Bradley E. Aouizerat

Abstract

Though pursuit of host genetic factors that influence the pathogenesis of HIV began over two decades ago, progress has been slow. Initial genome-level searches for variations associated with HIV-related traits have yielded interesting candidates, but less in the way of novel pathways to be exploited for therapeutic targets. More recent genome-wide association studies (GWAS) that include different phenotypes, novel designs, and that have examined different population characteristics suggest novel targets and affirm the utility of additional searches. Recent findings from these GWAS are reviewed, new directions for research are identified, and the promise of systems biology to yield novel insights is discussed.

Abstract

Symptom burden has been identified as a predictor of medication adherence, but little is known about which symptoms are most strongly implicated. This study examines self-reported medical adherence in relation to demographic, clinical, and symptom characteristics among 302 adults living with HIV. Only 12% reported missing medication during the 3-day assessment, but 75% gave at least one reason for missing it in the previous month. Poor adherence was associated with higher viral load and greater symptom burden. Trouble sleeping and difficulty concentrating were strongly associated with poor adherence. Given that " forgetting" was the most common reason for missing medication and nearly one third reported sleeping through dose time, future research should examine the influence of sleep disturbance on adherence. Effective management of common symptoms, such as sleep disturbance, fatigue, and gastrointestinal side-effects of medications may result in better adherence, as well as improved clinical outcomes and quality of life.

Abstract

Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.

Abstract

Background: Little is known about the relationships between sleep parameters and fatigue in patients at the initiation of radiation therapy (RT). Objectives: The objectives of this study were to describe values for nocturnal sleep/rest, daytime wake/activity, and circadian activity rhythm parameters measured using actigraphy and to evaluate the relationships between these objective parameters and subjective ratings of sleep disturbance and fatigue severity, in a sample of patients at the initiation of RT. Methods: Patients (n = 185) with breast, prostate, lung, or brain cancer completed self-report measures for sleep disturbance (ie, Pittsburgh Sleep Quality Index, General Sleep Disturbance Scale) and fatigue (Lee Fatigue Scale) and wore wrist actigraphs for a total of 48 hours prior to beginning RT. Actigraphy data were analyzed using the Cole-Kripke algorithm. Spearman rank correlations were calculated between variables. Results: Approximately 30% to 50% of patients experienced sleep disturbance, depending on whether clinically significant cutoffs for the subjective or objective measures were used to calculate occurrence rates. In addition, these patients reported moderate levels of fatigue. Only a limited number of significant correlations were found between the subjective and objective measures of sleep disturbance. Significant positive correlations were found between the subjective, but not the objective measures of sleep disturbance and fatigue. Conclusions: A significant percentage of oncology patients experience significant disturbances in sleep-wake circadian activity rhythms at the initiation of RT. The disturbances occur in both sleep initiation and sleep maintenance. Implications for Practice: Patients need to be assessed at the initiation of RT for sleep disturbance, so appropriate treatment is initiated.

Abstract

Purpose/Objectives: To describe the percentages of men with and without changes in sexual function from the beginning to end of radiation therapy and evaluate for differences in demographic and clinical characteristics, mood states, and quality of life (QOL) among patients who did and did not experience changes in sexual function. Design: Descriptive, longitudinal. Setting: Two radiation therapy departments in northern California. Sample: 70 men with prostate cancer who underwent primary or adjuvant radiation therapy. Methods: Self-report questionnaires, medical record reviews, and repeated measures analysis of variance. Main Research Variables: Changes in sexual function; depression, anxiety, and QOL. Findings: Patients were categorized into one of four sex groups (No Problem X 2, Problem-No Problem, No Problem-Problem, and Problem X 2) based on their responses to "Is your sexuality impacted by your illness?" at the beginning and end of radiation therapy. About 50% had a problem with sexual function either at the beginning or end of radiation therapy. Overall, men without sexual problems at both the beginning and end of radiation therapy had significantly less anxiety and depression and higher QOL scores than patients who developed a problem at the end and patients who had a problem at both time points. Conclusions: Changes in sexual function during the course of radiation therapy affect patients' mood and QOL. Implications for Nursing: Clinicians should evaluate the effects of radiation therapy on sexual function and monitor patients with prostate cancer for depression and anxiety as well as for changes in QOL.

