scholars
Association of genetic polymorphisms with age-related macular degeneration clinical and visual phenotypes and response to treatment Age-related macular degeneration (AMD) is a leading cause of irreversible severe vision loss in the geriatric population, with a complex etiology involving genetic and environmental factors. Recently, multiple distinct genetic susceptibility loci for AMD have been identified, including variants in the complement factor H gene (CFH), the LOC387715/HTRA1 locus, and the complement C3 gene. We have recently discovered novel associations between the CFH variant (CFH-Y402H) and patients' response to treatment for exudative macular degeneration, both with photodynamic therapy (PDT) and with intravitreal administration of the anti-vascular endothelial growth factor (anti-VEGF) antibody bevacizumab (Avastin). At present, the most common therapy for neovascular AMD is ranibizumab (Lucentis), an anti-VEGF antibody specifically designed for intraocular use. We hypothesize that these AMD-associated genetic polymorphisms are associated with specific AMD clinical phenotypes, including treatment response and patients' perception of visual function. We also hypothesize that other genes in the VEGF pathway may contain variants that are associated with neovascular AMD. We wish to investigate the association of specific genotypic variants with AMD phenotypes with a three-pronged approach: 1) to determine if the AMD-associated variants in the CFH, LOC387715/HTRA1, or C3 loci are associated with alterations in response to treatment with intravitreal ranibizumab, 2) to determine if the AMD-associated variants in the CFH, LOC387715/HTRA1, or C3 loci are associated with distinct clinical and visual phenotypes, evaluating and comparing patients with nonexudative AMD to patients with newly-diagnosed exudative AMD, and 3) to determine if polymorphisms in vascular endothelial growth factor (VEGF) receptor genes (VEGFR-1 and VEGFR-2) are linked with AMD, using a case-control methodology. AMD is the most common cause of severe vision loss in the elderly. Vision loss occurs due to progressive death of photoreceptors, the rods and cones, and the retinal pigment epithelial cells beneath them in eyes with AMD. Vision loss occurs when the cone photoreceptors die, because they are responsible for fine central vision that is necessary to read, write, drive and recognize faces. The pathogenesis of AMD is multifactorial, but most likely results from a combination of genetic and environmental factors including oxidative stress. A compound known as A2E is produced in response to oxidative stress. A2E accumulates in the retinal pigment epithelial cells of AMD patients and can be seen in patients using autofluorescence photos of the retina. We hypothesize that vision loss in AMD patients is due to loss of cones overlying autofluorescent A2E deposits. We will test this hypothesis using a novel instrument, the adaptive optics scanning laser ophthalmoscope (AOSLO) to image cones and retinal pigment epithelial cells in living eyes with single-cell resolution. First, we will use AOSLO to compare cone structure and autofluorescence levels in normal subjects aged 50 and over with subjects aged 18-40. Second, we will correlate cone structure and function with autofluorescence in patients with dry AMD and in older subjects without AMD. Third, we will study retinal pigment epithelial cell structure in regions of cone loss and increased autofluorescence in AMD patients. High-resolution images of cones and retinal pigment epithelial cells in aging eyes with and without AMD should provide insight into the association between A2E and cell death in AMD patients. If A2E is associated with cone death, therapies to reduce levels of A2E may prevent vision loss in AMD patients. Matthew Ho, MD, PhD, Charles R. Drew University of Medicine and Science, Los Angeles, CA The main aim of our research is to investigate the therapeutic use of adult stem cells derived from skeletal muscles, which are called muscle-derived stem cells (MDSC), for pelvic floor disorders in the elderly population. Pelvic floor disorders, such as pelvic organ prolapse, are common conditions with significant morbidity in older women. We plan to test the hypothesis that the repair and regeneration of the pelvic floor supports, including levator ani, vaginal tissues, and endopelvic fascia, to reverse their atrophy and defects can be achieved by the separate or concurrent implantation of MDSC in those tissues. The regeneration of skeletal and smooth muscle in the respective target organs may, consequently, ameliorate pelvic floor disorders such as pelvic organ prolapse. This repair will be due to an increase in skeletal muscle mass, myofiber size, and the number of satellite cells, with a reduction in fibrotic processes, namely interstitial myofibroblasts and collagen deposition, in the levator ani, and to a similar selective increase in smooth muscle in the vaginal wall and endopelvic fascia, triggered by paracrine modulation by the surrounding endogenous tissue. Cell-based therapies with autologous MDSC hold great promise for tissue repair with the ultimate goal of regenerating and restoring the normal function of support to the pelvic organs. The success of this study would have a dramatic impact on the development of novel approaches for the treatment of pelvic floor disorders. This study involves the isolation, purification, and characterization of MDSC for subsequent autologous implantation and the determination of the effects of implanting MDSC, separately or simultaneously, into the levator ani and vaginal walls on muscle regeneration in those tissues and their subsequent functional improvement. We will evaluate the efficacy of the implanted MDSC in the regeneration and repair of pelvic floor defects in an animal model.
