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Higher levels of omega-3 track with longer telomeres, lower inflammation, and blunted sympathetic and cardiovascular stress reactivity. Whether omega-3 supplementation alters the stress responsivity of telomerase, cortisol, and inflammation is unknown. This randomized, controlled trial examined the impact of omega-3 supplementation on cellular aging-related biomarkers following a laboratory speech stressor. In total, 138 sedentary, overweight, middle-aged participants (n = 93 women, n = 45 men) received either 2.5 g/d of omega-3, 1.25 g/d of omega-3, or a placebo for 4 months. Before and after the trial, participants underwent the Trier Social Stress Test. Saliva and blood samples were collected once before and repeatedly after the stressor to measure salivary cortisol, telomerase in peripheral blood lymphocytes, and serum anti-inflammatory (interleukin-10; IL-10) and pro-inflammatory (interleukin-6; IL-6, interleukin-12, tumor necrosis factor-alpha) cytokines. Adjusting for pre-supplementation reactivity, age, sagittal abdominal diameter, and sex, omega-3 supplementation altered telomerase (p = 0.05) and IL-10 (p = 0.05) stress reactivity; both supplementation groups were protected from the placebo group's 24% and 26% post-stress declines in the geometric means of telomerase and IL-10, respectively. Omega-3 also reduced overall cortisol (p = 0.03) and IL-6 (p = 0.03) throughout the stressor; the 2.5 g/d group had 19% and 33% lower overall cortisol levels and IL-6 geometric mean levels, respectively, compared to the placebo group. By lowering overall inflammation and cortisol levels during stress and boosting repair mechanisms during recovery, omega-3 may slow accelerated aging and reduce depression risk. ClinicalTrials.gov identifier: NCT00385723.

PURPOSE: Proton pump inhibitors (PPIs) are used in cancer patients to manage treatment-related gastrointestinal symptoms and to prevent damage to the gastric mucosal lining during treatment. However, PPI use may contribute to cognitive problems. To compare PPI-users and non-users, breast cancer survivors reported cognitive problems in three studies. METHODS: In Study 1, breast cancer survivors (N=209; n=173 non-users, n=36 PPI-users; stages 0-IIIC) rated their cognitive function on the Kohli scale prior to cancer treatment, as well as one and two years later. In Study 2, women (N=200; n=169 non-users, n=31 PPI-users, stages 0-IIIa, M=11 months post-treatment) rated their cognitive function on the Kohli scale and BCPT checklist at three visits over a six-month period. In Study 3, participants (N=142; n=121 non-users, n=21 PPI-users; stages I-IIIa, M=4 years post-treatment) rated their cognitive function on the Kohli scale, BCPT checklist, and Functional Assessment of Cancer Therapy cognitive scale (FACT-cog). RESULTS: In Study 1, PPI-users reported more severe concentration problems (p=0.039) but not memory problems (p=0.17) than non-users. In Study 2, PPI-users reported more severe concentration problems (p=0.022) than non-users, but not memory problems or symptoms on the BCPT (ps=0.11). Study 3’s PPI-users reported more severe memory problems (p=0.002), poorer overall cognitive function (p=0.006), lower quality of life related to cognitive problems (p=0.005), greater perceived cognitive impairment (p=0.013), and poorer cognitive abilities (p=0.046), but not more severe concentration problems (p=0.16), compared to non-users. CONCLUSIONS/IMPLICATIONS: PPI use may impair breast cancer survivors’ memory, concentration, and quality of life.

BACKGROUND: Prior to treatment, breast cancer patients are less physically fit compared to peers; during cancer treatment, their fitness typically declines. Depressive symptoms are associated with reduced activity up to 5 years post-treatment, but research has not identified mechanisms linking depression and lower activity. The current study assessed relationships among breast cancer patients’ depression and perceived exertion during exercise as well as heart rate, an objective indicator of exertion. METHODS: Participants were 106 breast cancer patients, stages I–IIIA, who completed surgery but had not started adjuvant treatment. Heart rate and self-rated exertion, measured using the Borg Scale of Perceived Exertion, were assessed every 2 min during a graded exercise test. Depression was assessed using the CES-D and a structured clinical interview. RESULTS: Compared to women below the CES-D clinical cutoff, women with significant depressive symptoms reported steeper increases in exertion during the exercise test (p = .010) but had similar heart rates (p = .224) compared to women below the cutoff. Major depression history was unrelated to perceived exertion (ps > .224) and heart rate (ps > .200) during exercise. CONCLUSIONS: Women with currently elevated depressive symptoms experienced exercise as more difficult compared to women below the CES-D cutoff, but these self-perceptions did not reflect actual heart rate differences. Depression may make exercise feel more demanding, which could ultimately decrease patients’ likelihood of engaging in regular exercise. Results support the use of depression screening tools following breast cancer surgery to identify and intervene on individuals at risk for decreased physical activity during survivorship.

Background Breast cancer survivors are prone to weakened gut barriers, allowing bacteria to migrate into the blood stream. Gut permeability fuels inflammation, which, among survivors, can elevate risk for comorbid disease development, cancer recurrence, and a poor quality of life; however, survivors’ satisfying relationships can provide health benefits. This longitudinal study used a conceptual model addressing how intimate relationships is associated with health through changes in gut permeability and inflammation. Method Breast cancer survivors (n=139, stages 0–IIIC) completed a baseline visit before treatment and two follow-up visits 6 and 18 months after treatment ended. Women who had an abnormal breast cancer test followed by a benign diagnosis completed visits within a comparable timeframe (noncancer patient controls; n=69). All women completed questionnaires assessing their relationship satisfaction and provided blood samples to assess two bacterial endotoxin biomarkers, lipopolysaccharide-binding protein (LBP) and soluble CD14 (sCD14), as well as C-reactive protein (CRP) and interleukin 6 (IL-6). Results Within-person multilevel mediation analyses showed that when a survivor’s relationship satisfaction was higher than usual, her own LBP and LBP/sCD14 were lower, which was associated with lower than her own average CRP and IL-6 (95% CIs [-0.0104, -0.0002]). IL-6 was also higher when older survivors, but not younger survivors, experienced higher than usual intestinal permeability (p=.001). These effects of satisfying relationships held after accounting for cancer-related and behavioral factors. Post-hoc analyses showed LBP, sCD14, and LBP/sCD14 were associated with CRP for the cancer survivors, but only LBP and LBP/sCD14 were linked to CRP among the noncancer control patients. Conclusion The gut environment is a new promising candidate for understanding a relationship’s long-term health impact, particularly among those with elevated health risks. Survivors may reap multiple physiological benefits from satisfying relationships.

