The main psychoactive and therapeutic effects of Δ9-tetrahydrocannabinol (THC) are mediated through cannabinoid type 1 receptors (CB1Rs). The therapeutic uses of THC are mitigated by the development of tolerance to these therapeutic effects, whereas tolerance does not readily develop to some of the side-effects of THC, like motor impairment and reward. The development of tolerance occurs through adaptations at CB1Rs, which include desensitization (G-protein uncoupling) and downregulation (receptor degradation). Brain region-dependent differences in THC-mediated adaptations are proposed to explain the differences in tolerance to various THC-mediated effects. These studies focused on whether ΔFosB, a stable transcription factor, could regulate CB1R adaptations since regions resistant to CB1R adaptations, like the basal ganglia, exhibit THC-mediated ΔFosB induction. The studies in this dissertation tested the hypothesis that THC-mediated induction of ΔFosB is regulated through interactions between cannabinoid and dopamine systems and that brain region-dependent differences in ΔFosB transcriptional regulation could explain some aspects of long-term CB1R signaling and CB1R adaptations. Results determined that THC induced ΔFosB primarily in forebrain areas, like striatum, that are innervated by midbrain dopamine neurons. An inverse, brain region-dependent correlation was found between CB1R desensitization and ΔFosB induction. Studies utilizing bitransgenic mice with overexpression of ΔFosB, or its dominant negative ∆cJun, determined that ΔFosB regulates CB1R signaling and reduces CB1R desensitization. Based on this regional profile, studies determined the role of dopamine signaling in THC-mediated ∆FosB induction. Results showed that THC-mediated induction of ΔFosB required dopamine type 1 receptors, but not the dopamine-and cAMP-dependent phosphoprotein of Mr 32kDA. Finally, the functional consequences of THC-mediated ΔFosB induction were assessed by measuring expression of known targets of ΔFosB following both acute and repeated THC administration. Results found that, in prefrontal cortex, known targets of ΔFosB exhibited functionally different signaling expression patterns when comparing acute THC with THC-challenge in THC-experienced mice, which enhanced ΔFosB induction. These studies establish a role for ΔFosB in regulating long-term CB1R signaling/adaptation following repeated THC administration and could have implications for changes in the effects of THC during repeated administration, including the development of differential tolerance to motor-impairing and rewarding effects of THC versus other pharmacological effects.

Introduction: Among women, breast cancer is the most prevalent cancer and the second leading cause of cancer death. Although technology advances have improved survival rates for breast cancer overall, improvements have not been universally experienced by all socioeconomic and racial groups. Known determinants of breast cancer care disparities include socioeconomic status, race, age, and social support. As a part of the Breast and Cervical Cancer Mortality Prevention Act of 1990 and with the help of CDC funding, the Virginia Breast and Cervical Cancer Early Detection Program (BCCEDP) or Every Woman’s Life (EWL) was created. EWL provides breast cancer screening to female VA residents between the ages of 18 and 64 who lack health insurance and fall at or below 200% of the Federal Poverty Level. Objective: The purpose of this study is to determine if delays in the diagnosis and treatment of breast cancer, within the VDH program EWL, differs based on sociodemographic characteristics and/ or regional location. Methods: From its inception to July 2008, 705 women received a breast cancer diagnosis through the EWL program. For these 705 cases prevalence and crude odds ratios were calculated for both diagnosis and treatment delays for all of the demographic variables along with 95% confidence intervals. Adjusted odds ratios were calculated for sociodemographic variables against screening to diagnosis delays and diagnosis to treatment disparities along with 95% confidence intervals. Results: According to the crude odds ratios more women who fall into the other category of race experienced diagnosis delays (OR=2.28 [1.11, 4.67]), but they were more likely to receive treatment in a timely manner (OR=0.29 [0.11, 0.79]). Women living alone were also more likely to experience diagnosis delays (OR=1.49 [1.10, 3.02]). Hispanic women were more likely to receive treatment in a more timely manner than non-Hispanic women (OR=0.21 [0.05, 0.81]). Also, women being treated in any other region than northern VA were more likely to experience treatment delays. However, according to the adjusted odds ratios, the only significant timing delay was the one experienced more often by women in the other race category. Conclusion: The research indicates known indicators of disparities within cancer care as socioeconomic status, race, ethnicity, age, and social support. The findings of this study indicate that the only significant indicator of disparity within the Every Women’s Life program is race. Although, African-American women were just as likely to receive timely diagnosis and treatment as white women in the program, it was the combined groups of Asian, American Indian, and other women that were more likely to experience diagnosis, but not treatment, delays. The fact that no other significant indicators of disparities were found within EWL indicates a success of the program, as EWL is targeting those women that would have otherwise been missed by the system.

