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Promoting retention in HIV-oriented primary medical care: The Healthy Connections for Positive Living Project.
Miguel Alampay, Anna Ford, and Janessa Landeck. School of Nursing and Health Studies, Health Studies individualized track (M.A.) and Nursing Program (A.F. and J.L.), Georgetown University.
Purpose: Retention in HIV care is essential to improving and maintaining a patient’s health status and quality of life. One of the most significant barriers to retention has been the affordability and access to services. To fully maximize the utilization programs, it is essential to identify the demographic and psychosocial profile of groups at greatest risk of being unable top consistently be retained in care. The awareness of these predictive characteristics will help design additional programs targeting those at greatest risk for non-retention.
Design and Methods: To determine interventions that promote retention in HIV-oriented primary medical care, a multimethod study was designed. To determine the psychosocial and dermographic profile of various types of users, a retrospective, chart audit was completed at a mid-Atlantic urban HIV/AIDS clinic. To determine the “lived” experience of regularly or sporadically using HIV-oriented primary medical care, a phenomenologic study was designed to examine the concepts of HIV related stigma, relationship with medical provider and individual support mechanisms available and utilized. To determine effectiveness of an outreach retention intervention, a case-control study was designed.
Conclusions: Results of the phase I study will be utilized to design phase II outreach retention intervention. Through the retrospective chart review, high-risk groups for non-retention will be identified for targeting during phase II. System variables related to HIV stigma and patient-provider relationships will be examined to strengthen a culturally sensitive, gender sensitive sexual orientation sensitive experience. Finally, the effectiveness of the current outreach retention intervention will be determined so that refinements can be made, implemented and empirically evaluated during phase II.
Sponsored by a grant from the Office of Science and Epidemiology, HIV/AIDS Bureau, Health Resource Services Administration, Department of Health and Human Services.
Investigators: Michael Relf, PhD, RN and Debra Dekker, PhD.
Relationship between Female Education and Empowerment and Rates of HIV/AIDS Infection in the sub-Saharan African Region.
Christine Bell. School of Nursing and Health Studies, International Program, Georgetown University.
Purpose: To determine the relationship between female education and empowerment and rates of HIV/AIDS infection in the sub-Saharan African region
Results: It is estimated that 36 million people worldwide are infected with the Human Immunodeficiency Virus, most of who will eventually contract the Acquired Immune Deficiency Syndrome, or AIDSA. 85% of all AIDS fatalities have occurred in the sub-Saharan region of Africa, a reality that serves as a barrier not only for the regions stabilization of public health but also to its struggle for economic, political and social development. Regarding the relationship of females and HIV-AIDS, there has been a disturbing change in the global trends of infection. As the epidemic has spread there has been a continuous shift towards heterosexual transmission and increasing infection rates in females. In sub-Saharan Africa women account for 55% of those infected with HIV/AIDS, in which the most frequent method of contraction is through sexual intercourse. Contrasting gender roles create differing circumstances that lead to HIV-AIDS infections in males and females, reflecting discrepancies in sexual behavior, social pressures, economic power and vulnerability. What global health leaders and national governments must develop is the utilitarian, gender rights approach to HIV/AIDS prevention, which will enhance the health behaviors and individual well-being of the sub-Saharan cultures and communities affected. As exemplified in my research of HIV-AIDS in the sub-Saharan African region, public health services and education programs that have been implemented have significantly decreased HIV/AIDS infection rates in females, such as the case of Uganda, where teenage girls, after receiving health education and other public information, reported more condom use than any other age group, which was reflected in the falling infection rates among 13-19 year old girls in Masaka, in rural Uganda.
Conclusion: As global health researchers and public health task forces continue their mission of controlling the epidemic, it is imperative for the world to realize that one of the most important steps for HIV/AIDS prevention is the education of girls, which not only will teach them about their health but will ultimately empower them in their society.
Elevated Endothelin Levels May Play a Critical Role in the Pathogenesis of Inflammatory Bowel Disease.
Dominick Bufalino, Melissa Bresnick, Christine Bell, Sarah Brill and Allan Angerio, Ph.D. School of Nursing and Health Studies, Health Studies Science Program, Georgetown University.
