Fatigue and Depressive Mood in Chronic Low Back Pain.

PURPOSE: Fatigue is prevalent, problematic, and co-occurs in chronic low back pain. When left untreated, fatigue can increase depressive mood, and intensify pain burden and disability in patients with chronic low back pain. The purpose of this study was to examine the relationship of fatigue to depressive mood, pain severity, and pain interference in patients with chronic low back pain. DESIGN AND METHODS: A cross-sectional design was used to enroll and evaluate adults (n = 67) with chronic low back pain (>6 months) during their visit to an outpatient pain clinic. Participants completed psychometric instruments for fatigue, depressive mood, pain severity, and pain interference. RESULTS: Participants were primarily women (73%), White (59%), with a median age of 59 years (range 22-70 years). Multiple regression models showed significant positive associations between fatigue and depressive mood (SD: 0.025 p = 0.017) with a coefficient of 0.069; fatigue and pain interference (SD: 0.123 p = 0.010) with a coefficient of 0.652; fatigue and pain severity (SD: 0.125 p-value <0.05) with a coefficient of 0.359. After adjusting for demographic factors (age, sex, and race/ethnicity) the associations remained significant. CONCLUSIONS: The findings suggest that fatigue is associated with greater depressive mood, pain severity, and pain interference in adults with chronic low back pain. CLINICAL IMPLICATIONS: Assessing the extent of fatigue and depressive mood as part of pain management may benefit patients with chronic low back, thereby reducing symptom burden.

Impact of a Mindfulness-Based Stress Reduction Program on Psychological Well-Being, Cortisol, and Inflammation in Women Veterans.

BACKGROUND: Women veterans experience higher levels of stress-related symptoms than their civilian counterparts. Psychological stress is associated with greater inflammation and may increase risk for cardiovascular disease (CVD). Mindfulness-based stress reduction (MBSR) has been found to improve psychological well-being in other populations but no randomized controlled trials (RCT) have been conducted examining the impact of MBSR on well-being and inflammation in women veterans at risk for CVD. OBJECTIVE: Determine the effectiveness of MBSR in improving psychological well-being, cortisol, and inflammation associated with CVD in women veterans. DESIGN: The design is a RCT comparing MBSR to an active control condition (ACC) consisting of a health education program. PARTICIPANTS: Women veterans (N=164) with risk factors for CVD from the Chicagoland area participated in the study. INTERVENTION: An 8-week MBSR program with weekly 2.5-h classes was compared to an ACC consisting of an 8-week health promotion education program with weekly 2.5-h classes. MAIN MEASURES: The outcomes were psychological well-being [perceived stress, depressive symptoms, loneliness, and post-traumatic stress disorder (PTSD)] symptoms and stress-related markers, including diurnal salivary cortisol and cytokines interleukin-6 (IL-6) and interferon gamma (IFN-γ). Data were collected at baseline, 4 weeks (mid-point of intervention), 8 weeks (completion of intervention), and 6 months after completion of MBSR or ACC. KEY RESULTS: Compared to the ACC, women who participated in MBSR reported less perceived stress, loneliness, and symptoms of PTSD. Although there were no significant differences between groups or changes over time in IL-6 or IFN-γ, participants in the MBSR program demonstrated a more rapid decline in diurnal salivary cortisol as compared to those in the ACC. CONCLUSIONS: MBSR was found to improve psychological well-being and decrease diurnal salivary cortisol in women veterans at risk for CVD. Health care providers may consider MBSR for women veterans as a means by which to improve their psychological well-being.

Social Support Is Inversely Associated With Sleep Disturbance, Inflammation, and Pain Severity in Chronic Low Back Pain.

