Faculty Bibliography
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319
Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations
UNLABELLED:Hepcidin regulation is linked to both iron and inflammatory signals and may influence iron loading in nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the relationships among HFE genotype, serum hepcidin level, hepatic iron deposition, and histology in nonalcoholic fatty liver disease (NAFLD). Single-nucleotide polymorphism genotyping for C282Y (rs1800562) and H63D (rs1799945) HFE mutations was performed in 786 adult subjects in the NASH Clinical Research Network (CRN). Clinical, histologic, and laboratory data were compared using nonparametric statistics and multivariate logistic regression. NAFLD patients with C282Y, but not H63D mutations, had lower median serum hepcidin levels (57 versus 65 ng/mL; P = 0.01) and higher mean hepatocellular (HC) iron grades (0.59 versus 0.28; P < 0.001), compared to wild-type (WT) subjects. Subjects with hepatic iron deposition had higher serum hepcidin levels than subjects without iron for all HFE genotypes (P < 0.0001). Hepcidin levels were highest among patients with mixed HC/reticuloendothelial system cell (RES) iron deposition. H63D mutations were associated with higher steatosis grades and NAFLD activity scores (odds ratio [OR], ≥1.4; 95% confidence interval [CI]: >1.0, ≤2.5; P ≤ 0.041), compared to WT, but not with either HC or RES iron. NAFLD patients with C282Y mutations had less ballooning or NASH (OR, ≤0.62; 95% CI: >0.39, <0.94; P ≤ 0.024), compared to WT subjects. CONCLUSIONS/CONCLUSIONS:The presence of C282Y mutations in patients with NAFLD is associated with greater HC iron deposition and decreased serum hepcidin levels, and there is a positive relationship between hepatic iron stores and serum hepcidin level across all HFE genotypes. These data suggest that body iron stores are the major determinant of hepcidin regulation in NAFLD, regardless of HFE genotype. A potential role for H63D mutations in NAFLD pathogenesis is possible through iron-independent mechanisms.
PMCID:3462887
PMID: 22611049
ISSN: 0270-9139
CID: 2807682
Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine
OBJECTIVE: CYP2B6 variation predicts pharmacokinetic characteristics of its substrates. Consideration for underlying genetic structure is critical to protect against spurious associations with the highly polymorphic CYP2B6 gene. DESIGN: The effect of CYP2B6 variation on response to its substrates, nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored in the Women's Interagency HIV Study. METHODS: Five putative functional polymorphisms were tested for associations with virologic suppression within 1 year after NNRTI initiation in women naive to antiretroviral agents (n = 91). Principal components were generated to control for population substructure. Logistic regression was used to test the joint effect of rs3745274 and rs28399499, which together indicate slow, intermediate, and extensive metabolizers. RESULTS: Rs3745274 was significantly associated with virologic suppression [odds ratio = 3.61, 95% confidence interval (CI) 1.16-11.22, P trend = 0.03]; the remaining polymorphisms tested were not significantly associated with response. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66 to infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for principal components (P trend = 0.005). Failure to control for genetic ancestry resulted in substantial confounding of the relationship between the metabolizer phenotype and treatment response. CONCLUSION: The CYP2B6 metabolizer phenotype was significantly associated with virologic response to NNRTIs; this relationship would have been masked by simple adjustment for self-reported ethnicity. Given the appreciable genetic heterogeneity that exists within self-reported ethnicity, these results exemplify the importance of characterizing underlying genetic structure in pharmacogenetic studies. Further follow-up of the CYP2B6 metabolizer phenotype is warranted, given the potential clinical importance of this finding.
PMCID:3940150
PMID: 22951632
ISSN: 1473-5571
CID: 1563832
Trajectories and predictors of symptom occurrence, severity, and distress in prostate cancer patients undergoing radiation therapy
CONTEXT: Radiation therapy (RT) is a common treatment for prostate cancer. Despite available research, prostate cancer patients report that information about side effects is their most important unmet need. Additional research is needed that focuses on specific dimensions of the patient's symptom experience. OBJECTIVES: The study's purposes were to evaluate the trajectories of occurrence, severity, and distress of the six most prevalent symptoms reported by patients undergoing RT for prostate cancer and the effects of selected demographic and clinical characteristics on these trajectories. METHODS: Patients completed the Memorial Symptom Assessment Scale 11 times before, during, and after RT. For problems with urination, pain, lack of energy, feeling drowsy, difficulty sleeping, and diarrhea, the trajectories of occurrence, severity, and distress were evaluated using multilevel generalized linear models. RESULTS: Across all three dimensions, pain, lack of energy, feeling drowsy, and difficulty sleeping followed a decreasing linear trend. Problems with urination and diarrhea demonstrated more complex patterns of change over time. CONCLUSION: Although longitudinal data on pain, lack of energy, feeling drowsy, and difficulty sleeping are limited, they are highly prevalent symptoms in these patients. In addition, diarrhea becomes a significant problem for these patients over the course of RT. A number of demographic and clinical characteristics affect the trajectories of these common symptoms differentially.