Effect of aging on regional aortic compliance before and after endografting; Implications for stent-graft design Purpose Significance Research Plan
Presbycusis is a common disability affecting the health of the elderly. We have little appreciation of how hearing is affected when the older ear is challenged by ototoxic agents. Cisplatin, a common chemotherapeutic agent, has multiple side effects, including ototoxicity. Elderly make up >60% of newly diagnosed malignancies. With improved treatment protocols and survival, specific attention needs to be directed at permanent side-effects of cancer treatment modalities, such as cisplatin-induced ototoxicity. Besides characterizing the deleterious interaction of cisplatin-induced ototoxicity with presbycusis, potential treatment strategies need to be identified that serve to protect the older ear. We propose to investigate these objectives by utilizing a mouse model of presbycusis, the CBA mouse. We hypothesize that aging and cisplatin-induced ototoxicity interact to produce greater hearing loss than would be expected from either factor alone, and that the aged ear can be protected against cisplatin-induced ototoxicity (mediated by generation of reactive oxygen and nitrogen species) by intratympanic corticosteroid administration (by suppressing inflammatory pathways that lead to generation of free radicals). In the first phase of the study ototoxicity will be assessed in young and old mice by serial measurements of auditory brainstem evoked responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) as a function of the concentration of a single dose of cisplatin. The goal of this phase is to identify an "optimal" ototoxic dose that will yield measurable hearing loss without significant morbidity or mortality. The second phase of this study will be directed at protection of the young and old ear against cisplatin-induced ototoxicity. Young and old mice will receive daily intratympanic injections of dexamethasone, after administration of the "optimal" ototoxic cisplatin dosage. ABRs and DPOAEs will be measured. The above functional measures will be correlated with cochlear histology using cochlear hair cell counts for each phase of the study. Jesse Pines, MD, MBA, MSCE, University of Pennsylvania School of Medicine, Philadelphia, PA Emergency department (ED) crowding is a public health crisis. The goal of this proposal is to test if ED crowding and long ED lengths of stay (LOS) harm older adults. The primary aim is to measure the association between ED crowding & LOS and the prevalence, development and progression of delirium in older adults. Delirium is a both common and undesirable outcome. At the time of admission, from 15-20% of older adults meet criteria for delirium. Delirium is associated with reduced cognitive and functional capacity, increases in rates of institutionalization, and poorer survival. Delirium often goes unrecognized in the ED. I propose a prospective cohort study of 1200 older adult patients seen in the ED at the Hospital of the University of Pennsylvania (HUP) over a one-year period. Research assistants will perform multiple measurements: the Confusion Assessment Method (CAM), the Mini-Mental Status Exam (MMSE), and the Brief Dementia Severity Rating Scale soon after room placement and then reassess cognitive status at six hours into the ED stay and shortly prior to arrival. They will measure ED crowding factors (waiting room, occupancy, etc.) at the time scales are administered. Enrollment will be performed by undergraduate research assistants who have been trained in administering these scales that are part of a highly successful research program in the HUP ED. I will use statistical methods to adjust for potential confounders that have been reported in other studies on patients with delirium including include logistic regression, time-series regression, and Cox-proportional hazards models. I hypothesize that 1) higher levels of ED crowding and longer ED stay increase the prevalence of delirium and worsen its severity and 2) patients with dementia will be at higher risk for these negative outcomes.
