The relationship of thymulin activity, immune parameters of HIV disease progression and substance use in a cohort of HIV seropositive alcohol and drug users

Zinc is essential for the activity of thymulin, a thymic hormone involved in T-lymphocyte differentiation and activation. Zinc deficiency is widespread in populations with HIV infection, and HIV+ drug users are particularly susceptible to zinc deficiency and immune suppression. This dissertation explored the relationship of zinc-bound active thymulin to plasma zinc, CD4+ and CD8+ cell count, the CD4+/CD8+ ratio, and drug use in HIV-infected drug users. Zinc-bound active thymulin was assessed in plasma of HIV+ drug users who were participating in a 30 month zinc supplementation trial. Plasma from 80 participants at the 12 month visit, and 40 of these same participants, randomly selected, at the baseline visit were assessed for zinc-bound active thymulin levels using a modification of the rosette inhibition assay. Thymulin activity was directly associated with CD4+ cell count (β = 0.127, p = 0.002) and inversely associated with cocaine use (β = −0.908, p = 0.026; R2 = 0.188, p = 0.019) independent of HIV viral load, age, gender and antiretroviral use. An increase in thymulin activity was 1.4 times more likely when CD4+ cell count increased (OR = 1.402, 95%CI: 1.006–1.956), independent of change in viral load, antiretroviral use, and age. Participants who used cocaine consistently, were 7.6 times less likely to have an increase in thymulin activity (OR = 0.133, 95%CI: 0.017–1.061). There was a direct correlation between change in plasma zinc and change in zinc-bound active thymulin (r = 0.243, p = 0.13). Analysis of CD4+ cell count decline in 222 participants in the zinc supplementation trial across the 30 months showed that both crack cocaine use and heavy alcohol use accelerated CD4+ cell count decline. Thymulin activity is directly associated with HIV disease progression, measured by CD4+ cell count, and is depressed with cocaine use independent of antiretroviral use and HIV viral load. Cocaine and heavy alcohol accelerate CD4+ cell count decline. The effect of cocaine on thymic output requires further evaluation as a mechanism for the association of cocaine use with faster HIV disease progression.

Maltreatment, psychiatric symptoms and human immunodeficiency virus/sexual transmitted infection risk behavior among youth with alcohol and other drug use problems: A person-centered analysis

Multi-problem youth undergoing treatment for substance use problems are at high behavioral risk for exposure to sexually transmitted infections (STIs), including human immunodeficiency virus (HIV). Specific risk factors include childhood adversities such as maltreatment experiences and subsequent forms of psychopathology. The current study used a person-centered analytical approach to examine how childhood maltreatment experiences were related to patterns of psychiatric symptoms and HIV/STI risk behaviors in a sample of adolescents (N = 408) receiving treatment services. Data were collected in face-to-face interviews at two community-based facilities. Descriptive statistics and Latent Profile Analysis (LPA) were used to (a) classify adolescents into groups based on past year psychiatric symptoms, and (b) examine relations between class membership and forms of childhood maltreatment experiences, as well as past year sexual risk behavior (SRB). ^ LPA results indicated significant heterogeneity in psychiatric symptoms among the participants. The three classes generated via the optimal LPA solution included: (a) a low psychiatric symptoms class, (b) a high alcohol symptoms class and (c) a high internalizing symptoms class. Class membership was associated significantly with adolescents’ self-reported scores for childhood sexual abuse and emotional neglect. ANOVAs documented significant differences in mean scores for multiple indices of SRB indices by class membership, demonstrating differential risk for HIV/STI exposure across classes. The two classes characterized by elevated psychiatric symptom profiles and more severe maltreatment histories were at increased behavioral risk for HIV/STI exposure, compared to the low psychiatric symptoms class. The high internalizing symptoms class reported the highest scores for most of the indices of SRB assessed. The heterogeneity of psychiatric symptom patterns documented in the current study has important implications for HIV/STI prevention programs implemented with multi-problem youth. The results highlight complex relations between childhood maltreatment experiences, psychopathology and multiple forms of health risk behavior among adolescents. The results underscore the importance of further integration between substance abuse treatment and HIV/STI risk reduction efforts to improve morbidity and mortality among vulnerable youth. ^

Implementing Employee Drug and Alcohol Testing: Implications for Hotel Managers

Abuse of drugs and alcohol in the workplace has reached epidemic proportions in the hotel industry. The authors review considerations for drug testing and discuss drug and alcohol testing methods and the manner in which an effective policy should be developed.