BACKGROUND: Chronic low back pain (CLBP) is a significant cause of disability, lost wages, and healthcare costs. Inflammatory mediators, such as interleukin-6 (IL-6), have been associated with LBP severity. Patients with CLBP commonly experience sleep disturbance, and poor sleep has been shown to increase pain severity and inflammation. In contrast, social support may benefit patients with CLBP by reducing pain intensity and inflammation. OBJECTIVES: The purpose of this study was to examine the influence of social support on the relationships among sleep disturbance, inflammation, and pain severity in patients with CLBP. METHODS: In a cross-sectional study, men and women with CLBP were enrolled from an outpatient pain clinic. Participants completed psychometric instruments for social support, sleep quality, and pain severity. Blood samples were obtained for measurement of the pro-inflammatory cytokine IL-6 by enzyme-linked immunoassay. RESULTS: Linear regression revealed greater sleep disturbance predicted greater pain severity. In contrast, participants who reported higher social support had lower sleep disturbance and lower pain severity. Mediation analysis revealed sleep disturbance to mediate the relationship between social support and pain, such that sleep disturbance reduced the benefit of social support on pain severity. Furthermore, greater sleep disturbance and lower social support predicted increased IL-6. However, IL-6 did not mediate the relationship between social support and pain. DISCUSSION: The findings suggest that increased social support is associated with lower sleep disturbance, lower inflammation, and lower pain severity in patients with CLBP. Assessing the extent of social support and fostering social support as part of a comprehensive pain management program may benefit patients with CLBP. Interventions to strengthen social support systems and cultivate support from family and/or informal social networks may reduce symptom burden and improve quality of life.

Behavioral Symptom Clusters, Inflammation, and Quality of Life in Chronic Low Back Pain.

BACKGROUND: Chronic low back pain is a prevalent condition, often involving an inflammatory process. Behavioral symptoms, including depressed mood, fatigue, and sleep disturbance, intensifies pain and reduces quality of life. AIMS: The objectives of this pilot study were to identify behavioral symptom clusters (depressive mood, fatigue, poor sleep) in individuals with chronic low back pain, and to determine whether there are differences in pain, quality of life and inflammation (plasma IL-6) based on cluster membership. DESIGN AND SETTINGS: A cross-sectional study was conducted in a pain clinic. PARTICIPANTS/ SUBJECTS: Participants between ages 21 to 70 years (N=69) were enrolled if they had chronic low back pain for at least six months. METHODS: Participants completed instruments measuring, pain, depressive mood, fatigue, sleep, and demographic form. Blood (10ml) was obtained. Latent class analysis was used to identify clusters. RESULTS AND CONCLUSIONS: Findings revealed a two-class model, with Class 1 characterized by more depressive mood, fatigue, and sleep disturbance compared to Class 2. Class 1 participants reported worse quality of life than those in Class 2. Pain severity and pain interference were not significantly different between the classes. Levels of IL-6 were significantly greater in Class 1 participants compared to Class 2 with higher levels of IL-6 correlating with greater pain severity and sleep disturbances. Logistic regression revealed higher levels of IL-6 predicted Class 1 membership. Behavioral symptoms cluster exist in chronic low back pain patients and impact quality of life. Inflammation may contribute to relationship between behavioral symptoms and pain severity.

A Behavioral Epigenetics Model to Predict Oral Feeding Skills in Preterm Infants.

BACKGROUND: Preterm infants experience a multitude of prenatal and postnatal stressors, resulting in cumulative stress exposure, which may jeopardize the timely attainment of developmental milestones, such as achieving oral feeding. Up to 70% of preterm infants admitted to the neonatal intensive care unit experience challenges while initiating oral feeding. Oral feeding skills require intact neurobehavioral development. Evolving evidence demonstrates that cumulative stress exposure results in epigenetic modification of glucocorticoid-related genes. Epigenetics is a field of study that focuses on phenotypic changes that do not involve alterations in the DNA sequence. Epigenetic modification of glucocorticoid-related genes alters cortisol reactivity to environmental stimuli, which may influence neurobehavioral development, and is the essence of the evolving field of Preterm Behavioral Epigenetics. It is plausible that early-life cumulative stress exposure and the ensuing epigenetic modification of glucocorticoid-related genes impair neurobehavioral development required for achievement of oral feeding skills in preterm infants. PURPOSE: The purpose of this article is to build upon the evolving science of Preterm Behavioral Epigenetics and present a conceptual model that explicates how cumulative stress exposure affects neurobehavioral development and achievement of oral feeding skills through epigenetic modification of glucocorticoid-related genes. METHODS/RESULTS: Using the Preterm Behavioral Epigenetics framework and supporting literature, we present a conceptual model in which early-life cumulative stress exposure, reflected by DNA methylation of glucocorticoid-related genes and altered cortisol reactivity, disrupts neurobehavioral development critical for achievement of oral feeding skills. IMPLICATIONS FOR PRACTICE AND RESEARCH: Future investigations guided by the proposed conceptual model will benefit preterm infant outcomes by introducing epigenetic-based approaches to assess and monitor preterm infant oral feeding skills. Furthermore, the proposed model can guide future investigations that develop and test epigenetic protective interventions to improve clinical outcomes, representing an innovation in neonatal care.