Objectives: This study estimates the proportion of intravenous drug use (IDU) partners and HIV positive sexual partners among black and white and examine the association between repeat HIV testing and sex with high risk partners. Methods: A cross-sectional study of MSM was conducted by using pooled data from counseling, Testing, Referral services in Virginia, USA 2002-2007. Results: We obtained a sample of 19679 MSM out of which 10924(56%) and 6739(34%) were white and black MSM respectively. The proportion of IDU partners and HIV positive partners were among white MSM (5% and 11%) and black MSM (3% and 9%) respectively. Age rather than race was significantly associated with having more IDU and HIV positive partners. MSM in 30 - 39 age groups were thrice likely to have sex with HIV partners compared to young MSM. 79% and 74% of the white MSM and black MSM had undergone previous HIV testing. Previously tested MSM were twice likely to report to have sex with HIV positive partners compared to first time testers. Discussion: These findings suggest that fewer black MSM compared with white MSM report having HIV positive sex partners. HIV test repeaters continue to engage in sex with high risk individuals. Further study is needed to compare high risk behaviors between HIV positive repeaters and HIV negative repeaters. Identifying the epidemiological dynamics driving HIV infection among black MSM that go beyond individual level risk behaviors may be warranted.

The purpose of this study was to compare shear bond strengths of brackets bonded to stainless steel crowns using various orthodontic adhesives and surface conditioning techniques. One hundred and twenty mandibular first molar stainless steel crowns were randomly divided into groups: (1): Aluminablasting + Metal Primer + Assure; (2): Aluminablasting + Silane Coupling Agent + Transbond; (3): Diamond Bur Abrasion + Metal Primer + Assure; (4): Diamond Bur Abrasion + Silane Coupling Agent + Transbond; (5: control): Acid Etching + Metal Primer + Assure; (6: control): Acid Etching + Silane Coupling Agent + Transbond. Bond strength was tested using a universal testing machine. Both aluminablasting and diamond bur abrasion surface preparation techniques, when used in conjunction with metal primer and Assure bonding resin, reached clinically acceptable bond strength values (9.05 and 9.30 MPa, respectively). These techniques seem to offer viable options to bond orthodontic brackets to stainless steel crowns.

The oxygen uptake (VO2) kinetic response to exercise provides insight into aerobic performance and the efficiency of the body to maintain oxygen demand during the initiation of exercise. Previous research in normal weight children reports insignificant differences in gender VO2 on-kinetic responses to moderate exercise. No study has evaluated the impact obesity may have on gender VO2 on-kinetics. PURPOSE: To determine if sex differences exist in the VO2 kinetic response to moderate exercise in obese adolescents. METHODS: Male (n=16) and female (n=39) adolescents completed a graded exercise test to exhaustion on a treadmill. Data from initial 4-min treadmill walking was used to determine a time constant. RESULTS: The time constant was significantly different (P=0.009) between obese male and female adolescents (15.42±7.31 s vs. 22.03±8.56 s, respectively). CONCLUSION: Sex differences exist in VO2 on-kinetics during moderate exercise in obese adolescents indicating an enhanced potential for males to deliver and/or utilize oxygen.

Breast cancer (BC) is one of the most common diagnosed malignancies in females. Although 90% of early diagnosed women are expected to survive for at least 5 years, their quality of life is adversely affected by a cluster of symptoms which we collectively named “psychoneurological symptoms’’ (PN). Given that acquired telomere attrition has been speculated to be a causal factor in chronic diseases and the lack in the literature of mechanisms giving rise to PN symptoms, this study was performed to assess telomere length using a chromosome-specific telomere assay before receiving chemotherapy and at the first chemotherapy. We showed significant telomere attrition on the short arm of chromosome 9. In addition, we showed a negative correlation between telomere length and depression. Furthermore, we evaluated several variables as predictors of the change in telomere length and showed that chemotherapy was predictive of shortened telomere length. Taken together, one can speculate that shortened telomeres could result in epigenetic alterations in the genes juxtaposed to the telomeric region, giving rise to the development and persistence of PN symptoms. Knowledge gained from this study will offer hope for the development of therapeutic interventions that could prevent undesirable side effects and ensure a better quality of life for patients with BC.