An investigation of the relationship between maltreatment and alcohol and other drug (AOD) problems in African -American and Hispanic adolescent girls

Maltreatment experienced in childhood or adolescence is a known risk factor for later problem alcohol and/or other drug (AOD) use (Bailey & McCloskey, 2005; Shin, Edwards, Heeren, 2009). A growing body of empirical work has found significant associations between adolescent girls’ AOD use and maltreatment experiences. However, questions remain as to how this relation unfolds with African-American and Hispanic adolescent girls. Guided by four relational models that have been proposed in the literature, this study examined the links between maltreatment, trauma symptoms, and alcohol and/or other drug (AOD) problems in a sample of 170 African-American and Hispanic adolescent girls who were participants in a school-based AOD use intervention. Results of this study revealed that maltreatment experiences (physical and emotional abuse) were positively related to trauma symptoms, which were positively related to AOD problem severity, alcohol abuse, alcohol dependency, drug abuse, and drug dependency. Perceived discrimination moderated this relation between sexual abuse and trauma symptoms, such that more perceived discrimination resulted in a stronger effect of sexual abuse on trauma symptoms. Ethnic identity moderated the relation between sexual abuse and AOD problem severity, such that ethnic identity demonstrated protective properties in the relation between sexual abuse and AOD problem severity. My research adds to extant knowledge on the relation between maltreatment and AOD use in adolescent girls and suggests the importance of developing interventions targeting maltreatment and AOD use concurrently.

The influence of neurocognitive impairment, alcohol and other drug (AOD) use, and psychosocial factors on antiretroviral treatment adherence, service utilization and viral load among HIV-seropositive adults

Among people living with HIV (PLWH), adherence to antiretroviral therapy (ART) can be affected by problems of neurocognitive (NC) impairment, stress, alcohol and other drug (AOD) abuse, and other barriers. The aims of this research were to: (1) examine factors associated with NC impairment, (2) explore relationships between psychosocial variables with ART adherence and viral load (VL), and (3) evaluate the efficacy of an evidence-based intervention in improving ART adherence, increasing service utilization, and decreasing VL. The first study (n=370) was cross sectional and used structural equation modeling to test whether AOD use, years living with HIV, and time from HIV diagnosis to seeking care were associated with poorer NC functioning. The second study (n=246) used similar methods to test the hypothesis that stress, barriers to adherence, NC impairment, poor social support, and AOD use were related to lower VL mediated by ART adherence. The third study (n=243) evaluated an evidence-based, eight-session program to improve ART adherence, reduce VL, and increase service utilization in a randomized controlled trial. Study participants were PLWH living in South Florida, 18 to 60 years old, with a history of alcohol abuse enrolled from January 2009 through November 2012. Secondary analysis of available data showed: (1) scores on interference with executive functioning increased by 0.32 for each day of marijuana use and 1.18 for each year living with HIV, but no association was found between alcohol use and NC functioning; (2) each barrier to adherence was associated with a 10% decrease in adherence to ART and a 0.42 unit increase in VL (log10) and the relationship between barriers and VL was partially mediated by ART adherence; (3) participants in the evidence-based program were more likely than the comparison group to report an undetectable VL (OR=2.25, p<0.01) at 6 months, but not 3 months, post-intervention. Psychosocial factors affect VL, but ART adherence is essential in achieving an undetectable VL in PLWH.

Maltreatment, Psychiatric Symptoms and Human Immunodeficiency Virus/Sexual Transmitted Infection Risk Behavior Among Youth with Alcohol and Other Drug Use Problems: A Person-Centered Analysis