Mindfulness based stress reduction provides psychological benefit and restores immune function of women newly diagnosed with breast cancer: A randomized trial with active control.

BACKGROUND: Women newly diagnosed with breast cancer experience psychological distress, accompanied by reduced Natural Killer Cell Activity (NKCA) and altered levels of cytokines, which may compromise cancer control. Few studies have evaluated psycho-immune outcomes of mindfulness-based stress reduction (MBSR) for women newly diagnosed with breast cancer in comparison to an active control condition. OBJECTIVE: The purpose of this study was to determine whether MBSR benefits psychological, behavioral, and immunological function in women recently diagnosed with breast cancer. DESIGN: After confirmation of breast cancer staging, women diagnosed with early-stage breast cancer (n = 192) were randomized to an 8-week MBSR program or an 8-week active control condition (ACC). The ACC consisted of a series of cancer recovery and health education classes. Both MBSR and the ACC were administered in group format. METHODS: Women completed psychometric instruments and provided blood for NKCA and cytokine levels at pre-, mid-, and completion of program, as well as at 1- and 6-months post-program. One hundred and twenty four women completed all five-assessments (MBSR, n = 63; ACC, n = 61). Hierarchical linear modeling was used to analyze trajectories of outcomes over time and between groups. RESULTS: Compared to the ACC group, women randomized to MBSR exhibited decreasing trajectories of perceived stress, fatigue, sleep disturbance, and depressive symptoms. Further, compared to women randomized to ACC, MBSR women exhibited trajectories demonstrating significantly more rapid restoration of NKCA, accompanied by lower circulating TNF-alpha levels, lower IL-6 production, and greater IFN-gamma production. CONCLUSIONS: These results demonstrate early provision of MBSR for women newly diagnosed with breast cancer provides not only psychological benefit, but also optimizes immune function supportive of cancer control.

Resilience in African American Women at Risk for Cardiovascular Disease: an Exploratory Study.

African Americans (AAs) have a higher risk for cardiovascular disease (CVD) which is not fully explained by traditional CVD risk factors such as smoking, obesity, hypertension, and diabetes. Evidence demonstrates that chronic stress, low subjective status, and lack of social support play important roles in increasing the risk for CVD, particularly in minority women. Increasing evidence demonstrates that resilience may ameliorate the effect of social stressors on the development of CVD. However, little is known about the social context that may influence resilience in AA women. Therefore, the purpose of this exploratory study was to examine the predictors of resilience in AA women at risk for CVD. A cross-sectional sample of AA women (N = 104) participated in the study. Participants completed measures of resilience, subjective social status, social support, and general stress. Findings revealed that participants had low levels of resilience as measured by the Connor-Davidson Resilience Scale (mean = 50.3 ± 11.4) compared to norms. Results of the multiple linear regression analysis demonstrated that both subjective social status in relation to others in the USA (p = 0.021) and perceived social support (p < 0.001) predicted greater level of resilience. The model, controlling for age, marital status, income, level of education, and general stress, accounted for a significant proportion of variance (F[8,75] = 6.6, p < .001), explaining 41.7% of the variation in resilience. Results suggest that subjective social status and social support contribute to perceived resilience in AA women. Additional research is needed to assess the association of subjective social status and social support in longitudinal studies.

Chromatin organization as an indicator of glucocorticoid induced natural killer cell dysfunction.

It is well-established that psychological distress reduces natural killer cell immune function and that this reduction can be due to the stress-induced release of glucocorticoids. Glucocorticoids are known to alter epigenetic marks associated with immune effector loci, and are also known to influence chromatin organization. The purpose of this investigation was to assess the effect of glucocorticoids on natural killer cell chromatin organization and to determine the relationship of chromatin organization to natural killer cell effector function, e.g. interferon gamma production. Interferon gamma production is the prototypic cytokine produced by natural killer cells and is known to modulate both innate and adaptive immunity. Glucocorticoid treatment of human peripheral blood mononuclear cells resulted in a significant reduction in interferon gamma production. Glucocorticoid treatment also resulted in a demonstrable natural killer cell nuclear phenotype. This phenotype was localization of the histone, post-translational epigenetic mark, H3K27me3, to the nuclear periphery. Peripheral nuclear localization of H3K27me3 was directly related to cellular levels of interferon gamma. This nuclear phenotype was determined by direct visual inspection and by use of an automated, high through-put technology, the Amnis ImageStream. This technology combines the per-cell information content provided by standard microscopy with the statistical significance afforded by large sample sizes common to standard flow cytometry. Most importantly, this technology provides for a direct assessment of the localization of signal intensity within individual cells. The results demonstrate glucocorticoids to dysregulate natural killer cell function at least in part through altered H3K27me3 nuclear organization and demonstrate H3K27me3 chromatin organization to be a predictive indicator of glucocorticoid induced immune dysregulation of natural killer cells.