BACKGROUND: Black breast cancer survivors have greater morbidity and mortality than White survivors. However, evidence comparing Black survivors’ psychological symptoms with their White counterparts has been mixed. Prior studies have not compared Black and White survivor’s distress-related symptom trajectories from pre- to post-treatment – the goal of the current study. METHODS: At three annual visits from shortly after diagnosis to 6 and 18 months post-treatment, 195 women (n=163 White; n=32 Black) reported their cancer-related distress (intrusive thoughts and avoidance), perceived stress, anxiety and depressive symptoms, fatigue, and pain. RESULTS: Adjusting for age, educational attainment, income, treatment type, stage at diagnosis, and physical comorbidities, Black and White breast cancer survivors had different trajectories of cancer-related distress (p=.004), intrusive thoughts about cancer diagnosis and treatment (p=.002), perceived stress (p=.04), emotional fatigue (p=.01), and vigor (p=.02). Specifically, among White women, these distress-related symptoms improved from diagnosis to 6 months post-treatment (ps.09). CONCLUSION: Longitudinal assessment of the same breast cancer survivors from diagnosis to early survivorship revealed that Black and White survivors had divergent trajectories of psychological distress symptoms that were not reliably evident at a single timepoint. Overall, White women reported less psychological distress from pre- to post-treatment, but Black women’s distress remained high from diagnosis to 18 months post-treatment. If left untreated, Black women’s high distress levels may contribute to their poorer health throughout survivorship.

Background The Center for Disease Control (CDC) recently named childhood abuse histories as a public health risk. Clear links between abuse histories and inflammation exist. However, it remains unknown how abuse histories impact inflammatory trajectories throughout adulthood. Accordingly, this study assessed inflammatory trajectories across three visits among healthy adults with and without abuse histories. Method In this secondary analysis of data from a longitudinal observational study of cancer survivors and noncancer controls, 157 noncancer controls (Mage = 55.8, range = 32–83) completed the Childhood Experiences Questionnaire (CTQ), providing data on physical, emotional, and sexual abuse prior to age 18. Cytokines interleukin-6 (IL-6), interleukin 1-beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) were collected at the baseline visit and two follow-up visits approximately one (M months = 11.52, SD = 4.10) and two years (M months = 23.79, SD = 4.40) later. To represent inflammatory changes, cytokine data at each visit were combined into a composite z-score. Covariates in all analyses included age, biological sex, race, income, body mass index, menopause status, psychological diagnosis history, and medical comorbidities. Results Compared to their nonabused peers, those who had experienced any type of abuse in childhood demonstrated steeper rises in inflammation across time. Inflammation rose more steeply for individuals with physical and emotional abuse histories compared to those without such histories. Conclusion Overall, these data suggest that childhood abuse histories may quicken age-related increases in inflammation, contributing to accelerated aging, morbidity, and early mortality. These findings provide mechanistic insight into why child abuse is a public health risk.

PURPOSE: A number of studies have shown that self-rated health reliably predicts mortality. This study assessed the impact of perseveration on self-rated health, physical functioning, and physical symptoms (pain, fatigue, breast cancer symptoms) among breast cancer patients. We hypothesized that cancer-related distress would serve as an intervening variable between both worry and rumination and self-rated health, physical functioning, and physical symptoms. METHODS: Women (N=124) who were approximately seven weeks post-surgery but pre adjuvant treatment completed the Impact of Events Scale, the Penn State Worry Questionnaire, and the Rumination Scale. They also rated their pain, fatigue, physical functioning, and self-rated health using the RAND-36 and breast cancer symptoms with the Breast Cancer Prevention Trial Symptom Checklist (BCPT). Covariates included body mass index, age, cancer stage, menopause status, and physical comorbidities. RESULTS: Worry was associated with higher cancer-related distress, which in turn predicted greater pain and breast cancer symptoms, poorer physical functioning, and lower self-rated health. Rumination also predicted greater cancer-related distress, which ultimately contributed to greater pain along with poorer physical functioning and self-rated health. Models with fatigue as an outcome were not significant. CONCLUSIONS: These findings suggest that perseveration can heighten cancer-related distress and subsequent perceptions of physical symptoms and health among breast cancer patients prior to adjuvant treatment. Perseveration early in the cancer trajectory can adversely increase the impact of a cancer diagnosis and treatment on functioning and quality of life.

BACKGROUND: Saturated-fat intake and endotoxemia can impair cognition. However, their acute impact on cognitive performance is unknown. OBJECTIVE: This study assessed the impact of 2 high-fat meals and endotoxemia on attention. METHODS: In this double-blind, randomized crossover trial, 51 women (n = 32 breast cancer survivors, n = 19 noncancer controls; mean ± SD age: 53 ± 8 y) completed the Continuous Performance Test (CPT) and had their blood drawn to assess endotoxemia markers LPS binding protein (LBP), soluble CD14 (sCD14), and the LBP to sCD14 ratio 1 h prior to eating either a high-saturated-fat meal or a high-oleic-sunflower-oil meal. Women again completed the CPT 5 h postmeal. At 1 to 4 wk later, women completed the same protocol but consumed the other meal. RESULTS: In adjusted models, women had more difficulty distinguishing target stimuli from distractors after consuming the high-saturated-fat meal than they did after the oleic-sunflower-oil meal (B = 4.44, SE = 1.88, P = 0.02). Women with higher baseline LBP had less consistent response times (B = 0.002, SE = 0.0008, P = 0.04). Those with higher LBP and LBP:sCD14 were less able to sustain their attention throughout the entire CPT, as reflected by their progressively slower (B = 0.002, SE = 0.0006, P = 0.003; and B = 2.43, SE = 0.090, P = 0.008, respectively) and more erratic (B = 0.003, SE = 0.0008, P

The Western diet, characterized by high intake of saturated fat, sugar, and salt, is associated with elevated inflammation and chronic disease risk. Few studies have investigated molecular mechanisms linking diet and inflammation; however, a small number of randomized controlled trials suggest that consuming an anti-inflammatory diet (i.e., a primarily plant-based diet rich in monounsaturated fat and lean protein) decreases proinflammatory gene expression. The current study investigated the association between everyday diet and proinflammatory gene expression, as well as the extent to which central adiposity and social involvement modulate risk. Participants were healthy middle-aged and older adults (N = 105) who completed a food frequency questionnaire and reported how many close social roles they have. Anthropometric measurements and blood samples also were collected; gene expression data were analyzed from LPS-stimulated peripheral blood mononuclear cells for interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. The inflammatory potential of each participant’s diet was calculated using the Dietary Inflammatory Index (DII®). Participants with higher DII® scores, indicating a more proinflammatory diet, had greater IL-6 (b = −0.02, SE = 0.008, p = .01), IL-1β (b = −0.01, SE = 0.006, p = .03), and TNF-α (b = −0.01, SE = 0.005, p = .04) gene expression if they had a smaller sagittal abdominal diameter (SAD); effects were not seen among those with higher SADs. Social involvement served a protective role, such that participants with smaller SADs had greater IL-6 (b = 0.01, SE = 0.004, p = .049) and IL-1β (b = 0.01, SE = 0.003, p = .045) gene expression only if they had less social involvement; there was no effect of diet on gene expression among those who reported greater social participation. Results are the first to demonstrate a link between self-reported diet and proinflammatory gene expression. Importantly, the effect of diet on gene expression depended upon both body fat composition and social participation, both of which have previously been linked directly with proinflammatory gene expression and inflammation.