Multi-problem youth undergoing treatment for substance use problems are at high behavioral risk for exposure to sexually transmitted infections (STIs), including human immunodeficiency virus (HIV). Specific risk factors include childhood adversities such as maltreatment experiences and subsequent forms of psychopathology. The current study used a person-centered analytical approach to examine how childhood maltreatment experiences were related to patterns of psychiatric symptoms and HIV/STI risk behaviors in a sample of adolescents (N = 408) receiving treatment services. Data were collected in face-to-face interviews at two community-based facilities. Descriptive statistics and Latent Profile Analysis (LPA) were used to (a) classify adolescents into groups based on past year psychiatric symptoms, and (b) examine relations between class membership and forms of childhood maltreatment experiences, as well as past year sexual risk behavior (SRB). LPA results indicated significant heterogeneity in psychiatric symptoms among the participants. The three classes generated via the optimal LPA solution included: (a) a low psychiatric symptoms class, (b) a high alcohol symptoms class and (c) a high internalizing symptoms class. Class membership was associated significantly with adolescents’ self-reported scores for childhood sexual abuse and emotional neglect. ANOVAs documented significant differences in mean scores for multiple indices of SRB indices by class membership, demonstrating differential risk for HIV/STI exposure across classes. The two classes characterized by elevated psychiatric symptom profiles and more severe maltreatment histories were at increased behavioral risk for HIV/STI exposure, compared to the low psychiatric symptoms class. The high internalizing symptoms class reported the highest scores for most of the indices of SRB assessed. The heterogeneity of psychiatric symptom patterns documented in the current study has important implications for HIV/STI prevention programs implemented with multi-problem youth. The results highlight complex relations between childhood maltreatment experiences, psychopathology and multiple forms of health risk behavior among adolescents. The results underscore the importance of further integration between substance abuse treatment and HIV/STI risk reduction efforts to improve morbidity and mortality among vulnerable youth.

An Investigation of the Relationship Between Maltreatment and Alcohol and Other Drug (AOD) Use Among African-American and Hispanic Adolescent Girls

Maltreatment experienced in childhood or adolescence is a known risk factor for later problem alcohol and/or other drug (AOD) use (Bailey & McCloskey, 2005; Shin, Edwards, Heeren, 2009). A growing body of empirical work has found significant associations between adolescent girls’ AOD use and maltreatment experiences. However, questions remain as to how this relation unfolds with African-American and Hispanic adolescent girls. Guided by four relational models that have been proposed in the literature, this study examined the links between maltreatment, trauma symptoms, and alcohol and/or other drug (AOD) problems in a sample of 170 African-American and Hispanic adolescent girls who were participants in a school-based AOD use intervention. Results of this study revealed that maltreatment experiences (physical and emotional abuse) were positively related to trauma symptoms, which were positively related to AOD problem severity, alcohol abuse, alcohol dependency, drug abuse, and drug dependency. Perceived discrimination moderated this relation between sexual abuse and trauma symptoms, such that more perceived discrimination resulted in a stronger effect of sexual abuse on trauma symptoms. Ethnic identity moderated the relation between sexual abuse and AOD problem severity, such that ethnic identity demonstrated protective properties in the relation between sexual abuse and AOD problem severity. My research adds to extant knowledge on the relation between maltreatment and AOD use in adolescent girls and suggests the importance of developing interventions targeting maltreatment and AOD use concurrently.

The international evidence on the prevention of drug and alcohol use Summary and examples of implementation in England

The United Nations Office of Drug Control (UNODC) published ‘International Standards on Drug Use Prevention’ in 2013. The Standards were developed through a systematic assessment of the international evidence on prevention and they provide a summary of the available scientific evidence. The briefing provides a summary of the UNODC prevention standards and gives corresponding examples of relevant UK guidelines,programmes and interventions currently available in England. Its aim is to help people who commission, develop and implement prevention strategies and interventions to translate the standards into the English operating landscape. It also aims to support local authority commissioners to develop their prevention strategies and implement them in line with evidence.  

Renal Drug Transporters – Clinical Significance and Role in Drug-Drug Interactions

Thesis (Ph.D.)--University of Washington, 2016-07

Applications of functional nucleic acids in imaging, sensing and drug delivery and investigations of DNAzyme-metal interactions