Perceived discrimination is associated with the inflammatory response to acute laboratory stress in women at risk for cardiovascular disease.

Cardiovascular disease (CVD) is the leading cause of death in the United States and exacts a disproportionate toll on minorities. Growing evidence demonstrates that perceived discrimination is a significant contributing factor to psychological distress, chronic low-grade inflammation, and cardiovascular health. However, little is known regarding the extent to which perceived discrimination contributes to the inflammatory response to acute stress. Therefore, the purpose of this study was to examine the influence of perceived discrimination on the inflammatory response to a laboratory acute stress paradigm in women at risk for CVD. A cross-sectional sample of 99 postmenopausal women (50 African American and 49 non-Hispanic White) (mean age 60.2 years) with at least two risk factors for CVD underwent the Trier Social Stress Test (TSST). Subjects completed the Detroit Area Study Discrimination Scale (DAS-DS) Everyday Discrimination subscale and provided blood and saliva samples prior to the TSST and every 15 min up to 90 min post-TSST to measure a pro-inflammatory cytokine, interleukin-6 (IL-6). Perceived discrimination was significantly associated with the salivary IL-6 response to the TSST (b = 0.49, SE = 0.13, p = <0.001) controlling for age, race, marital status, household income, BMI, statin use, childhood maltreatment, depressive symptoms, and subjective social status. Women who reported higher levels of perceived discrimination had higher levels of salivary IL-6 at baseline and following the TSST as compared to women who reported lower levels of perceived discrimination. Results suggest that higher levels of perceived discrimination, regardless of race and socioeconomic status, may heighten levels of inflammation, prior to and following an acute stress exposure. The circulating Il-6 response was associated with BMI only and did not correlate with salivary IL-6. These data suggest that perceived discrimination may contribute to the salivary-IL-6 acute stress response. However, more research is needed to help clarify the complex relationships among stress and salivary proinflammatory cytokines.

During stress, heart rate variability moderates the impact of childhood adversity in women with breast cancer.

Childhood adversity has long-lasting neuro-biological effects that can manifest as exaggerated stress responsivity to environmental challenge. These manifestations include a dysregulated hypothalamic-pituitary-adrenocortical (HPA) axis as well as increased levels of inflammatory mediators in response to stress. In this investigation, vagal parasympathetic activity was assessed for its capacity to moderate the relationship between childhood adversity and stress responsivity (cortisol and inflammation) during an acute laboratory challenge (Trier Social Stress Test-TSST). Thirty women recently diagnosed with breast cancer underwent the TSST during which their heart rate was recorded and saliva samples collected for measurement of cortisol and the proinflammatory cytokine, IL-6. Vagal activity during the TSST was calculated as the high-frequency (HF) component of heart rate variability (HRV). Vagal activity during the TSST moderated the effect of childhood adversity on both the cortisol and the IL-6 response. Women who had lower vagal stress-reactivity during the TSST and reported greater childhood adversity showed a larger rise in cortisol and IL-6 when compared to women with lower childhood adversity. The findings demonstrate that women with exposure to childhood adversity and low vagal stress-reactivity (reduced parasympathetic activity) exhibit an elevated stress response characterized by greater cortisol and proinflammatory cytokine release. Inflammatory burden and HPA dysregulation subsequent to stress may impair cancer control.

Obesity Prevention Behaviors in Asian Indian Adolescent Girls: A Pilot Study.