Objectives Marital support is central to couples’ relationships, yet support’s health implications can vary widely. Guided by attribution bias and aging theories, the current study examined whether age and marital satisfaction moderate the links of perceived and received spousal support to aging-related biomarkers. Methods Couples (N = 93, ages 22–77) rated marital satisfaction, overall perceived spousal support, and the quality of support received from their spouse in a lab-based discussion. Blood samples collected at baseline, immediately post-discussion, 3 hr post-discussion, and end-of-visit were assayed for proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6, as well as insulin-like growth factor (IGF)-1. Results Consistent with predictions, less satisfied older couples who received lower-quality spousal support during their discussion had greater increases in TNF-α than those who received higher-quality support; highly satisfied couples of all ages and less satisfied younger couples did not show these inflammatory changes. Highly satisfied older couples with greater perceived spousal support had lower TNF-α across the day and higher IGF-1. Discussion Marital satisfaction and age may shape spousal support’s significance for healthy aging. Rose-colored lenses worn only in the most satisfying marriages may protect couples from the possible health risks of low-quality received support and enhance potential benefits of perceived support. For better or worse, these health implications may grow with older age.

The gut microbiota plays a role in a wide range of diseases and disorders, with low microbial diversity and richness emerging as notable risk factors. This longitudinal study addressed the impact of marital quality (assessed by the Couples Satisfaction Index) on changes in depressive symptoms, and gut diversity, richness, and permeability. On two occasions an average of 90 days apart, 162 people provided stool and blood samples, and completed questionnaires. Depressive symptoms, assessed by the Center for Epidemiological Studies Depression Scale (CES-D), increased from visit 1 to visit 2 in those with clinically significant relationship problems, in contrast to the lack of change among their more satisfied counterparts. These changes in depression were consequential: the gut microbiota’s diversity and richness decreased in tandem with the increase in depressive symptoms. Lower relationship satisfaction also foreshadowed increases in lipopolysaccharide binding protein from visit 1 to visit 2, reflecting greater translocation of bacterial endotoxin from the gut to blood circulation, a process that fuels inflammation. Lower diversity and richness provide a pathway from depressive symptoms and marital distress to subsequent health risk.

Depression, stress, and diet can all alter inflammation. This double-blind, randomized crossover study addressed the impact of daily stressors and a history of major depressive disorder (MDD) on inflammatory responses to high-fat meals. During two separate 9.5 hour admissions, 58 healthy women (38 breast cancer survivors and 20 demographically-similar controls), mean age 53.1 years, received either a high saturated fat meal or a high oleic sunflower oil meal. The Daily Inventory of Stressful Events assessed prior day stressors and the Structured Clinical Interview for DSM-IV evaluated MDD. As expected, for a woman with no prior day stressors, C-reactive protein (CRP), serum amyloid A (SAA), intercellular adhesion molecule-1 (sICAM-1), and vascular cell adhesion molecule-1 (sVCAM-1) were higher following the saturated fat meal than the high oleic sunflower oil meal after controlling for pre-meal measures, age, trunk fat, and physical activity. But if a woman had prior day stressors, these meal-related differences disappeared – because the stressors heightened CRP, SAA, sICAM-1, and sVCAM-1 responses to the sunflower oil meal, making it look more like the responses to the saturated fat meal. In addition, women with an MDD history had higher post-meal blood pressure responses than those without a similar history. These data show how recent stressors and an MDD history can reverberate through metabolic alterations, promoting inflammatory and atherogenic responses.

To compare healthcare costs and utilization among participants in a study of two active lifestyle interventions implemented in the workplace and designed to foster awareness of and attention to health with a propensity score matched control group.We retrospectively compared changes in healthcare (HC) utilization among participants in the mindfulness intervention (n=84) and the diet/exercise intervention (n=86) to a retrospectively matched control group (n=258) drawn for this study. The control group was matched from the non-participant population on age, gender, relative risk score, and HC expenditures in the 9 month preceding the study.Measures included number of primary care visits, number and cost of pharmacy prescriptions, number of hospital admissions, and overall healthcare costs tracked for 5 years after the intervention.Significantly fewer primary care visits (p.001) for both intervention groups as compared to controls, with a non-significant trend towards lower overall HC utilization (4,300.00 actual dollar differences) and hospital admissions for the intervention groups after five years. Pharmacy costs and number of prescriptions were significantly higher for the two intervention groups compared to controls over the five years (p0.05), yet still resulted in less HC utilization costs, potentially indicating greater self-management of care.This study provides valuable information as to the cost savings and value of providing workplace lifestyle interventions that focus on awareness of one's body and health. Health economic studies validate the scale of personal and organization health cost savings that such programs can generate.

Patients with symptoms but without an identified disease are a challenge to primary care providers. A 22-item measure is introduced and evaluated to offer medical care providers with an instrument to assess and discuss possible deficiencies in resilience resources that may contribute to symptoms without identifiable pathology. This instrument highlights psychosocial and lifestyle resources that serve as buffers to life’s stressors rather than focusing on stress and its related symptoms. The measure included items from five resilience domains—relational engagement, emotional sensibility, meaningful action, awareness of self and others, and physical health behaviors (REMAP). Its structure and function were evaluated using two different samples. Results suggest that scores from the REMAP have reasonable psychometric properties. Higher REMAP scores were predictive of fewer health symptoms in a sample representative of the US population. In a second sample, REMAP was positively associated with perceived resilience, ego strength and mindfulness attention and negatively related to perceived stress, depression, sleep disturbances, and loneliness, providing evidence of convergent and divergent validity. Furthermore, the REMAP scale was sensitive to change following a life style intervention. This suggests that REMAP can be a useful tool in practice settings for counseling patients with unexplained symptoms. With insight into the biopsychosocial aspect of their symptoms, patients may become more receptive to cognitive behavioral options to improve their resilience resources and lifestyle choices.

