Faculty Bibliography

CONTEXT: Patients with venous leg ulcers experience multiple symptoms, including pain, depression, and discomfort from lower leg inflammation and wound exudate. Some of these symptoms impair wound healing and decrease quality of life (QOL). The presence of co-occurring symptoms may have a negative effect on these outcomes. The identification of symptom clusters could potentially lead to improvements in symptom management and QOL. OBJECTIVES: To identify the prevalence and severity of common symptoms and the occurrence of symptom clusters in patients with venous leg ulcers. METHODS: For this secondary analysis, data on sociodemographic characteristics, medical history, venous history, ulcer and lower limb clinical characteristics, symptoms, treatments, healing, and QOL were analyzed from a sample of 318 patients with venous leg ulcers who were recruited from hospital outpatient and community nursing clinics for leg ulcers. Exploratory factor analysis was used to identify symptom clusters. RESULTS: Almost two-thirds (64%) of the patients experienced four or more concurrent symptoms. The most frequent symptoms were sleep disturbance (80%), pain (74%), and lower limb swelling (67%). Sixty percent of patients reported three or more symptoms at a moderate-to-severe level of intensity (e.g., 78% reported disturbed sleep frequently or always; the mean pain severity score was 49 of 100, SD 26.5). Exploratory factor analysis identified two symptom clusters: pain, depression, sleep disturbance, and fatigue; and swelling, inflammation, exudate, and fatigue. CONCLUSION: Two symptom clusters were identified in this sample of patients with venous leg ulcers. Further research is needed to verify these symptom clusters and to evaluate their effect on patient outcomes.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the Ryanodine receptor 3 (RYR3) gene are associated with common carotid intima media thickness (CCA cIMT) in HIV-infected men. We evaluated SNPs in the RYR3 gene among HIV-infected women participating in Women's Interagency HIV Study (WIHS). METHODS: CCA cIMT was measured using B-mode ultrasound and the 838 SNPs in the RYR3 gene region were genotyped using the Illumina HumanOmni2.5-quad beadchip. The CCA cIMT genetic association was assessed using linear regression analyses among 1213 women and also separately among White (n=139), Black (n=720) and Hispanic (n=354) women after adjusting for confounders. A summary measure of pooled association was estimated using a meta-analytic approach by combining the effect estimates from the three races. Haploblocks were inferred using Gabriel's method and haplotype association analyses were conducted among the three races separately. RESULTS: SNP rs62012610 was associated with CCA cIMT among the Hispanics (p=4.41x10(-5)), rs11856930 among Whites (p=5.62x10(-4)), and rs2572204 among Blacks (p=2.45x10(-3)). Meta-analysis revealed several associations of SNPs in the same direction and of similar magnitude, particularly among Blacks and Hispanics. Additionally, several haplotypes within three haploblocks containing SNPs previously related with CCA cIMT were also associated in Whites and Hispanics. DISCUSSION: Consistent with previous research among HIV-infected men, SNPs within the RYR3 region were associated with subclinical atherosclerosis among HIV-infected women. Allelic heterogeneity observed across the three races suggests that the contribution of the RYR3 gene to CCA cIMT is complex, and warrants future studies to better understand regional SNP function.

Subgroups of individuals may be at greater risk of cytokine-induced changes in attentional function. The purposes of this study were to identify subgroups of individuals with distinct trajectories of attentional function and evaluate for phenotypic and genotypic (i.e., cytokine gene polymorphisms) differences among these subgroups. Self-reported attentional function was evaluated in 252 participants (167 oncology patients and 85 family caregivers) using the Attentional Function Index before radiation therapy and at six additional assessments over 6 months. Three latent classes of attentional function were identified using growth mixture modeling: moderate (36.5%), moderate-to-high (48.0%), and high (15.5%) attentional function. Participants in the moderate class were significantly younger, with more comorbidities and lower functional status, than those in the other two classes. However, only functional status remained significant in multivariable models. Included in the genetic association analyses were 92 single nucleotide polymorphisms (SNPs) among 15 candidate genes. Additive, dominant, and recessive genetic models were assessed for each SNP. Controlling for functional status, only Interleukin 6 (IL6) rs1800795 remained a significant genotypic predictor of class membership in multivariable models. Each additional copy of the rare "G" allele was associated with a 4-fold increase in the odds of belonging to the lower attentional function class (95% confidence interval: [1.78, 8.92]; p = .001). Findings provide preliminary evidence of subgroups of individuals with distinct trajectories of attentional function and of a genetic association with an IL6 promoter polymorphism.