PMCID:3463773
PMID: 22771128
ISSN: 1873-6513
CID: 1563842
Identification of distinct subgroups of breast cancer patients based on self-reported changes in sleep disturbance
PURPOSE: The purposes of this study were to identify distinct subgroups of patients based on self-reported sleep disturbance prior to through 6 months after breast cancer surgery and evaluate for differences in demographic, clinical, and symptom characteristics among these latent classes. METHODS: Women (n = 398) who underwent unilateral breast cancer surgery were enrolled prior to surgery. Patients completed measures of functional status, sleep disturbance (i.e., General Sleep Disturbance Scale (GSDS); higher scores indicate higher levels of sleep disturbance), fatigue, attentional fatigue, depressive symptoms, and anxiety prior to surgery and monthly for 6 months. RESULTS: Three distinct classes of sleep disturbance trajectories were identified using growth mixture modeling. The high sustained class (55.0%) had high and the low sustained class (39.7%) had low GSDS scores prior to surgery that persisted for 6 months. The decreasing class (5.3%) had high GSDS score prior to surgery that decreased over time. Women in the high sustained class were significantly younger, had more comorbidity and poorer function, and were more likely to report hot flashes compared to the low sustained class. More women who underwent mastectomy or breast reconstruction were in the decreasing class. Decreasing and high sustained classes reported higher levels of physical fatigue, attentional fatigue, depressive symptoms, and anxiety compared to the low sustained class. CONCLUSIONS: A high percentage of women has significant sleep disturbance prior to surgery that persists during subsequent treatments (i.e., radiation therapy and chemotherapy). Clinicians need to perform routine assessments and initiate appropriate interventions to improve sleep prior to and following surgery.
PMID: 22290719
ISSN: 1433-7339
CID: 1563852
Determination of cutpoints for low and high number of symptoms in patients with advanced cancer
While patients with advanced cancer experience a wide range of symptoms, no work has been done to determine an optimal cutpoint for a low versus a high number of symptoms. Analytic approaches that established clinically meaningful cutpoints for the severity of cancer pain and fatigue provided the foundation for this study. The purpose of this study was to determine the optimal cutpoint for low and high numbers of symptoms using a range of potential cutpoints and to determine if those cutpoints distinguished between the two symptom groups on demographic and clinical characteristics and depression, anxiety, and quality of life (QOL). Patients with advanced cancer (n=110) completed a symptom assessment scale, and measures of depression, anxiety, and QOL. Combinations of cutpoints were tested to yield one- and two-cutpoint solutions. Using analysis of variance for QOL scores, the F-ratio that indicated the highest between-group difference was determined to be the optimal cutpoint between low and high number of symptoms. A cutpoint of
PMCID:3422053
PMID: 22853731
ISSN: 1557-7740
CID: 1563862
A longitudinal study of measures of objective and subjective sleep disturbance in patients with breast cancer before, during, and after radiation therapy
CONTEXT: Sleep disturbance is a significant problem in oncology patients. OBJECTIVES: To examine how actigraphy and self-report ratings of sleep disturbance changed over the course of and after radiation therapy (RT); investigate whether specific patient, disease, and symptom characteristics predicted the initial levels and/or the characteristics of the trajectories of sleep disturbance; and compare predictors of subjective and objective sleep disturbance. METHODS: Patients (n=73) completed self-report questionnaires that assessed sleep disturbance, fatigue, depressive symptoms, anxiety, and pain before the initiation of RT through four months after the completion of RT. Wrist actigraphy was used as the objective measure of sleep disturbance. Hierarchical linear modeling was used for data analyses. RESULTS: Mean wake after sleep onset was 11.9% and mean total score on the General Sleep Disturbance Scale was 45. More than 85% of the patients had an abnormally high number of nighttime awakenings. Substantial interindividual variability was found for both objective and subjective measures of sleep disturbance. Body mass index predicted baseline levels of objective sleep disturbance. Comorbidity, evening fatigue, and depressive symptoms predicted baseline levels of subjective sleep disturbance, and depressive symptoms predicted the trajectory of subjective sleep disturbance. CONCLUSION: Different variables predicted sleep disturbance using subjective and objective measures. The slightly elevated wake after sleep onset found may be an underestimation of the degree of sleep disturbance when it is evaluated in the context of the high number of nighttime awakenings and patient's perception of poor sleep quality and quantity.