Objective Cross-sectional data have linked gut barrier abnormalities and endotoxemia with depression, even among those without gastrointestinal symptoms. This study examined longitudinal associations between endotoxemia markers and depressive symptoms, as well as the role of inflammation in this relationship. Design At three annual visits, 315 women (n=209 breast cancer survivors, n = 106 non-cancer patient controls, M=55 years old) completed the Center for Epidemiological Studies Depression questionnaire (CES-D) and provided blood samples to assess inflammatory markers – interleukin-6, tumor necrosis factor-alpha, and C-reactive protein – and endotoxemia markers – lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14), and their ratio. Results Adjusting for key demographic variables, health behaviors, visit 1 depressive symptoms, and cancer status and treatment, women with higher visit 1 LBP and LBP/sCD14 had more depressive symptoms at the two subsequent annual visits. Illustrating the notable impact, a woman at the 75th percentile for LBP or LBP/sCD14 at visit 1 was 18 % more likely to report clinically significant depressive symptoms (CES-D ≥16) at follow-up than a woman in the lowest quartile. Cancer status and treatment type did not modulate this relationship. In contrast, visit 1 depressive symptoms did not predict endotoxemia at follow-up. A significant interaction between LBP/sCD14 and inflammatory burden suggested that visit 1 endotoxemia fueled depressive symptoms only in the context of elevated inflammation. Conclusion These results suggest that endotoxemia, combined with systemic inflammation, can drive depressive symptoms. These findings may implicate bacterial endotoxin translocation from the gut to the bloodstream in depression etiology. Interventions that reduce endotoxemia and inflammation may lessen the risk of depression.

Spouses share common risks for cardiometabolic diseases: a person’s diabetes or hypertension raises the partner’s odds of developing the same condition. The mechanisms responsible for this disease concordance remain poorly understood. To examine three factors that may modulate partners’ cardiometabolic similarity—closeness, hostile marital behavior, and age—and to explore whether health behavior concordance plays a role, on two separate occasions 43 healthy couples ages 24–61 provided fasting glucose, metabolic data (fat and carbohydrate oxidation), and resting blood pressure before discussing one of their most severe marital disagreements. Accounting for the fixed effects of sex, age, study visit, and abdominal fat on cardiometabolic levels, we found that aspects of health behavior concordance were associated with greater similarity in glucose, diastolic blood pressure (DBP), and carbohydrate and fat metabolism. Independent of health behavior concordance, partners who felt closer and behaved in a less hostile way had more similar rates of fat oxidation; less hostile partners also shared greater overlap in carbohydrate oxidation. Likewise, fasting glucose and DBP were more similar within older couples compared to younger pairs, beyond the effects of health behavior concordance. In sum, our data captured preclinical similarities in cardiometabolic health among disease-free couples, which may form the basis for their long-term overlapping disease risks. Closer, less hostile, and older couples shared more similar fasting glucose, metabolic data, and blood pressure; importantly, health behavior concordance did not explain all associations. These novel data suggest that multiple paths may lead to couples’ shared disease risks.

Social-emotional aging theories suggest that older adults maintain well-being and health in part by avoiding interpersonal stressors; yet, most marital research has examined age differences during conflict. Alternatively, marital support is likely relevant for couples of all ages. To address differences in support-health associations by age and marital satisfaction, 186 people (n=93 couples) ages 22 – 77 rated interaction quality after a marital support task, and perceived available partner support. Among unhappier couples, older adults reported less available partner support than younger adults. Unhappier, older people who received lower-quality support had higher plasma epinephrine and TNF-α than better-supported peers. Conversely, happier, older couples who perceived more available support had healthier physiological profiles—i.e., lower plasma TNF-α and higher insulin growth factor-1. These data suggest that the importance of partner support for health increases with age, and marital quality may drive the benefits or risks.

Background Marital distress and depression work in tandem to escalate risks for inflammation-related disorders. Translocation of bacterial endotoxin (lipopolysaccharide, LPS) from the gut microbiota to blood circulation stimulates systemic inflammatory responses. Methods To investigate increased gut permeability (a “leaky gut”) as one potential mechanistic pathway from marital distress and depression to heightened inflammation, this secondary analysis of a double-blind, randomized crossover study examined serial assessments of two endotoxin biomarkers, LPS-binding protein (LBP) and soluble CD14 (sCD14), as well as C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) during two separate 9.5 h visits. The 43 (N = 86) healthy married couples, ages 24–61 (mean = 38.22), discussed a marital disagreement during both visits; behavioral coding of these interactions provided data on hostile marital behaviors, a hallmark of marital distress. The Structured Diagnostic Interview for DSM-IV assessed participants’ mood disorder history. Results Participants with more hostile marital interactions had higher LBP than those who were less hostile. Additionally, the combination of more hostile marital interactions with a mood disorder history was associated with higher LBP/sCD14 ratios. Higher LBP and LBP/sCD14 were associated with greater CRP production; for example, only 21% of low LBP participants (lowest quartile) had average CRP across the day > 3, compared to 79% of those in the highest quartile. Higher sCD14 was associated with higher IL-6. Conclusions These bacterial LPS translocation data illustrate how a distressed marriage and a mood disorder history can promote a proinflammatory milieu through increased gut permeability, thus fueling inflammation-related disorders.

BACKGROUND AND OBJECTIVES: Stress can trigger physical pain and disturb sleep. Whether dementia family caregivers experience heightened pain is unknown. Cycles of unwanted thoughts about caregiving stressors and avoidance of these thoughts—that is, caregiving-related distress—may exacerbate both pain and sleep disturbances, and genetic susceptibility to stress may further modulate these associations. RESEARCH DESIGN AND METHODS: Dementia caregivers (72 spouses, 58 adult children, ages 34–89) rated the extent to which they experienced unintended thoughts about caregiving and tried to suppress such thoughts. They also reported their pain levels, sleep problems, and depressive symptoms. Peripheral blood leukocytes were genotyped for 5-HTTLPR (serotonin-transporter-linked polymorphic region) and 5-HT(1A) receptor polymorphism rs6295 on the 5HTR1A locus. RESULTS: Short-allele carriers for 5-HTTLPR experienced more pain and sleep problems in association with greater caregiving-related distress than those with other genotypes. For rs6295, C carriers also showed the strongest links between distress and sleep problems. Those who experienced more avoidance and intrusive thoughts about caregiving had more severe depressive symptoms, consistent with past work. DISCUSSION AND IMPLICATIONS: Caregivers’ genetic profiles helped to explain whether caregiving-related distress predicted worse pain and sleep problems. These data reveal new somatic risks of caregiver distress and provide targets for intervention. According to plasticity theories, caregivers genetically predisposed to greater stress reactivity may also respond particularly well to interventions, and many brief treatments may effectively address caregivers’ intrusions and avoidance.

In brief A college wrestler's weight, body brief fat, and hormone levels were measured during 2 years of competition. Marked weight loss during the initial season was associated with lower serum levels of testosterone and several other hormones, as well as a decrease in reported sexual activity. All values returned to normal after the season. The following year, with less weight loss, the wrestler had only a transient decrease in testosterone and prolactin and reported no decline in sexual activity. Body fat greater than 5% seemed essential to maintaining normal endocrine function.

