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.

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.

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.

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.

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.

Protocol for a pilot study assessing a virtual mindfulness intervention for postpartum African American women.

Elevated perinatal depressive symptoms are more common among disadvantaged African American women, and they are almost four times as likely to have postpartum posttraumatic stress compared to white women. For new mothers, depressive symptoms and posttraumatic stress can lead to negative parenting, poor mother-infant bonding, and delayed infant development. For African American women, a culturally adapted mindfulness-based intervention offers great potential as an acceptable approach to reduce psycho-behavioral symptoms and improve mother-infant interactions (i.e., bonding). Additionally, it is critical that mindfulness interventions consider time constraints of new mothers, provide accessible intervention delivery, address parenting, and consider the challenges of caring for an infant. Given these considerations, we describe a pilot research protocol in which we evaluate a culturally adapted mindfulness program: Mindfulness for African Americans Postpartum (MAAP). The intervention is based upon Kabat-Zinn's Mindfulness Based Stress Reduction program, but is adapted to include culturally relevant concepts of spirituality, inter-dependence, self-empowerment, and storytelling, which are salient to African American culture. To accommodate the needs of new mothers, a certified mindfulness interventionist delivers each session virtually using Zoom. The investigation uses a randomized controlled design in which African American women within 12 months of giving birth are randomized either to the MAAP intervention or to an Education Program. The primary aim is to determine the extent to which the MAAP intervention decreases maternal psycho-behavioral symptoms (perceived stress, depressive symptoms, anxiety, poor sleep, posttraumatic stress, and fatigue) and improves mother-infant bonding. A secondary aim is to explore the effects of MAAP on proinflammatory cytokines and oxytocin. Culturally adapted mindfulness interventions delivered virtually will make mindfulness more accessible and meaningful to populations, like African American new mothers, who are at higher risk for postpartum mood disorders and poor infant outcomes.

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.

Epigenetics and psychoneuroimmunology: mechanisms and models.

In this Introduction to the Named Series "Epigenetics, Brain, Behavior, and Immunity" an overview of epigenetics is provided with a consideration of the nature of epigenetic regulation including DNA methylation, histone modification and chromatin re-modeling. Illustrative examples of recent scientific developments are highlighted to demonstrate the influence of epigenetics in areas of research relevant to those who investigate phenomena within the scientific discipline of psychoneuroimmunology. These examples are presented in order to provide a perspective on how epigenetic analysis will add insight into the molecular processes that connect the brain with behavior, neuroendocrine responsivity and immune outcome.

Glucocorticoid dysregulation of natural killer cell function through epigenetic modification.

It is well-established that psychological distress reduces natural killer cell activity (NKCA) and dysregulates cytokine balance. This may be mediated by stress-induced release of glucocorticoids, which have broad effects on the immune system, including the suppression of NKCA and alteration of cytokine production. The purpose of this study was to evaluate epigenetic mechanisms that may underlie the effect of glucocorticoids on NK cells, using the human NK cell line, NK92. Treatment of NK92 cells with the synthetic glucocorticoid, dexamethasone, at a concentration of 10⁻7M, produced a significant reduction in NKCA. Glucocorticoid inhibition was a consequence of not only a reduced capacity of the NK cells to bind to tumor targets but also a reduced production of granule constituents (perforin and granzyme B) with no detectable effect on granule exocytosis. Glucocorticoids also reduced the constitutive and the stimulated production of the cytokines, IL-6, TNF alpha and IFN gamma, and reduced the surface expression of LFA-1. Glucocorticoid treatment also reduced global histone acetylation, the acetylation of histone 4 lysine position 8, and the accessibility of the proximal promoters of perforin, interferon gamma and granzyme B. Histone acetylation was recovered by treatment of the NK cells with a histone deacetylase inhibitor, which also restored NKCA and IFN gamma production. These results demonstrate glucocorticoids to dysregulate NK cell function at least in part through an epigenetic mechanism, which reduces promoter accessibility through modification of histone acetylation status. This epigenetic modification decreases the expression of effector proteins necessary to the full functional activity of NK cells.

Epigenetic patterns associated with the immune dysregulation that accompanies psychosocial distress.