PURPOSE: The purpose of this pilot study was to evaluate obesity prevention behaviors of Asian Indian adolescent females and determine the relationship of these behaviors to cardiovascular risk factors. DESIGN AND METHODS: A purposive sample of twenty females, 14-18 years of age, was enrolled. Body mass index, percent body fat, waist circumference, and blood pressure were measured to assess cardiovascular risk. Measures of obesity prevention behaviors were physical activity, dietary and sleeping behaviors. To quantify engagement in physical activity, participants wore an accelerometer. The dietary intake was assessed using the web based SuperTracker. Pittsburgh Sleep Quality Index was used to assess sleep behaviors. For data analysis, descriptive statistics was used for demographic characteristics. Correlations were calculated to evaluate the relationship between cardiovascular risk factors and obesity prevention behaviors. RESULTS: The majority of the adolescents did not meet recommended physical activity levels. Most reported unhealthy eating behaviors with higher saturated fat intake correlating with higher percent body fat. The cardiovascular risk measures fell below normative values. However, more time spent in sedentary behaviors was related to higher systolic blood pressure, while poor sleep quality was associated with higher diastolic blood pressure and greater BMI. CONCLUSIONS: The findings support the unhealthy patterns of physical activity, dietary and sleep behaviors in Asian Adolescent girls and the need for promoting healthy behaviors in this at risk population. PRACTICE IMPLICATIONS: The study findings provide a basis for education on healthy behaviors and development of culturally appropriate interventions to prevent obesity.

Relationship of childhood adversity and neighborhood violence to a proinflammatory phenotype in emerging adult African American men: An epigenetic link.

African American men (AAM) who are exposed to trauma and adversity during their early life are at greater risk for poor health over their lifespan. Exposure to adversity during critical developmental windows may embed an epigenetic signature that alters expression of genes that regulate stress response systems, including those genes that regulate the inflammatory response to stress. Such an epigenetic signature may increase risk for diseases exacerbated by inflammation, and may contribute to health disparity. The purpose of this study was to evaluate the extent to which exposure to early life adversity influences the psychological, cortisol, and proinflammatory response to acute stress (Trier Social Stress Test - TSST) in emerging adult AAM, ages 18-25years (N=34). Hierarchical linear modeling was used to examine the cortisol and IL-6 pattern of response to the TSST with respect to childhood adversity factors and DNA methylation of the IL-6 promoter. Findings revealed that in response to the TSST, greater levels of childhood trauma and indirect exposure to neighborhood violence were associated with a greater TSST-induced IL-6 response, and a blunted cortisol response. Reduced methylation of the IL6 promoter was related to increased exposure to childhood trauma and greater TSST-induced IL-6 levels. These results support the concept that exposure to childhood adversity amplifies the adult proinflammatory response to stress, which is related to epigenetic signature.

Exploring Spirituality Among African American Women: Implications for Promoting Breast Health Behaviors.

The purpose of this qualitative study was to gain understanding of the definition, meaning, and function of spirituality to African American women. Four categories emerged that add insight for nurses to develop innovative spiritual-based strategies to promote African American women's positive health behaviors. Implications for promoting breast health behaviors are described.

Relationships among psychosocial factors, biomarkers, preeclampsia, and preterm birth in African American women: a pilot.

AIM: To explore the relationships among psychosocial factors (optimism, uncertainty, social support, coping, psychological distress), biomarkers (cortisol, cytokines), preeclampsia, and preterm birth in African American women. METHODS: Forty-nine pregnant African American women completed psychosocial questionnaires and had blood collected for biomarkers between 26 and 36 weeks of gestation. Birth outcomes were obtained from birth records. RESULTS: Women reporting higher levels of social support had lower levels of pro-inflammatory cytokines (IL-2, IL-5, and IL-6). Surprisingly, compared with low-risk pregnant women, women diagnosed with preeclampsia reported more optimism and less avoidance, and had lower levels of cortisol and IFN-γ. Similarly, compared to women with full-term birth, women with preterm birth reported higher levels of optimism and lower levels of avoidance, and had lower levels of IL-10. CONCLUSION: Psychosocial factors influence inflammation and pregnancy outcomes. Close assessment and monitoring of psychosocial factors may contribute to improved pregnancy outcomes.

Glucocorticoids regulate natural killer cell function epigenetically.