Exposure to adverse childhood experiences (ACE) has been associated with elevated circulating inflammatory markers in adulthood. Despite the robust effect of ACE on later health outcomes, not all individuals exposed to ACE suffer from poor health. The goal of this study was to evaluate whether current resilience resources may attenuate the impact of ACE on inflammatory markers among individuals with elevated C-reactive protein (CRP) levels. Participants (N = 174) completed one-time self-report questionnaires assessing ACE exposure within the first 18 years of life and current resilience resources, and provided blood samples for interleukin-6 (IL-6) and CRP. Individuals who were exposed to multiple ACE had greater IL-6 than participants with lesser ACE exposure. However, current resilience resources significantly moderated this effect. Among individuals who reported multiple ACE, higher resilience resources were associated with lower IL-6 levels. These data suggest that resilience resources might attenuate the association between ACE and later health outcomes.

Objectives: Cancersurvivorsoftenreportcognitiveproblems.Furthermore,decreasesinphysicalactivity typically occur over the course of cancer treatment. Although physical activity benefits cognitive function in noncancer populations, evidence linking physical activity to cognitive function in cancer survivors is limited. In our recent randomized controlled trial, breast cancer survivors who received a yoga intervention had lower fatigue and inflammation following the trial compared with a wait list control group. This secondary analysis of the parent trial addressed yoga’s impact on cognitive complaints. Methods: Posttreatment stage 0–IIIA breast cancer survivors (n=200) were randomized to a 12-week, twice-weekly Hatha yoga intervention or a wait list control group. Participants reported cognitive complaints using the Breast Cancer Prevention Trial Cognitive Problems Scale at baseline, immediately postintervention, and 3-month follow-up. Results: Cognitive complaints did not differ significantly between groups immediately postintervention (p=0.250). However, at 3-month follow-up, yoga participants’ Breast Cancer Prevention Trial Cognitive Problems Scale scores were an average of 23% lower than wait list participants’ scores (p=0.003). These group differences in cognitive complaints remained after controlling for psychological distress, fatigue, and sleep quality. Consistent with the primary results, those who practiced yoga more frequently reported significantly fewer cognitive problems at 3-month follow-up than those who practiced less frequently (p

Lonely people’s heightened risks for chronic health conditions and early mortality may emerge in part through cellular aging. Lonelier people have more severe responses to acute stress, increasing their risk for herpesvirus reactivation, a possible path to shorter telomeres. Lower parasympathetic activity may modulate this risk. To examine the associations among loneliness, parasympathetic activity, herpesvirus reactivation, and telomere length, 113 healthy men and women ages 40–85 provided blood samples that were assayed for telomere length, as well as the latent herpesviruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV). They also provided heart rate variability (HRV), a measure of parasympathetic activity, and reported on their feelings of loneliness. Lonelier people with lower HRV (i.e., lower parasympathetic activity) had greater CMV reactivation and shorter telomeres compared to their less lonely counterparts, above and beyond demographics, health behaviors, resting heart rate, and social network size. However, loneliness was not associated with viral reactivation or telomere shortening among those with higher HRV. In turn, greater CMV and EBV reactivation was associated with shorter telomeres. Taken together, these data implicate parasympathetic function in a novel route through which loneliness may accelerate cellular aging and hasten mortality.

We have developed a low dose Mindfulness Based Intervention (MBI-ld) that reduces the time committed to meetings and formal mindfulness practice, while conducting the sessions during the workday. This reduced the barriers commonly mentioned for non-participation in mindfulness programs. In a controlled randomized trial we studied university faculty and staff (n=186) who were found to have an elevated CRP level, >3.0 mg/ml, and who either had, or were at risk for cardiovascular disease. This study was designed to evaluate if MBI-ld could produce a greater decrease in CRP, IL-6 and cortisol than an active control group receiving a lifestyle education program when measured at the end of the 2 month interventions. We found that MBI-ld significantly enhanced mindfulness by 2-months and it was maintained for up to a year when compared to the education control. No significant changes were noted between interventions in cortisol, IL-6 levels or self-reported measures of perceived stress, depression and sleep quality at 2-months. Although not statistically significant (p=.08), the CRP level at 2-months was one mg/ml lower in the MBI-ld group than in the education control group, a change which may have clinical significance (Ridker et al., 2000, Wassel et al., 2010). A larger MBI-ld effect on CRP (as compared to control) occurred among participants who had a baseline BMI30 (−0.18mg/ml). We conclude that MBI-ld should be more fully investigated as a low-cost self-directed complementary strategy for decreasing inflammation, and it seems most promising for non-obese subjects.

Observational studies have linked lower levels of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) with inflammation and depression. This study was designed to determine whether n-3 supplementation would decrease serum cytokine production and depressive symptoms in 138 healthy middle-aged and older adults (average age=51.04, SD=7.76) who were sedentary and overweight (average BMI=30.59, SD=4.50). This three-arm randomized, placebo-controlled, double-blind 4-month trial compared responses to (1) 2.5 g/d n-3 PUFAs, or (2) 1.25 g/d n-3 PUFAs, or (3) placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Serum interleukin-6 decreased by 10% and 12% in our low and high dose n-3 groups, respectively, compared to a 36% increase in the placebo group. Similarly, low and high dose n-3 groups showed modest 0.2% and -2.3% changes in serum tumor necrosis factor alpha, compared to a 12% increase in the control group. Depressive symptoms were quite low at baseline and did not change significantly in response to supplementation. Our data suggest that n-3 PUFAs can reduce inflammation in overweight, sedentary middle-aged and older adults, and thus could have broad health benefits. These data provide a window into the ways in which the n-3 PUFAs may impact disease initiation, progression, and resolution. ClinicalTrials.gov identifier: NCT00385723.

The chronic stress of caregiving for a loved one with dementia has been associated with a state of immune dysregulation evidenced by weakened control over the expression of latent herpes viruses, impaired wound healing, poorer responses to vaccines, and a state of chronic low-grade elevations in circulating inflammatory markers (Gouin, Hantsoo, & Kiecolt-Glaser, 2008). Elevations in systemic IL-6 and CRP levels have been related to greater incidence of depression, cardiovascular disorder, diabetes, certain cancers, autoimmune diseases, frailty, and mortality (Maggio, Guralnik, Longo, & Ferrucci, 2006), providing a plausible physiological pathway via which chronic stress may lead to poor health. Acute laboratory stressors lead to transient increases in circulating IL-1β, IL-6, and CRP (Steptoe, Hamer, & Chida, 2007). Stress-induced elevations in IL-6 have been observed up to 22 hours following exposure to laboratory social stressor (Kiecolt-Glaser, et al., 2005). Furthermore, in a daily diary study greater interpersonal stress during a 2-week period was related to higher CRP (Fuligni, et al., 2009), suggesting that recent stressors can impact circulating inflammatory markers. Family dementia caregivers experience numerous daily stressors. These daily hassles can lead to repeated and sustained activation of the stress system. The occurrence of recurring daily stressors may then fuel chronic or sustained elevations in circulating markers of inflammation. Two main models can explain the relationship between daily and chronic stressors (Almeida, 2005). The exposure model suggests that the experience of a large number of daily stressors has a cumulative, detrimental impact on health. The reactivity model stipulates that chronic stress impacts health by increasing psychological and physiological reactivity to daily events. The goals of this study were to investigate whether greater exposure and reactivity to daily stressors may fuel overproduction of inflammatory biomarkers among family dementia caregivers. The hypotheses were 1) caregivers will report more daily stressors than controls; 2) the number of daily stressors will be associated with IL-6 and CRP; 3) caregivers will display a stronger association between daily stressors and IL-6 and CRP levels than controls.