The molecular basis for psychosocial-distress mediated immune-dysregulation is not well understood. The purpose of this study was to determine whether peripheral blood mononuclear cell (PBMC) epigenetic pattern associates with this form of immune dysregulation. Women newly diagnosed with early stage breast cancer were enrolled into the study and psychosocial, immunological and epigenetic assessments were made at diagnosis and four months later, after completion of cancer treatment. At diagnosis women reported increased perceived stress, anxiety, and mood disturbance and the PBMC of these women exhibited reduced natural killer cell activity and reduced production of interferon gamma, which contrasted with results, obtained after completion of treatment. At the epigenetic level, a PBMC subset derived from women at diagnosis exhibited a distinct epigenetic pattern, with reduced nuclear acetylation of histone residues H4-K8 and H4-K12, as well as reduced phosphorylation of H3-S10, when compared to similar cells derived after the completion of treatment. Natural killer cell activity and interferon-gamma production were associated with nuclear acetylation and phosphorylation status of these histone residues. These findings demonstrate associations among nuclear epigenetic pattern and the immune dysregulation that accompanies psychosocial distress.

Mindfulness Predicts Psycho-behavioral Improvement after Breast Cancer Diagnosis: Influence of Childhood Adversity.

Mindfulness-based interventions provide psychological benefit after breast cancer diagnosis. The aims of this study were to determine whether within-person change in facets of mindfulness predict psycho-behavioral improvements in women with breast cancer, and to assess the influence of childhood adversity on those improvements. Women randomized to the mindfulness arm of a larger trial were evaluated. Psychometric instruments and the Five Facets of Mindfulness Questionnaire were completed pre-, mid-, at completion, one, and six months post program. A subsample completed the Childhood Trauma Questionnaire. Hierarchical linear modeling revealed that significant change in nonjudgment and nonreactivity to inner experience were associated with more rapid decrease in stress, depressive symptoms, fatigue, sleep disturbance, and more rapid increase in quality of life. For women with greater exposure to childhood adversity, a greater increase in nonreactivity to inner experience significantly associated with greater improvements in stress, depressive symptoms, and quality of life.

Heart Rate Variability and Inflammatory Stress Response in Young African American Men: Implications for Cardiovascular Risk.

Background: African American men have a disproportionately higher incidence of and suffer greater severity and earlier death from cardiovascular disease (CVD). A common feature of many diseases, which disproportionately afflict disadvantaged African Americans, is inflammation. In particular, inflammation plays a decisive role in the pathogenesis of CVD in that persistent inflammation contributes to plaque evolution and destabilization. Adverse childhood experiences increase the risk for adult inflammatory based disease, particularly cardiovascular disease. This inflammatory burden becomes evident during stressful events and may be related to alterations in autonomic nervous system (ANS) activity. We previously reported that African American men who experienced childhood adversity exhibited a greater inflammatory (IL-6) response to acute stress challenge (Trier Social Stress Test - TSST). The purpose of this study was to determine whether altered ANS activity, as measured by heart rate variability (HRV), contributes to a greater proinflammatory response to stress in those exposed to childhood adversity. Methods: Thirty-four African American adult males underwent the TSST while instrumented with Holter monitors to record continuous heart rate for HRV determination. HRV was calculated as the low frequency (LF) to high frequency (HF) heart rate ratio (LF/HF), with higher LF/HF ratios corresponding to higher sympathetic vs. parasympathetic activity. Salivary samples were collected pre- and post-TSST to measure the proinflammatory cytokine IL-6. Childhood adversity was assessed by the Childhood Trauma Questionnaire. Results: Hierarchical linear modeling demonstrated that higher levels of physical abuse were related to a steeper rise in LF/HF ratio during the TSST. Further, a higher LF/HF ratio, in combination with greater exposure to emotional and physical abuse was associated with a greater IL-6 response to the TSST. Conclusions: These findings suggest that adverse childhood experiences associate with an adult phenotype characterized by an altered ANS response to stress as well as a greater proinflammatory (IL-6) response to an acute stressor. Elevations in salivary inflammatory markers have been associated with increased CVD risk. In conclusion, these findings suggest a role for the ANS in the underlying neuro-biological processes whereby childhood adversity predisposes to a more intense inflammatory response to stressful challenge during adulthood.