Abstract

UNLABELLED: The rising incidence of obesity and diabetes coincides with a marked increase in fructose consumption. Fructose consumption is higher in individuals with nonalcoholic fatty liver disease (NAFLD) than in age-matched and body mass index (BMI)-matched controls. Because fructose elicits metabolic perturbations that may be hepatotoxic, we investigated the relationship between fructose consumption and disease severity in NAFLD. We studied 427 adults enrolled in the NASH Clinical Research Network for whom Block food questionnaire data were collected within 3 months of a liver biopsy. Fructose consumption was estimated based on reporting (frequency x amount) of Kool-aid, fruit juices, and nondietary soda intake, expressed as servings per week, and classified into none, minimum to moderate (<7 servings/week), and daily (> or =7 servings/week). The association of fructose intake with metabolic and histological features of NAFLD was analyzed using multiple linear and ordinal logistic regression analyses with and without controlling for other confounding factors. Increased fructose consumption was univariately associated with decreased age (P < 0.0001), male sex (P < 0.0001), hypertriglyceridemia (P < 0.04), low high-density lipoprotein (HDL) cholesterol (<0.0001), decreased serum glucose (P < 0.001), increased calorie intake (P < 0.0001), and hyperuricemia (P < 0.0001). After controlling for age, sex, BMI, and total calorie intake, daily fructose consumption was associated with lower steatosis grade and higher fibrosis stage (P < 0.05 for each). In older adults (age > or = 48 years), daily fructose consumption was associated with increased hepatic inflammation (P < 0.05) and hepatocyte ballooning (P = 0.05).CONCLUSION: In patients with NAFLD, daily fructose ingestion is associated with reduced hepatic steatosis but increased fibrosis. These results identify a readily modifiable environmental risk factor that may ameliorate disease progression in patients with NAFLD.

Abstract

Background: Metabolic syndrome is a combination of risk factors for cardiovascular disease and diabetes, It has been reported to be increased in human immunodeficiency virus (HIV)-infected individuals. Methods: In a cohort of HIV-infected adults we examined parameters that contribute to defining the metabolic syndrome and to estimating the 10-year risk of coronary heart disease (CHD). The study group consisted of 296 participants (217 men and 79 women) of mixed ethnicity with a mean age of 45.3 years. Results: There was an appreciable prevalence of metabolic syndrome (30.0%), with the frequency increasing to 42.5% in those over 50 years of age. Those with the metabolic syndrome had a lower viral load. More women had abdominal obesity (59.5%) than men (20.7%, P < 0.001). The frequency of elevated plasma glucose was higher in females (37.2%) compared to males (16.9%, P = 0.004). High frequencies of decreased high-density lipoprotein cholesterol (HDL-C) and elevated blood pressure were seen in both sexes. Hypertriglyceridemia was less prevalent in African Americans. In those under 50 years of age, the 10-year CHD risk score for men was double that for women (6.2% vs 2.7%, P < 0.001). In older participants, the risk was similar between the sexes, with a third having scores over 10%. Conclusions: The prevalence of metabolic syndrome was higher than in most other HIV cohorts. Those with the syndrome had significantly lower viral loads. Mean 10-year Framingham Cardiovascular Risk (FCR) scores were nearly doubled for those with metabolic syndrome. Both researchers and clinicians should consider age as well as sex when assessing patients with HIV infection for risks associated with metabolic syndrome.