Although glucocorticoids are well known for their capacity to suppress the immune response, glucocorticoids can also promote immune responsiveness. It was the purpose of this investigation to evaluate the molecular basis for this apparent dichotomous immunologic effect. Glucocorticoid treatment of natural killer cells (NK) was shown to reduce NK cell cytolytic activity by reduction of histone promoter acetylation for perforin and granzyme B, which corresponded with reduced mRNA and protein for each. In contrast, glucocorticoid treatment increased histone acetylation at regulatory regions for interferon gamma and IL-6, as well as chromatin accessibility for each. This increase in histone acetylation was associated with increased proinflammatory cytokine mRNA and protein production upon cellular stimulation. These immunologic effects were evident at the level of the individual cell and demonstrate glucocorticoids to epigenetically reduce NK cell cytolytic activity while at the same time to prime NK cells for proinflammatory cytokine production.

Day-to-day dynamics of associations between sleep, napping, fatigue, and the cortisol diurnal rhythm in women diagnosed as having breast cancer.

OBJECTIVES: To examine whether day-to-day variations in sleep behaviors, ongoing sleep disturbance, and fatigue predict the cortisol diurnal rhythm in women recently diagnosed as having early-stage breast cancer. METHODS: Women (N = 130, mean [standard deviation] age = 55.6 [9.4] years) collected saliva 5×/day/2 days for cortisol. Diaries were used to assess prior-day nap duration, nocturnal awakenings, sleep latency, and morning restfulness. Ongoing fatigue and sleep disturbance were measured using the Multidimensional Fatigue Symptom Inventory and the Pittsburg Sleep Quality Inventory. Data were analyzed using a multilevel growth curve modeling. RESULTS: Greater ongoing fatigue (b = 0.035, p = .032), or sleep disturbance (b = 0.026, p = .006) predicted a slower cortisol decline. Greater ongoing fatigue also predicted higher awakening cortisol (b = 0.154, p = .030) and lower cortisol awakening response (CAR; b = -0.146, p = .005). Longer prior-day naps predicted higher CAR (b = 0.042, p = .050) and a steeper cortisol decline (b = -0.035, p = .003). Longer sleep latency predicted both a greater cortisol linear decline (b = -0.013, p < .001) and a greater quadratic slope curvature (b = 0.0007, p < .001). Feeling less rested in the morning predicted lower awakening cortisol (b = -0.187, p = .004), higher CAR (b = 0.124, p = .016), and a slower cortisol decline (b = 0.023, p = .042). CONCLUSIONS: Both daily variations in sleep behaviors and ongoing sleep disturbance and fatigue are associated with a disrupted cortisol rhythm. In contrast, prior-day napping is associated with a more robust cortisol rhythm. These findings are particularly relevant to women with breast cancer who often experience sleep disturbance and fatigue. Additional research is needed to determine causal pathways between sleep disturbance and dysregulation of the hypothalamic-pituitary-adrenal axis in patients with breast cancer.

Influence of sense of coherence, spirituality, social support and health perception on breast cancer screening motivation and behaviors in African American women.

Despite formidable barriers, some African American women (AAW) engage in breast cancer screening (BCS) behaviors. Understanding individual characteristics that allow AAW to overcome barriers to BCS is critical to reduce breast cancer mortality among AAW. A salutogenic model of health was used to evaluate the influence of sense of coherence, social support, spirituality and health perception on BCS motivation and behaviors in AAW, and to determine differences in these factors in AAW who participate in free BCS programs compared to AAW who do not. Findings revealed that greater levels of spirituality were significantly associated with greater motivation to practice BCS. Further, women who utilized free BCS programs reported significantly greater rates of both performing and of intent to perform breast self examinations (BSE) in the future, obtaining clinical breast exams and mammograms. Findings can inform the development of culturally specific programs to improve the utilization of BCS programs by AAW.

Childhood adversity increases vulnerability for behavioral symptoms and immune dysregulation in women with breast cancer.