Naegleria fowleri (N. fowleri) and Naegleria lovaniensis (N. lovaniensis) are closely related amebae found in the environment. N. fowleri causes Primary Amebic Meningoencephalitis (PAM), a fatal disease of the central nervous system, while N. lovaniensis is nonpathogenic. N. fowleri infection occurs when amebae enter the nasal passages, and migrate to the brain. The molecular mechanisms involved in the pathogenesis of PAM are not well-defined. Therefore, the purpose of this study was to define phenotypic characteristics that may be functionally linked to the pathogenicity associated with N. fowleri. Studies revealed that N. fowleri has a faster growth rate and is more resistant to complement-mediated lysis when compared to N. lovaniensis. Additionally, contact-independent cytotoxicity was observed only for N. fowleri. The ability to invade tissues can be a characteristic that distinguishes pathogens from nonpathogens. Therefore, adhesion to extracellular matrix components (ECM), laminin-1, fibronectin, and collagen I, was assessed. N. fowleri exhibited a higher level of adhesion to ECM components and was shown to invade tri-dimensional ECM scaffolds (matrigel and collagen I) to a greater extent than N. lovaniensis. Scanning electron microscopy revealed that N. fowleri attached on ECM substrata exhibited a spread-out appearance that included the presence of focal adhesion-like structures. Attachment of N. fowleri to ECM components was decreased significantly when amebae were pretreated with trypsin, suggesting a role for a surface protein in this process. Pretreatment of N. fowleri amebae with periodate, a sugar oxidant, led to a decrease in attachment to laminin-1 and fibronectin suggesting that the surface component contained a sugar moiety. Western immunoblotting revealed two integrin-like proteins for both species. However, one with a molecular mass of approximately 70 kDa, was detected at a higher level for N. fowleri. Confocal microscopy indicated that the integrin-like proteins co-localized to the focal adhesion-like structures. An anti-integrin antibody decreased adhesion of N. fowleri to ECM components. Zymographic analysis demonstrated differential expression of proteases occurs when N. fowleri and N. lovaniensis invade ECM components using an in vitro invasion assay. These results indicate a distinction in adhesion to, and invasion of, extracellular matrix proteins between N. fowleri and N. lovaniensis.

The chemokine receptor CCR5 has been implicated in the pathogenesis of cancers and AIDS. A series of novel piperidine derivatives were designed, synthesized, and evaluated as CCR5 antagonists. The ability of the new ligands to inhibit the increment of intracellular calcium level stimulated by endogenous ligand CCL5 was measured in the calcium mobilization assay as an indication of its CCR5 receptor antagonism. The anti-proliferation assay was performed to measure the ability of these new compounds to inhibit the proliferation of prostate cancer cell lines, PC-3 and M12. A new lead compound has been identified which showed micromolar level of inhibition to PC-3 cell line proliferation as well as calcium mobilization. These studies are the beginning of a thorough analysis of the CCR5 receptor antagonist binding pocket in the CCR5 receptor. Further examination may help identify next generation lead to develop highly selective CCR5 receptor antagonists and anti prostate cancer agents.

Background: Women account for about a third of all new cases of HIV in India. Based on research examining trends of HIV infection in women, male perception and behaviors have emerged as strong potential risk factors. However, there has been limited research examining the relationship between male’s attitudes toward women and their sexual risk-taking behaviors. This study examined the degree to which men’s beliefs about power dynamics in heterosexual relationships are related to risky sexual behaviors in Indian men. Methods: Data on Indian men from the 2005-2006 National Family Health Survey (NFHS-3) was analyzed (N= 44,727). The outcome variable, risky sexual behavior, was created using a composite variables characterized by multiple sexual partners, pay for sex, sexual relationships with individuals other than wife or girlfriend, or a history of sexually transmitted diseases in the past 12 months. Men’s beliefs about power dynamics in heterosexual relationships was examined using the following predictor variables: a) women’s role in decision-making, b) acceptability of domestic violence, and c) acceptability of refusing sex. Age, marital status, standard of living, education, religion, region, knowledge of HIV, alcohol use, and family history of domestic violence were examined as covariates. Multiple logistic regression was used to examine the association. Results: Men who believed that women should rarely OR=1.73 [CI 1.36, 2.20] or sometimes be involved with decision-making OR=1.33 [CI 1.13, 1.56] were more likely to report risky sexual behavior as compared to those who believed that women should be involved most of the time. Additionally, men who had favorable attitude towards perpetrating domestic violence were 56% more likely to report risky sexual behavior OR=1.56 [CI 1.37, 1.79]. Similarly, men who believed that it was never acceptable for a woman to refuse sex were 43% less likely to engage in risky sex OR=1.43 [CI 1.27, 1.69]. Conclusion: Men who expressed a preference for male-dominant decision making, acceptance of violence towards women, or the belief that women should not have autonomy in sexual matters are more likely to engage in behaviors that put themselves and their female partners at risk for HIV infection. Comprehensive HIV prevention programs should address power dynamics as a component of HIV risk.

Little is known about the health of the indigenous peoples in Virginia. When compared to the total U.S. population, indigenous peoples nationwide disproportionately experience disparities in health status across multiple health indicators. Research shows that these disparities are largely due to the inequitable distribution of social and economic determinants present within indigenous communities. Because the indigenous peoples of Virginia are affected by inequitable social and economic conditions, there is reason to believe that health indicators may mirror that of the indigenous population at-large. Outlined in this paper is a framework for exploring the needs, strengths, and priorities of indigenous communities in Virginia. This paper proposes that the use of a culturally relevant methodology, such as Talking Circle, combined with an emergent and community-based participatory approach, will lead to a more authentic identification of the strengths, needs, and priorities of indigenous communities than traditional public health surveillance methodology, as well as build community capacity for on-going engagement.