Crohn’s disease (CD) and ulcerative colitis (UC) are chronic intestine disorders of unknown etiology and pathogenesis. They are collectively known as the two main inflammatory bowel diseases (IBD). The main distinction between CD and UC is their location in the gastrointestinal (GI) tract. CD involves the small intestine while UC the large intestine. Endothelin (ET-1) was first characterized as a potent vasoconstrictor produced by endothelial cells. Recent studies report that ET-1 is also produced by mast, epithelial, and smooth muscle cells. These cells are found in the GI tract and participate in inflammation. We suggest that ET-01 may play a role in IBD by promoting and exacerbating the inflammatory response. ET-1 antagonists may prove useful in treating IBD and reducing the incidence of cancer associated with UC.
Thromboembolic Disease in Cancer.
Dorothy A. Fink and Allan Angerio, Ph.D. School of Nursing and Health Studies, Health Studies Science Program, Georgetown University.
Hypoxia-induced endothelin (ET) and vascular endothelial growth factor (VEGF) play an important role in tumor biology by promoting angiogenesis. Angiogenesis alters hemostasis and promotes thromboembolic disease. Therapeutic angiogenesis directed against ET and VEGF may reduce the incidence of thromboembolic disease in cancer patients.
Effect of Estradiol and Heregulin β-1 on Anchorage-independent Cell Growth in MCF-7 Cells.
Mary Iann, Mary Beth Martin, Ph.D., and Adriana Stoica, Ph.D., School of Nursing and Health Studies, Health Studies Science Program (M.I. and A.S.) and Department of Oncology (M.B.M. and A.S.), Georgetown University.
The presence of the estrogen receptor-α (ER-α) is used to predict those patents who will benefit from hormonal therapy. The antiestrogen tamoxifen competitively binds ER-α inhibiting estrogen-stimulated growth. Most ER-positive breast cancers initially respond to tamoxifen, but can develop resistance. These cells produce growth factors that bind to cell surface receptor tyrosine kinase (RTKs), initiating a cascade of phosphorylation/dephosphorylation reactions. One of these RTKs is ErbB2, overexpressed in beast cancer.
Previously, we have shown that estradiol and heregulin β-1 (HRG β-1) alter ER-α activity in MCF-7 cells via the phosphatidylinositol 3-kinase (PI 3-K)/protein kinase Akt, two downstream targets of growth factors. Additionally, we can rapidly activate PI-3K/Akt through the ErbB2 pathway. We report here that the effect of estradiol or HRG β on anchorage-independent growth can also be altered by ErbB2 and Akt.
The ability of MCF-7 cells (parental or stably transfected with a constitutively-active and two dominant negative Akt mutants) to induce cell growth was tested through a soft agar assay. In parental cells, both estradiol and HRG β-1 stimulated growth when compared with cells grow in estrogen-depleted medium, effect blocked by the antiestrogens, tamoxifen and ICI 182,780. In cells stably transfected with constitutively active Akt, cells grew similar to estradiol. Tamoxifen only partially inhibited the growth of these cells. In contrast, cell growth was blocked by the pure antiestrogen ICI 182,780. In stably transfected cells with the dominant negative Akt mutants, however, the effect of estradiol or HRG β-1 were similarly inhibited, and both antiestrogens could block their residual effects.
These results suggest that Akt can present estrogen-like activity on anchorage-independent cell growth and its effect is mediated by ErbB2 and ER-α. Therefore, activation of the ErbB2/P13-K/Akt pathway may lead to tamoxifen resistance in breast cancer cells and inn increased tumor proliferation.
Identification and cDNA Cloning of a Protein that Inhibits the Binding of Estrogen to its Receptor.
Meredith Lahey, Daniel Gamett, Ph.D., and Mary Beth Martin, Ph.D. School of Nursing and Health Studies, Health Studies Science Program (M.L. and D.G.) and Department of Oncology (M.B.M.), Georgetown University.
Background: Experiments completed in Dr. Mary Beth Martin’s Laboratory (Lombardi Cancer Center) have shown that MCF-7 breast cancer cells, after being treated with Tetradecanoylphorbol Acetate (TPA), lose their ability to bind estrogen (E2) even though estrogen receptors (ER) remain present in the cells. This mimics a condition seen in some cancer patients in which tumors have ER but are unable to bind E2 or the drug tamoxifen.