OBJECTIVE: Dopamine, iron, and inflammatory pathways are considered important to the development of restless legs syndrome (RLS). Recent genetic studies support involvement of dopamine and iron; however, cytokine gene variation in the inflammatory component remains unexplored. A recent study reported a high prevalence of RLS among HIV-infected adults. We estimate occurrence of RLS in an ethnically diverse sample of HIV-infected adults and examine differences in demographic factors, clinical characteristics, and biomarkers relating to dopamine, iron, and inflammation between adults with and without RLS symptoms. DESIGN: A prospective longitudinal study aimed at identifying biomarkers of RLS symptom experience among HIV-infected adults. METHOD: 316 HIV-positive adults were evaluated using International RLS Study Group criteria. Genes were chosen for hypothesized relationships to dopamine (NOS1, NOS2), iron (HFE) or inflammation-mediated by cytokine genes (interferon [IFN], interleukin [IL], nuclear factor kappa-B [NFKB], and tumor necrosis factor alpha [TNFA]). RESULTS: Similar to general population estimates, 11% of the sample met all four RLS diagnostic criteria. Controlling for race, gender, and hemoglobin, carrying two copies of the minor allele for IL1B rs1143643, rs1143634, or rs1143633 or carrying the minor allele for IL17A rs8193036 was associated with increased likelihood of meeting RLS diagnostic criteria. CONCLUSION: This study provides preliminary evidence of a genetic association between IL1B and IL17A genes and RLS.

BACKGROUND: Abnormal calcium handling plays a crucial role in arrhythmias, sudden cardiac arrest (SCA), and congestive heart failure (CHF). Calsequestrin 2 (CASQ2) mutations affect calcium release and initiate malignant ventricular arrhythmias (VAs) and SCA syndromes. Common single nucleotide polymorphisms (SNPs) in CASQ2 may be associated with SCA in patients with coronary artery disease (CAD). OBJECTIVE: The purpose of this study was to examine the association of common CASQ2 SNPs with the risk of SCA in patients with CAD. METHODS: CASQ2 SNPs (n = 14) were genotyped and analyzed in a case control study comparing 114 patients with CAD and SCA due to VA to 311 CAD controls without VA or SCA. RESULTS: Multivariate logistic regression adjusting for age and CHF status identified an association between rs7521023 with SCA (odds ratio [OR] 2.72, 95% confidence interval [CI] 1.44-5.13, P = .002). The substantial impact of CHF on SCA in the model (OR 26.6, 95% CI 13.40-52.70, P <.001) led us to further examine the relationship between CHF, SCA, and CASQ2 SNPs. We identified 2 CASQ2 variants (rs7521023: OR 0.4, 95% CI 0.25-0.76, P = .003; rs6684209: OR 19.8, 95% CI 3.63-108.2, P <.001) associated with CHF after adjusting for SCA, age, gender, and hypertension. CONCLUSION: We observed association between a CASQ2 polymorphism and SCA due to VA in patients with CAD adjusting for CHF and independent associations between CASQ2 SNPs and CHF adjusting for SCA. Further investigation in independent cohorts is needed to confirm these findings.

CONTEXT: The relatively low number of older patients in cancer trials limits knowledge of how older adults experience symptoms associated with cancer and its treatment. OBJECTIVES: This study evaluated for differences in the symptom experience across four older age groups (60-64, 65-69, 70-74, >/=75 years). METHODS: Demographic, clinical, and symptom data from 330 patients aged >60 years who participated in one Australian and two U.S. studies were evaluated. The Memorial Symptom Assessment Scale was used to evaluate the occurrence, severity, frequency, and distress of 32 symptoms commonly associated with cancer and its treatment. RESULTS: On average, regardless of the age group, patients reported 10 concurrent symptoms. The most prevalent symptoms were physical in nature. Worrying was the most common psychological symptom. For 28 (87.5%) of the 32 Memorial Symptom Assessment Scale symptoms, no age-related differences were found in symptom occurrence rates. For symptom severity ratings, an age-related trend was found for difficulty swallowing. As age increased, severity of difficulty swallowing decreased. For symptom frequency, age-related trends were found for feeling irritable and diarrhea, with both decreasing in frequency as age increased. For symptom distress, age-related trends were found for lack of energy, shortness of breath, feeling bloated, and difficulty swallowing. As age increased, these symptoms received lower average distress ratings. CONCLUSION: Additional research is warranted to examine how age differences in symptom experience are influenced by treatment differences, aging-related changes in biological or psychological processes, or age-related response shift.