Abstract

Purpose/Objectives: To examine how attentional fatigue changed from the time of simulation to four months after the completion of radiation therapy and to investigate whether specific variables predicted initial levels and trajectories of attentional fatigue. Design: Descriptive, longitudinal study. Setting: Two radiation therapy departments. Sample: 73 women with breast cancer who received primary or adjuvant radiation therapy. Methods: Participants completed questionnaires prior to, during, and after radiation therapy. Descriptive statistics and hierarchical linear modeling were used for data analysis. Main Research Variables: Attentional fatigue; demographic, clinical, and symptom characteristics. Findings: Large amounts of interindividual variability were found in the trajectories of attentional fatigue. At baseline, higher levels of attentional fatigue were associated with younger age, not working, a higher number of comorbidities, and higher levels of trait anxiety. The trajectory of attentional fatigue improved over time for women with higher body mass index at baseline. Conclusions: This study is the first to identify predictors of interindividual variability in attentional fatigue in women with breast cancer undergoing radiation therapy. The predictors should be considered in the design of future correlational and interventional studies. Implications for Nursing: Nurses could use knowledge of the predictors to identify patients at risk for higher levels of attentional fatigue. In addition, nurses could use the information to educate patients about how attentional fatigue may change during and following radiation therapy for breast cancer.

Abstract

Context: Fatigue and sleep disturbance are common problems in oncology patients and their family caregivers (FCs). However, little is known about factors that contribute to interindividual variability in these symptoms or to their underlying biologic mechanisms. Objectives: An evaluation was done on whether genetic variation in a prominent proinflammatory cytokine, interleukin-6 (IL-6 c.-6101A>T [rs4719714]), was associated with mean ratings of evening fatigue, morning fatigue, and sleep disturbance, as well as with the trajectories of these symptoms. Methods: Over six months, participants completed standardized measures of fatigue and sleep disturbance. Linear regression was used to assess the effect of the IL-6 genotype and other covariates on mean fatigue and sleep disturbance scores. Hierarchical linear modeling was used to determine the effect of the IL-6 genotype on symptom trajectories. Results: Common allele homozygotes reported higher levels of evening fatigue (P = 0.003), morning fatigue (P = 0.09), and sleep disturbance (P = 0.003) than minor allele carriers. Predictors of baseline level and trajectories of evening fatigue included age, gender, and genotype (intercepts) and baseline level of evening fatigue (slope). Predictors of baseline level and trajectories of morning fatigue included age and genotype (intercept) and age and baseline level of morning fatigue (slope). Predictors of baseline level and trajectories of sleep disturbance included age and genotype (intercept) and baseline level of sleep disturbance (slope). Conclusions: Findings provide preliminary evidence of a genetic association between a functional promoter polymorphism in the IL-6 gene and severity of evening fatigue, morning fatigue, and sleep disturbance in oncology patients and their FCs.

Abstract

Aims/hypothesis: The aim of this study was to define the prevalence of the metabolic syndrome and its component risk factors among individuals of South Asian origin living in the United States. Methods: We analyzed baseline data from 1,445 participants enrolled in a cohort study investigating risk factors for cardiovascular disease in South Asians. We defined the metabolic syndrome using the International Diabetes Federation criteria for waist circumference (>90cm for men; >80cm, women), triglycerides (>150mg/dL), high-density lipoprotein cholesterol (HDL-C) (<40mg/dL (men), <45mg/dL (women)), blood pressure (>135/80mmHg), and fasting glucose (>100mg/dL). Results: The mean age was 43±10 years, and 30% of participants were women. The prevalence of metabolic syndrome was 27% (31% men vs. 17% women, P<0.05). Fifty-nine percent of the cohort had high waist circumference (58% men vs. 62% women, P = not significant [N.S.]), 47% had low HDL-C [46% men vs. 48% women (NS)], 19% had elevated triglycerides (23% men vs. 8% women, P<0.05), 14% had hypertension (16% men vs. 9% women, P< 0.05), and 13% had elevated fasting glucose (18% men vs. 11% women, P<0.05). The most common metabolic syndrome phenotype is low HDL-C with elevated triglycerides. Conclusions: Although the prevalence of the metabolic syndrome is lower than previous reports of South Asians, the prevalence is still unacceptably high despite the presence of protective demographic factors.