Fatigue is a notable clinical problem in cancer survivors, and understanding its pathophysiology is important. The current study sought to determine biomarkers of fatigue that exist before cancer treatment. Relationships between the expression of latent Epstein–Barr virus (EBV) and cytomegalovirus (CMV) and fatigue were examined in 158 women newly diagnosed with breast cancer or awaiting a positive diagnostic result. Higher CMV antibody titers, but not EBV antibody titers, were associated with a greater likelihood of being fatigued. Associations between fatigue and higher CMV antibody titers remained after controlling for alcohol use, smoking, comorbidities, depressive symptoms, age, BMI, cancer stage, and sleep problems. More sleep problems and higher levels of depressive symptoms were also associated with a greater likelihood of being fatigued. CMV antibody titers, but not EBV antibody titers, were associated with higher levels of C-reactive protein (CRP), but CRP was not associated with fatigue. When the cellular immune system is compromised, reactivation of latent herpesviruses may fuel chronic inflammatory responses. Prior work has suggested that fatigue may be related to inflammation and its associated sickness behaviors; accordingly, our findings may be tapping into this same physiological substrate.

Aging and psychological stress are associated with impaired wound healing. Aerobic exercise (AE) has been associated with accelerated rates of wound healing among healthy older adults. This study evaluated the influence of AE on wound healing among healthy, stressed older adults. 77 community-residing older adults (mean age=65.0±7.9 years; range: 55–84 years; 64% women) reporting elevated daily stress were randomly assigned to an AE group or a balance and flexibility (BF) control group. Both groups attended sessions 3x/week for 12 weeks. Participants completed comprehensive assessments prior to randomization and at study conclusion, including exercise capacity (VO2peak) and psychological stress (Perceived Stress Scale-10), as well as additional self-report and biological markers. After 2 weeks of group sessions (AE or BF), participants underwent a standardized experimental wound procedure, and wounds were measured 3x/week until healed to calculate wound healing rate. Repeated measures analysis of variance (ANOVA) revealed a time by group interaction for VO2peak [F(1,66)=10.07, p=.002], with a 13% gain in AE versus 2% in BF. As expected, in the full sample older age was associated with slower wound healing (r=.24, p=.040). Surprisingly, ANOVA revealed no difference in wound healing rate across groups, but wound healing was faster among men than among women [F(1,67)=5.46, p=.022]. Also, there was a significant sex by group interaction [F(1,67)=6.15, p=.016]: among women, wounds healed faster in the AE group, but among men wounds healed faster in the BF group. Thus, among stressed older adults, AE may be more relevant for wound healing of women than of men.

Observational studies have linked lower omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and higher omega-6 (n-6) PUFAs with inflammation and depression, but randomized controlled trial (RCT) data have been mixed. To determine whether n-3 decreases proinflammatory cytokine production and depressive and anxiety symptoms in healthy young adults, this parallel group, placebo-controlled, double-blind 12-week RCT compared n-3 supplementation with placebo. The participants, 68 medical students, provided serial blood samples during lower-stress periods as well as on days before an exam. The students received either n-3 (2.5 g/d, 2085 mg eicosapentaenoic acid and 348 mg docosahexanoic acid) or placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Compared to controls, those students who received n-3 showed a 14% decrease in lipopolysaccharide (LPS) stimulated interleukin 6 (IL-6) production and a 20% reduction in anxiety symptoms, without significant change in depressive symptoms. Individuals differ in absorption and metabolism of n-3 PUFA supplements, as well as in adherence; accordingly, planned secondary analyses that used the plasma n-6:n-3 ratio in place of treatment group showed that decreasing n-6:n-3 ratios led to lower anxiety and reductions in stimulated IL-6 and tumor necrosis factor alpha (TNF-α) production, as well as marginal differences in serum TNF-α. These data suggest that n-3 supplementation can reduce inflammation and anxiety even among healthy young adults. The reduction in anxiety symptoms associated with n-3 supplementation provides the first evidence that n-3 may have potential anxiolytic benefits for individuals without an anxiety disorder diagnosis. ClinicalTrials.gov identifier: NCT00519779.

Summary Objective Self-rated health is a strong independent predictor of mortality after accounting for objective health status, behavioral risk factors, and sociodemographic characteristics. However, mechanisms underlying this association are largely unexplained. Inflammation has been associated with increased risk of morbidity and mortality in the elderly. The current study aimed to: (1) examine associations between self-rated health and serum inflammatory markers in older adults; (2) examine the relative strength of these associations for self-rated health versus self-rated change in recent health; (3) examine components of self-rated health that may underlie the association between inflammation and global self-rated health. Methods Self-rated health, as measured by the RAND health survey, and serum interleukin (IL)-6 and C-reactive protein (CRP) were assessed among 250 generally healthy older adults (185 women, 65 men; average age = 63.8 ± 13.7 years). Results A series of linear regression analyses demonstrated that poorer self-rated health was significantly associated with higher IL-6 and CRP. These relationships remained after controlling for age, body mass index, gender, and objective health conditions. These associations also remained after controlling for depressive symptoms, neuroticism, perceived change in health over the past year, and health behaviors (smoking, sleep quality, and physical activity). Analyses of RAND component measures demonstrated that poorer physical functioning was significantly associated with IL-6; the relationship between global self-rated health and both IL-6 and CRP remained after accounting for perceived physical functioning. Conclusions Poorer self-rated health is associated with elevated serum inflammatory markers among generally healthy older adults. The relationship of self-rated health with inflammatory markers is not secondary to depressive symptoms, neuroticism, or recent changes in perceived health. Subjective ratings of health provide important clinical information regarding inflammatory status, beyond traditional objective risk factors, even among generally healthy individuals.