STUDY OBJECTIVES: Cytokine activity and polymorphisms have been associated with sleep outcomes in prior animal and human research. The purpose of this study was to determine whether circulating plasma cytokines and cytokine polymorphisms are associated with the poor sleep maintenance commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). DESIGN: Cross-sectional descriptive study. SETTING: HIV clinics and community sites in the San Francisco Bay area. PARTICIPANTS: A convenience sample of 289 adults (193 men, 73 women, and 23 transgender) living with HIV/AIDS. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: A wrist actigraph was worn for 72 h to estimate the percentage of wake after sleep onset (WASO%) and total sleep time (TST), plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL1B, IL1R2, IL1R2, IL2, IL4, IL6, IL8, IL10, IL13, IL17A), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB1 and NFKB2), and tumor necrosis factor-alpha (TNFA). Controlling for demographic variables such as race and sex, and clinical variables such as CD4+ count and medications, higher WASO% was associated with single nucleotide polymorphisms (SNPs) of IL1R2 rs11674595 and TNFA rs1041981 and less WASO% was associated with IL2 rs2069776. IL1R2 rs11674595 and TNFA rs1041981 were also associated with short sleep duration. CONCLUSIONS: This study strengthens the evidence for an association between inflammation and sleep maintenance problems. In this chronic illness population, cytokine polymorphisms associated with wake after sleep onset provide direction for intervention research aimed at comparing anti-inflammatory mechanisms with hypnotic agents for improving sleep maintenance and total sleep time.

Abstract Background: Lymphedema (LE) is a frequent complication following breast cancer treatment. While progress is being made in the identification of phenotypic risk factors for the development of LE, little information is available on the molecular characterization of LE. The purpose of this study was to determine if variations in pro- and anti-inflammatory cytokine genes were associated with LE following breast cancer treatment. Methods and Results: Breast cancer patients completed a number of self-report questionnaires. LE was evaluated using bioimpedance spectroscopy. Genotyping was done using a custom genotyping array. No differences were found between patients with (n=155) and without LE (n=387) for the majority of the demographic and clinical characteristics. Patients with LE had a significantly higher body mass index, more advanced disease, and a higher number of lymph nodes removed. Genetic associations were identified for three genes (i.e., interleukin (IL4) 4 (rs2227284), IL 10 (rs1518111), and nuclear kappa factor beta 2 (NFKB2 (rs1056890)) associated with inflammatory responses. Conclusions: These genetic associations suggest a role for a number of pro- and anti-inflammatory genes in the development of LE following breast cancer treatment.

Abstract Preoperative breast pain in women with breast cancer may result from a number of causes. Previous work from our team found that breast pain occurred in 28.2% of women (n = 398) who were about to undergo breast cancer surgery. The occurrence of preoperative breast pain was associated with a number of demographic and clinical characteristics, as well as variation in two cytokine genes. Given that ion channels regulate excitability of sensory neurons, we hypothesized that variations in potassium channel genes would be associated with preoperative breast pain in these patients. Therefore, in this study, we evaluated for associations between single-nucleotide polymorphisms and inferred haplotypes among 10 potassium channel genes and the occurrence of preoperative breast pain in patients scheduled to undergo breast cancer surgery. Multivariable logistic regression analyses were used to identify those genetic variations that were associated with the occurrence of preoperative breast pain while controlling for age and genomic estimates of and self-reported race/ethnicity. Variations in four potassium channel genes: (1) potassium voltage-gated channel, delayed rectifier, subfamily S, member 1 (KCNS1); (2) potassium inwardly rectifying channel, subfamily J, member 3 (KCNJ3); (3) KCNJ6; and (4) potassium channel, subfamily K, member 9 (KCNK9) were associated with the occurrence of breast pain. Findings from this study warrant replication in an independent sample of women who report breast pain following one or more breast biopsies.