Functional nucleic acids (FNA), including nucleic acids catalysts (ribozymes and DNAzymes) and ligands (aptamers), have been discovered in nature or isolated in a laboratory through a process called in vitro selection. They are nucleic acids with functions similar to protein enzymes or antibodies. They have been developed into sensors with high sensitivity and selectivity; it is realized by converting the reaction catalyzed by a DNAzyme/ribozyme or the binding event of an aptamer to a fluorescent, colorimetric or electrochemical signal. While a number of studies have been reported for in vitro sensing using DNAzymes or aptamers, there are few reports on in vivo sensing or imaging. MRI is a non-invasive imaging technique; smart MRI contrast agents were synthesized for molecular imaging purposes. However, their rational design remains a challenge due to the difficulty to predict molecular interactions. Chapter 2 focuses on rational design of smart T1-weighted MRI contrast agents with high specificity based on DNAzymes and aptamers. It was realized by changing the molecular weight of the gadolinium conjugated DNA strand with the analytes, which lead to analyte-specific water proton relaxation responses and contrast changes on an MRI image. The designs are general; the high selectivity of FNA was retained. Most FNA-based fluorescent sensors require covalent labeling of fluorophore/quencher to FNAs, which incurrs extra expenses and could interfere the function of FNAs. Chapter 3 describes a new sensor design avoiding the covalent labeling of fluorophore and quencher. The fluorescence of malachite green (MG) was regulated by the presence of adenosine. Conjugate of aptamers of MG and adenosine and a bridge strand were annealed in a solution containing MG. The MG aptamer did not bind MG because of its hybridization to the bridge strand, resulting in low fluorescence signal of MG. The hybridization was weakened in the presence of adenosine, leading to the binding of MG to its aptamer and a fluorescence increase. The sensor has comparable detection limit (20 micromolar) and specificity to its labeled derivatives. Enzymatic activity of most DNAzymes requires metal cations. The research on the metal-DNAzyme interaction is of interest and challenge to scientists because of the lack of structural information. Chapters 4 presents the research on the characterization of the interaction between a Cu2+-dependent DNAzyme and Cu2+. Electron paramagnetic resonance (EPR) and UV-Vis spectroscopy were used to probe the binding of Cu2+ to the DNAzyme; circular dichroism was used to probe the conformational change of the DNAzyme induced by Cu2+. It was proposed that the conformational change by the Cu2+ binding is important for the activity of the DNAzyme. Chapter 5 reports the dependence of the activity of 8-17 DNAzyme on the presence of both Pb2+ and other metal cations including Zn2+, Cd2+ and Mg2+. It was discovered that presence of those metal cations can be cooperative or inhibitive to 8-17 activity. It is hypothesized that the 8-17 DNAzyme had multiple binding sites for metal cations based on the results. Cisplatin is effective killing tumor cells, but with significant side effects, which can be minimized by its targeted delivery. Chapter 6 focuses on the effort to functionalize liposomes encapsulating cisplatin by an aptamer that selectively bind nucleolin, an overexpressed protein by breast cancer cells. The study proved the selective cytotoxicity to breast cancer cells of the aptamer-functionalized liposome.

Interactions between drugs and drug-nutrient in enteral nutrition: a review based on evidences

Introduction: Enteral nutrition (EN) provides calories, macronutrients and micronutrients in adequate quantity and quality to meet the patient's needs. Some drugs when crushed and diluted may have their properties altered, including the reduction of bioavailability causing the reduction of the serum concentration of the drug; tube obstruction; drug-drug interaction or drug-nutrient interaction. Methods: The study was conducted through review of submitted articles in the databases of the Virtual Health Library (VHL): MEDLINE (National Library of Medicine, USA), Lilacs (Latin American and Caribbean Literature on Health Sciences) PUBMED - NCBI (National Center for Biotechnology Information) and COCHRANE. Results: For this survey, 42 articles were identified during database searching. After applying the inclusion and exclusion criteria, 08 articles were selected, obtained from the MEDLINE and Lilacs. Discussion: Some interactions were found such as the aluminium hydroxide and lactulose with the enteral nutrition, which may result in a precipitation and reduction of drug bioavailability. Mineral oil will alter the absorption of fat-soluble vitamins and reduces the tube light. Others results were found as phenytoin, warfarin, captopril and furosemide with enteral nutrition may reduce the maximum serum concentration. Conclusion: Drug interactions are more common in day-to-day activities than health professionals may suppose. Knowledge on the matter may also assist in reducing cases of obstruction of tubes, through which enteral nutrition and medications are administered. Thus, the multidisciplinary team, acting together, may have more beneficial effects to the patient.