A Placebo Controlled Trial of L-Tryptophan in Post-Operative Delirium
Background: Post-operative delirium is a very common and deleterious complication in the elderly.1 Tryptophan is an amino acid precursor to the neurotransmitters serotonin and melatonin which affect mood.2 Supplemental oral L-tryptophan has been shown to improve mood in subjects under stress.3 Our previous work has shown markedly lower levels of tryptophan in elderly patients who develop post-operative delirium. Jeremiah Schuur, MD, MHS, Harvard Medical School, Boston, MA Developing Emergency Department Quality of Care Indicators for Community Dwelling Elders Older adults (age =75) visit Emergency Departments (EDs) at rates almost two-thirds higher than the population at large. Once in the ED, they require more time and resources than younger adults. Yet there is growing evidence that the current model of emergency care, based on the acute injury model, is inadequate for older ED patients and may even exacerbate the very conditions that bring them there. Elders' reduced physiologic reserves, multiple co-morbidities and medications, geriatric syndromes and complex social situations require more background information, more thorough evaluations and generate more issues related to transitional care. Commentators have recommended a different approach to evaluation and management of elderly patients in the ED. A decade of research reveals troubling patterns of care including missed diagnosis, under-treatment of important medical conditions and over-treatment with dangerous medications. Despite this, there is little evidence that EDs or emergency physicians have significantly changes their policies, procedures, and practice. Performance measurement is a proven technique to guide quality improvement in health care. Currently there are few measures of quality care for elders in the ED in contrast to measures developed to address geriatric care generally. This project aims to develop and evaluate a set of performance measures of quality care for community dwelling elders age =75 in the ED, focusing on structures and processes of care. During year one, I will assemble a technical expert panel to develop a set of quality statements and performance measures using a modified Delphi process. During year two I will pilot the measures in the EDs of the Partners healthcare system to evaluate feasibility and to describe the quality of current geriatric EM practice. The result will be a set of measures that EDs can use to quantify and improve the quality of care they deliver to elders.
Investigation into the use of serum biomarkers as an improved diagnostic tool for active pain generators in aging patients with low back pain
Intervertebral disc degeneration, as assessed by imaging studies, is ubiquitous among aging patients. However, only 42% of older adults report low back pain during the prior 12 months1. Correct identification of pain generators is critical to guiding appropriate and successful evaluation strategies and approaches to treatment. This is of paramount concern in the aging population, in which imaging findings have poor correlation with symptoms and multiple pain generators frequently co-exist. Nevertheless, interventions are frequently planned based on imaging studies, likely resulting in unnecessary procedures and associated morbidity. Because serum levels of inflammatory and matrix breakdown products address disease activity, evaluation of biomarkers has the potential to provide assessment of active pain generators above and beyond the changes observable on imaging studies. We propose to measure serum biomarker levels of molecules representing key mediators in the inflammatory, catabolic, and pain pathways in older patients with chronic low back pain (CLBP). Ascertaining which of these pathways are linked to pain and pain related functional impairments may identify individuals requiring therapeutic intervention versus those in whom alternative pain generators should be sought. This would be an improvement over our current imaging based diagnostic studies, which are insufficient and often result in unnecessary procedures with associated morbidity. The proposed research will provide the initial building blocks for future studies designed to develop more specific diagnostic capabilities which correlate better with pain and pain related function in the aging population. It is the candidate's long term goal to combine her current basic science findings of a reparative effect of motion with more sensitive metrics such as biomarkers to result in rational design of motion based therapies. It is hoped that such an approach will facilitate improved activity levels and reduce the risk of future disability among our aging patients. | ||||||
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Milam A. Brantley, Jr., MD, Washington University at St Louis School of Medicine, St. Louis, MO
Jacque Duncan, MD, University of California, San Francisco, San Francisco, CA
Bart Muhs, MD, PhD, Yale University School of Medicine, New Haven ,CT
Kourosh Parham, MD, PhD, University of Connecticut Health Center, Farmington, CT
Thomas Robinson, MD, University of Colorado at Denver Health Science Center, Denver, CO
Gwendolyn Sowa, MD, PhD, University of Pittsburgh, Pittsburgh, PA