Women respond differentially to the stress-associated with breast cancer diagnosis and treatment, with some women experiencing more intense and/or sustained behavioral symptoms and immune dysregulation than others. Childhood adversity has been identified to produce long-term dysregulation of stress response systems, increasing reactivity to stressors encountered during adulthood. This study determined whether childhood adversity increased vulnerability for more intense and sustained behavioral symptoms (fatigue, perceived stress, and depressive symptoms), poorer quality of life, and greater immune dysregulation in women (N=40) with breast cancer. Evaluation was after breast surgery and through early survivorship. Hierarchical linear modeling was used to examine intra-individual and inter-individual differences with respect to initial status and to the pattern of change (i.e. trajectory) of outcomes. At initial assessment, women exposed to childhood emotional neglect/abuse had greater perceived stress, fatigue, depressive symptoms and poorer quality of life, as well as lower natural killer cell activity (NKCA). Although these outcomes improved over time, women with greater childhood emotional neglect/abuse exhibited worse outcomes through early survivorship. No effect was observed on the pattern of change for these outcomes. In contrast, childhood physical neglect predicted sustained trajectories of greater perceived stress, worse quality of life, and elevated plasma IL-6; with no effect observed at initial assessment. Thus, childhood adversity leaves an enduring imprint, increasing vulnerability for behavioral symptoms, poor quality of life, and elevations in IL-6 in women with breast cancer. Further, childhood adversity predisposes to lower NKCA at a critical time when this immune-effector mechanism is most effective at halting nascent tumor seeding.

Glucocorticoid receptor mediated suppression of natural killer cell activity: identification of associated deacetylase and corepressor molecules.

Physical and psychological stressors reduce natural killer cell function. This reduction in cellular function results from stress-induced release of glucocorticoids. Glucocorticoids act upon natural killer cells to deacetylate and transrepress immune response genes through epigenetic processes. However, other than the glucocorticoid receptor, the proteins that participate in this process are not well described in natural killer cells. The purpose of this study was to identify the proteins associated with the glucocorticoid receptor that are likely epigenetic participants in this process. Treatment of natural killer cells with the synthetic glucocorticoid, dexamethasone, produced a significant time dependent reduction in natural killer cell activity as early as 8h post treatment. This reduction in natural killer cell activity was preceded by nuclear localization of the glucocorticoid receptor with histone deacetylase 1 and the corepressor, SMRT. Other class I histone deacetylases were not associated with the glucocorticoid receptor nor was the corepressor NCoR. These results demonstrate histone deacetylase 1 and SMRT to associate with the ligand activated glucocorticoid receptor within the nuclei of natural killer cells and to be the likely participants in the histone deacetylation and transrepression that accompanies glucocorticoid mediated reductions in natural killer cell function.

Impact of partial versus whole breast radiation therapy on fatigue, perceived stress, quality of life and natural killer cell activity in women with breast cancer.

INTRODUCTION: This pilot study used a prospective longitudinal design to compare the effect of adjuvant whole breast radiation therapy (WBRT) versus partial breast radiation therapy (PBRT) on fatigue, perceived stress, quality of life and natural killer cell activity (NKCA) in women receiving radiation after breast cancer surgery. METHODS: Women (N = 30) with early-stage breast cancer received either PBRT, Mammosite brachytherapy at dose of 34 Gy 10 fractions/5 days, (N = 15) or WBRT, 3-D conformal techniques at dose of 50 Gy +10 Gy Boost/30 fractions, (N = 15). Treatment was determined by the attending oncologist after discussion with the patient and the choice was based on tumor stage and clinical need. Women were assessed prior to initiation of radiation therapy and twice after completion of radiation therapy. At each assessment, blood was obtained for determination of NKCA and the following instruments were administered: Perceived Stress Scale (PSS), Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and Functional Assessment of Cancer Therapy-General (FACT-G). Hierarchical linear modeling (HLM) was used to evaluate group differences in initial outcomes and change in outcomes over time. RESULTS: Fatigue (FACT-F) levels, which were similar prior to radiation therapy, demonstrated a significant difference in trajectory. Women who received PBRT reported progressively lower fatigue; conversely fatigue worsened over time for women who received WBRT. No difference in perceived stress was observed between women who received PBRT or WBRT. Both groups of women reported similar levels of quality of life (FACT-G) prior to initiation of radiation therapy. However, HLM analysis revealed significant group differences in the trajectory of quality of life, such that women receiving PBRT exhibited a linear increase in quality of life over time after completion of radiation therapy; whereas women receiving WBRT showed a decreasing trajectory. NKCA was also similar between therapy groups but additional post hoc analysis revealed that better quality of life significantly predicted higher NKCA regardless of therapy. CONCLUSIONS: Compared to WBRT, PBRT results in more rapid recovery from cancer-related fatigue with improved restoration of quality of life after radiation therapy. Additionally, better quality of life predicts higher NKCA against tumor targets, emphasizing the importance of fostering quality of life for women undergoing adjuvant radiation therapy.