Hypothesis: Treatment of MCF-7 cells with TPA causes expression of a new protein that binds to the estrogen receptor rendering it inactive.
Purpose: Our goal is to clone the cDNA that codes for this hypothetical protein that binds to the ER.
Procedure: The yeast te0hydrid system is a way of cloning genes that encode pairs of proteins that bind to each other. In our case, one member of the pair is the ER (the ‘bait’) and the other member is an unknown protein found in YTPA-treated cells (the ‘target’). A plasmid to express the bait was constructed by subcloning ER cDNA into plasmid pGBKT7. To express the target, RNA was extracted from TPA-treated, ER+, E2 non-responsive MCF-7 cells. CDNA was synthesized and ligated into pGADTR7-Rec, creating a population of plasmids with various lengths of of cDNA inserts. These plasmids were then introduced into yeast cells together with the ‘bait’ plasmid. Plasmids that express proteins that bind to the ‘bait’ enable the yeast to survive in selective medium.
Results: 8 yeast colonies were isolated. Plasmids collected from these colonies are being transformed into bacteria in order to obtain enough DNA for sequencing.
Future Prospects: DNA sequences in the cloned plasmids will be compared to the human genome.
The Role of ET-1 in Sickle Cell Disease.
Nicole Lee and Allan Angerio, Ph.D. School of Nursing and Health Studies, Health Studies Science Program, Georgetown University.
Sickle cells disease (SCD) is a molecular defect in the beta globin gene. This defect is characterized by the vascular occlusion and vasomotor instability of the interactions between the abnormal sickle red blood cells and the cells of the blood vessel wall. In conditions of low oxygen or dehydration, the chemical changes in hemoglobin causes the shape of the molecule to change and the cell become sickle-shaped, making it difficult to pass through the blood vessel. Endothelin is a potent vasoconstrictor produce by the endothelial and vascular smooth muscle cells in response to low oxygen concentration levels (hypoxia). The most prominent of the endothelin group is endothelin-1 (ET-1). A cycle involving the release of ET-1 occurs in patients with SCD. When ET-01 is present, apoptosis (or natural cell death) is inhibited which leads to an increase in circulating endothelial cells. Therefore, the increased circulating endothelial cells come into greater contact with the sickled cells. This greater contact leads to an increase in the potent vasoconstrictor ET-1. Greater concentrations of ET-1 causes the constriction of the blood vessels. Thus the sickle cells, in patients with SCD, will have a more difficult time passing through the blood vessels leading to painful crisis.
Conclusion: Endothelin-1 does play a significant role in SCD. The future of SCD treatment may involve hydroxyurea therapy, which seems to be a safer treatment than bone marrow transplantation.
The Role of Tobacco Smoke Condensate Fractions in the Activity of the Estrogen Receptor-α.
Julie Richards, Mary Beth Martin, Ph.D., and Adriana Stoica, Ph.D.
School of Nursing and Health Studies, Health Studies Science Program (J.R. and A.S.) and Department of Oncology (M.B.M. and A.S.), Georgetown University.
The estrogen receptor-α (ER-α) is an important mediator of growth signaling pathways. When the receptor is in the inactive state it is in a complex with a variety of proteins and does not interact wit the cellular transcription apparatus. When estradiol binds to the receptor it becomes active and undergoes a conformation change, which allows it to bind co-activators and initiate transcription. Due to the receptor’s role in growth signaling pathways, substances that act like estradiol and activate the estrogen receptor increase the risk for breast cancer.
Divalent heavy metals have been shown to activate the estrogen receptor. Tobacco smoke condensate (TSC) contains many metals and previous research has demonstrated its ability to cause estrogen like effects. TSC has been shown to activate ER-α in CHO (Chinese hamster ovary) cells transiently transfected with a wild-type estrogen receptor and an estrogen response element luciferase (ERE-luciferase) reporter gene.