PMCID:3414693
PMID: 22795049
ISSN: 1873-6513
CID: 1563872
A comparison of the cyclic variation in serum levels of CA125 across the menstrual cycle using two commercial assays
BACKGROUND: Clinicians use CA125, a tumor-associated antigen, primarily to monitor epithelial ovarian cancer. However, CA125 lacks the sensitivity and specificity necessary for population-based screening in healthy women. The purpose of this study was to determine if serum concentrations of CA125 differed across the three phases of the menstrual cycle in healthy, premenopausal women using two commercially available assays. METHODS: Healthy, Caucasian women between the ages of 18 and 39 were enrolled using strict criteria to exclude factors known to contribute to CA125 fluctuations. Menstrual cycle regularity was determined using calendars maintained by participants for 3 months. After cycle regularity was established, blood was drawn at three time points for CA125 determination using two commercial assays (i.e., Siemens and Panomics). RESULTS: Regardless of the assay used, CA125 values were highest during menses. The CA125 values decreased 0.2 U/ml per day from menses to the end of the same cycle, which resulted in a net decrease of 5.8 U/ml across the cycle. CONCLUSIONS: The two commercial assays for CA125 determination demonstrated good concordance in terms of reference ranges regardless of epitope differences. While CA125 levels changed over the course of the menstrual cycle, these changes may not be clinically significant in healthy women. This study is the first to control for factors known to contribute to CA125 elevations; to quantify a decrease in CA125 levels across the menstrual cycle; and to confirm concordance in the relative decreases in serum CA125 levels across the menstrual cycle between two frequently used commercial assays.
PMID: 21765119
ISSN: 1552-4175
CID: 1563882
Association between pro- and anti-inflammatory cytokine genes and a symptom cluster of pain, fatigue, sleep disturbance, and depression
Because multiple symptoms associated with "sickness behavior" have a negative impact on functional status and quality of life, increased information on the mechanisms that underlie inter-individual variability in this symptom experience is needed. The purposes of this study were to determine: if distinct classes of individuals could be identified based on their experience with pain, fatigue, sleep disturbance, and depression; if these classes differed on demographic and clinical characteristics; and if variations in pro- and anti- inflammatory cytokine genes were associated with latent class membership. Self-report measures of pain, fatigue, sleep disturbance, and depression were completed by 168 oncology outpatients and 85 family caregivers (FCs). Using latent class profile analysis (LCPA), three relatively distinct classes were identified: those who reported low depression and low pain (83%), those who reported high depression and low pain (4.7%), and those who reported high levels of all four symptoms (12.3%). The minor allele of IL4 rs2243248 was associated with membership in the "All high" class along with younger age, being White, being a patient (versus a FC), having a lower functional status score, and having a higher number of comorbid conditions. Findings suggest that LPCA can be used to differentiate distinct phenotypes based on a symptom cluster associated with sickness behavior. Identification of distinct phenotypes provides new evidence for the role of IL4 in the modulation of a sickness behavior symptom cluster in oncology patients and their FCs.
PMCID:3340525
PMID: 22450224
ISSN: 1096-0023
CID: 1563892
Associations between pro- and anti-inflammatory cytokine genes and breast pain in women prior to breast cancer surgery
The purposes of this study were to determine the occurrence rate for preoperative breast pain; describe the characteristics of this pain; evaluate for differences in demographic and clinical characteristics; and evaluate for variations in pro- and anti-inflammatory cytokine genes between women who did and did not report pain. Patients (n = 398) were recruited prior to surgery and completed self-report questionnaires on a number of pain characteristics. Genotyping was done using a custom genotyping array. Women (28.2%) who reported breast pain were significantly younger (P < .001); more likely to be nonwhite (P = .032); reported significantly lower Karnofsky Performance Status scores (P = .008); were less likely to be postmenopausal (P = .012); and had undergone significantly more biopsies (P = .006). Carriers of the minor allele for a single nucleotide polymorphism in interleukin (IL)1-receptor 1 (IL1R1) (rs2110726) were less likely to report breast pain prior to surgery (P = .007). Carriers of the minor allele for a single nucleotide polymorphism in IL13 (rs1295686) were more likely to report breast pain prior to surgery (P = .019). Findings suggest that breast pain occurs in over a quarter of women who are about to undergo breast cancer surgery. Based on phenotypic and genotypic characteristics found, inflammatory mechanisms contribute to preoperative breast pain. PERSPECTIVE: In women with breast cancer, preoperative pain may be associated with increases in inflammatory responses associated with an increased number of biopsies. In addition, differences in cytokine genes may contribute to this preoperative breast pain.
PMCID:3348353
PMID: 22515947
ISSN: 1526-5900
CID: 166983
Biomarkers: symptoms, survivorship, and quality of life
OBJECTIVES: To review the evidence on a number of biomarkers that show potential clinical utility in the prediction of and treatment responsiveness for the four most common symptoms associated with cancer and its treatment (ie, pain, fatigue, sleep disturbance, depression). DATA SOURCES: Review and synthesis of review articles and data-based publications. CONCLUSION: A growing body of evidence suggests that sensitive and specific biomarkers will be available to assist clinicians with the assessment and management of symptoms. IMPLICATIONS FOR NURSING PRACTICE: Nurses will play a critical role in educating patients about their risk for specific symptoms based on an evaluation of specific biomarkers. Nurses will be involved in using biomarker data to titrate medications based on patient's responses to symptom management interventions.
PMCID:3340583
PMID: 22542321
ISSN: 1878-3449
CID: 1563902