Previous investigations of somatic hypersensitivity in IBS patients have typically involved only a single stimulus modality, and little information exists regarding whether patterns of somatic pain perception vary across stimulus modalities within a group of patients with IBS. Therefore, the current study was designed to characterize differences in perceptual responses to a battery of noxious somatic stimuli in IBS patients compared to controls. A total of 78 diarrhea-predominant and 57 controls participated in the study. We evaluated pain threshold and tolerance and sensory and affective ratings of contact thermal, mechanical pressure, ischemic stimuli, and cold pressor stimuli. In addition to assessing perceptual responses, we also evaluated differences in neuroendocrine and cardiovascular responses to these experimental somatic pain stimuli. A subset of IBS patients demonstrated the presence of somatic hypersensitivity to thermal, ischemic, and cold pressor nociceptive stimuli. The somatic hypersensitivity in IBS patients was somatotopically organized in that the lower extremities that share viscerosomatic convergence with the colon demonstrate the greatest hypersensitivity. There were also changes in ACTH, cortisol, and systolic blood pressure in response to the ischemic pain testing in IBS patients when compared to controls. The results of this study suggest that a more widespread alteration in central pain processing in a subset of IBS patients may be present as they display hypersensitivity to heat, ischemic, and cold pressor stimuli.

Inflammation is a robust and reliable predictor of all-cause mortality in older adults (1). Proinflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) play a role in cardiovascular disease, type II diabetes, arthritis, osteoporosis, Alzheimer’s disease, periodontal disease, and frailty and functional decline (2–3). In addition, inflammation is now regarded as a risk factor for most cancers because of the evidence that inflammation influences tumor promotion, survival, proliferation, invasion, angiogenesis, and metastases (4). Behavioral lifestyle factors can substantially influence inflammation. Obesity has been characterized as a state of chronic inflammation because of the elevated plasma levels of IL-6, TNF-α, and CRP (5). One obvious mechanism is provided by the fact that adipocytes (fat cells) are capable of producing and secreting IL-6 and TNF-α; in fact, up to 30% of IL-6 may be derived from adipose tissue (6). Physical activity is also an important behavioral cofactor; people who describe themselves as active have lower levels of inflammatory biomarkers than their sedentary counterparts (7). Indeed, when physical or cardiorespiratory fitness is assessed rigorously and objectively by maximal exercise testing, fitness is inversely associated with inflammation, even after adjusting for confounds including age, smoking, medications, and visceral fat (8–11). Although regular physical activity is associated with lower levels of IL-6 and other proinflammatory cytokines, acute exercise transiently boosts production and release of IL-6 from skeletal muscles; the IL-6 that is released during physical activity inhibits TNF-α production and can induce IL-10 production, one mechanism underlying exercise’s anti-inflammatory function (1). Lower levels of circulating IL-6 at rest as well as following exercise appear to be the normal adaptation to training (12) In addition to exercise and obesity, behavior affects inflammation through other pathways; even relatively modest levels of anxiety and depressive symptoms can raise proinflammatory cytokine production (13). Additionally, psychological stressors can directly provoke transient increases in proinflammatory cytokines (14–15), and chronic stressors have been linked to sustained overproduction of IL-6 (16–17). Yoga’s reputation for stress reduction and mental health benefits has bolstered its popularity in recent years, and data from randomized trials suggest that yoga reduces symptoms of anxiety and depression (18–19). Hatha yoga, the most common form practiced in the western world, combines body postures or asanas, breath control or pranayama, and meditation (20). Mechanistic explanations for yoga’s potential mental and physical health benefits have highlighted reductions in sympathetic nervous system tone (21–22), and increases in vagal activity (22), both of which could have favorable endocrine and immune consequences, including lower inflammation. In fact, one recent randomized trial suggested that yoga might have positive benefits for inflammation; 9 heart failure patients randomized to a two-month hatha yoga intervention showed a 22% reduction in IL-6 and a 20% reduction in CRP compared to minimal change in the 10 patients who received standard medical care (23). In contrast, CRP did not change following a 6-week nonrandomized trial in 33 individuals both with and without established coronary artery disease, but the group did show significant reductions in blood pressure, heart rate, and body mass index (BMI) (24). Surprisingly few studies have attempted to relate endocrine or immune function to yoga practice, even though some hatha yoga postures are characterized as immune enhancing or restorative (25). We assessed cardiovascular, inflammatory, and endocrine responses in novice and expert yoga practitioners before, during, and after a hatha yoga session, as well as in two control conditions. To test yoga's restorative potential, stressors preceded each of the three conditions, providing data on the extent to which yoga speeded an individual's physiological recovery. In addition, tape stripping a small area of forearm skin before each of the conditions provided data on the course of skin barrier repair, a stress-sensitive process modulated by both cortisol and cytokine production (26–27). The ability to minimize autonomic and inflammatory responses in stressful situations undoubtedly influences the burden that stressors place on an individual. Thus, we designed this study to assess yoga’s ability to promote recovery from a stressor. We elected to conduct the yoga session after the stressor, rather than prior to the stressor, for several reasons. First, anticipation of a stressor following the yoga session could reduce participants’ ability to fully relax and concentrate during the yoga session, particularly among novices; completing the stressor prior to the yoga session could allow for a more relaxing yoga experience, providing greater power to detect effects of yoga. In addition, our ability to track changes in physiological markers of interest during the yoga session was improved by eliciting a physiological response prior to the session. Finally, using a stressor prior to the yoga session allowed us to examine whether regular yoga practice resulted in differential magnitude of reactivity to the stressor, independent of the effects of a recent yoga session. We hypothesized that: (1) experienced yoga practitioners would have lower levels of inflammation, and smaller autonomic, endocrine, and inflammatory responses to the stressors than novices. (2) During and following the yoga session, subjects would demonstrate more rapid declines (recovery) in stress hormones and proinflammatory cytokine production, and better skin barrier repair than evidenced following either of the control conditions. Mood measures would reflect greater positive change following yoga compared to the control conditions.

Individuals with spinal cord injury (SCI) are highly susceptible to infection. This post-traumatic immune suppression is thought to occur via alterations in sympathetic nervous system (SNS) or hypothalamic-pituitary-adrenal (HPA) axis function. Normally, the HPA axis and SNS help coordinate proper immune function. After SCI, the HPA axis becomes activated and descending input to sympathetic preganglionic neurons (SPNs) is impaired. Because lymphoid organs are innervated by SPNs distributed throughout the thoracolumbar spinal cord, we predicted level-dependent immune suppression after SCI due to activation of the HPA axis and loss of descending input to SPNs. We tested this hypothesis by measuring indices of HPA (circulating corticosterone; CORT) and SNS function (norepinephrine (NE) in spleen) as well as antigen-specific antibody synthesis against an exogenous non-self protein following high- or low-level SCI. Using a mid-thoracic (T9) spinal contusion injury model, we found that CORT was elevated after SCI with aberrant patterns of diurnal CORT synthesis evident through at least the first 24 h post-injury. However, splenic NE and antibody synthesis were similar to uninjured controls. Injury severity did not change these parameters. Indeed, CORT, NE and antibody synthesis were similar after T9 contusion or transection SCI. In contrast, high-level SCI (T3) caused sustained increases in CORT and splenic NE along with impaired antibody synthesis and elevated splenocyte apoptosis. The immunosuppressive effects of T3 SCI were caused by NE acting at beta2-adrenergic receptors (beta2AR) and could be reversed using beta2AR blockers. Interestingly, impaired antibody after T3 SCI could be mimicked after T9 SCI with a beta2AR agonist. These data illustrate the immunosuppressive effects of the SNS after high-level SCI and indicate that immune deficits may be overcome using beta-blockers.