The purpose of the current research is to identify if metals in the inorganic fraction of TSC are responsible for the activation of the ER by TSC. The inorganic fraction was separated via solvent extraction with H2O and low methanol concentrations. The transfected CHO cells were treated with each TSC fraction and the luciferase activity was measured. Estradiol and whole TSC extracted with DMSO were used as positive controls.
Early findings reveal that the inorganic fraction is responsible for the estrogen receptor activity. To determine which metals within this fraction are responsible for the activity, ion-exchange chromatography will be performed. Further investigation will be performed to determine if the organic fraction from TSC can also activate the estrogen receptor.
Identification and clarification of the mechanism by which TSC activates the estrogen receptor represents a significant step in breast cancer prevention and treatment.
Health Education to Improve Health Outcomes of Teenage Mothers.
Elissa Thorner. School of Nursing and Health Studies, Health Studies individualized track, Georgetown University.
In the past, teenage mothers have been conceptualized by mainstream American society as simultaneously and paradoxically defenseless, neglected, and manipulated yet also socially deviant, self-destructive, and irresponsible. In response, my own research examines the outcomes and perceived consequences teenage Latina mothers experience after childbirth and what programs can be implemented to change at-risk behaviors. The mission of this research was to support and advocate for 21 teenage mothers at a District of Columbia high school and more importantly, to employ health education and emphasize personal resources in order to inspire in them positive changes to their health behaviors.
I instigated a position at a Washington, D.C. high school as a health educator with Latina high school students who were mothers between the ages of 14-19. I collected qualitative data from informal conversations, surveys, home visits, family workshops, semi-structured interviews, community outreach, and through leading a weekly, mandatory class for the students. I designed a curriculum based on group health needs after completing a needs assessment that was made with the students and staff at the high school. The Social Cognitive Theory, Theory of Reasoned Action, and the Health Belief Model were implemented to increase achievement of goals and objectives.
Results showed students engaged in new behaviors evidenced through healthier outcomes. Trust between myself, as the researcher, and teen mothers was in most cases established and has been maintained. Tremendous success has been reached in the prevention of second pregnancies. There have been no second pregnancies to report in this year amongst the 21 students. This is 30% lower than the program’s history.
In conclusion, achievement of the majority of designated goals and objectives demonstrates health positions are changing and individual success is leading to the improvement in the quality of life of these teens. This analysis is a preliminary step in unfolding how health attitudes can be modified after teenage motherhood.
Effect of AKT on Tumor Growth in Mice Xenografts.
Abigail Winder, Mary Beth Martin, Ph.D. and Adriana Stoica, Ph.D., School of Nursing and Health Studies, Health Studies Science Program (A.W. and A. S.) and Department of Oncology (M.B.M. and A.S.), Georgetown University.
Estrogen typically binds to the estrogen receptor (ER) in the nucleus. In more than 60% of human breast cancers significant quantities of ER are detectable. However, at most two-thirds of breast tumors respond to hormone therapy, such as tamoxifen, and 5-10% of ER negative breast tumors also respond to hormone therapy. A better understanding of the mechanisms that regulate expression and activity of ER will improve the prognostic and therapeutic treatments for breast cancer patients.
The ErbB2 pathway mediates the activation of phosphatidyl inositol 3-kinase (PI3-K)/serine/threonine protein kinase (Akt) when estradiol stimulates membrane ER. Akt, similar to estradiol can induce anchorage-dependent and independent cell growth in the ER-positive breast cancer cell line, MCF-7.
We will measure tumor growth over 120 days under different treatments in nude mice inoculated with MCF-7 cells (parental or stably transfected with a constitutively active or dominant negative Akt). The effect of estradiol in the presence or absence of an anti-estrogen or a selective ErbB2 inhibitor will be compared in the three different xenografts.
The mice were inoculated on February 14, 2003 and a table of tumor size and animal weight is currently being made.
If we demonstrate that similar to our in vitro studies, Akt can induce tumor growth and its effects can not be fully abolished by the anti-estrogen tamoxifen, but can be totally blocked by an ErbB2 inhibitor or by a dominant-negative Akt mutant, then we can use Akt and/or ErbB2 as targets for therapy in a hormone-dependent breast cancer. Akt may also represent a new prognostic marker.