Background: Human and animal laboratory studies have shown that stress delays healing of standardized punch biopsy wounds. Purpose: This 5-week prospective study of 17 women who underwent elective gastric bypass surgery addressed the association between postsurgical pain intensity and subsequent healing of a standard 2.0-mm punch biopsy wound. Methods: Participants were assessed 1 week before surgery, within 3 hr before surgery, 1 to 3 days postsurgery, and at weekly intervals for 4 weeks following surgery. Results: Patient ratings of greater acute postsurgical pain, averaged over Days 1 and 2 postsurgery, and greater persistent postsurgical pain, averaged over 4 weekly postsurgery pain ratings, were significantly associated with subsequent delayed healing of the punch biopsy wound. Presence of depressive symptoms on the day of surgery, pre-existing persistent pain, and medical complications following initial discharge from the hospital were not related to wound healing. Depressive symptoms on the day of surgery and pre-existing persistent pain did predict persistent postsurgical pain intensity. Conclusions: These findings extend the previous laboratory models of wound healing to a surgical population, providing the first evidence that pain plays an important role in postsurgery wound healing, a key variable in postsurgical recovery.

Background. Older adults are likely to experience delayed rates of wound healing, impaired neuroendocrine responsiveness, and increased daily stress. Exercise activity has been shown to have a positive effect on physiological functioning and psychological functioning among older adults. This study evaluated the effect of a 3-month exercise program on wound healing, neuroendocrine function, and perceived stress among healthy older adults. Methods. Twenty-eight healthy older adults (mean age 61.0 6 5.5 years) were assigned randomly to an exercise activity group (n ¼ 13) or to a nonexercise control group (n ¼ 15). One month following baseline randomization, after exercise participants had acclimated to the exercise routine, all participants underwent an experimental wound procedure. Wounds were measured 3 times per week until healed to calculate rate of wound healing. All participants completed assessments of exercise endurance, salivary cortisol, and self-reported stress prior to randomization and at the conclusion of the intervention. Results. Exercise participants achieved significant improvements in cardiorespiratory fitness, as reflected by increased oxygen consumption (VO2max) and exercise duration. Wound healing occurred at a significantly faster rate in the exercise group [mean ¼ 29.2 (9.0) days] than in the nonexercise group [38.9 (7.4) days; p ¼ .012]. Exercise participants also experienced increased cortisol secretion during stress testing following the intervention. Group differences in wound healing and neuroendocrine responsiveness were found despite low levels of self-reported stress. Conclusions. A relatively short-term exercise intervention is associated with enhanced rates of wound healing among healthy older adults. Thus, exercise activity may be an important component of health care to promote wound healing.

Cancer-related distress is common among breast cancer survivors prior to treatment and is associated with adverse health effects. Moreover, many survivors continue to experience distress after treatment ends, and the impact of prolonged cancer-related distress on health is unknown. The aim of the current study was to investigate the effects of cancer-related distress on inflammation changes among breast cancer survivors. In a parent study, survivors stages 0- IIIC (N = 126 ) provided data prior to primary cancer treatment (i.e., surgery, radiation, or chemotherapy) and 18 months post-treatment. The current study utilized the Impact of Events Scale-Revised (IES-R) and proinflammatory cytokine interleukin-6 (IL-6). Cross-sectional analyses indicated that women reporting more cancer-related distress 18-months post- treatment evidenced greater inflammation compared to those with lower distress (b = 0.009 , SE = 0.004 , p = .050 ). Additionally, women who experienced greater declines in cancer-related distress evidenced smaller IL-6 increases from pre to post-treatment (b = 0.007 , SE = 0.003 , p = .041 ). Follow-up analyses indicated that changes in avoidance were related to changes in inflammation (b = 0.014 , SE = 0.005 , p = .010 ), but changes in intrusive thoughts were not (b = 0.005 , SE = 0.006 , p = .453 ). Women who experience prolonged cancer-related distress, and avoidant emotional coping in particular, may experience more persistent inflammation during survivorship, leaving them vulnerable to increased risk of recurrence and morbidity.

Purpose To evaluate yoga's impact on inflammation, mood, and fatigue. Patients and Methods A randomized controlled 3-month trial was conducted with two post-treatment assessments of 200 breast cancer survivors assigned to either 12 weeks of 90-minute twice per week hatha yoga classes or a wait-list control. The main outcome measures were lipopolysaccharide-stimulated production of proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), and scores on the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), the vitality scale from the Medical Outcomes Study 36-item Short Form (SF-36), and the Center for Epidemiological Studies-Depression (CES-D) scale. Results Immediately post-treatment, fatigue was not lower (P > .05) but vitality was higher (P = .01) in the yoga group compared with the control group. At 3 months post-treatment, fatigue was lower in the yoga group (P = .002), vitality was higher (P = .01), and IL-6 (P = .027), TNF-α (P = .027), and IL-1β (P = .037) were lower for yoga participants compared with the control group. Groups did not differ on depression at either time (P > .2). Planned secondary analyses showed that the frequency of yoga practice had stronger associations with fatigue at both post-treatment visits (P = .019; P < .001), as well as vitality (P = .016; P = .0045), but not depression (P > .05) than simple group assignment; more frequent practice produced larger changes. At 3 months post-treatment, increasing yoga practice also led to a decrease in IL-6 (P = .01) and IL-1β (P = .03) production but not in TNF-α production (P > .05). Conclusion Chronic inflammation may fuel declines in physical function leading to frailty and disability. If yoga dampens or limits both fatigue and inflammation, then regular practice could have substantial health benefits.

Anxiety and psychological stress affect allergy-related immune function. How these relations influence the evaluations of patients with allergic rhinitis is unknown.To examine whether anxiety and stress exposure affect skin prick test (SPT) responses to common allergens for which patients with atopy showed no prior positive SPT response.Patients with allergic rhinitis, evidenced by clinical history and SPT results, were admitted twice to a hospital research unit for 4 hours. In a crossover design, SPT wheals were assessed before and after the Trier Social Stress Test and then the following morning; for comparison, SPT wheals were assessed before and after a laboratory session without a stressor. Analyses focused on wheal responses for common allergens that tested negative (wheal size3 mm larger than saline) from SPTs performed at multiple baseline assessments.After the Trier Social Stress Test, more anxious patients with atopy had a higher incidence of positive SPT reactions to antigens that previously tested negative. Anxiety was unrelated to positive SPT incidence under nonstressful conditions. Based on clinical symptom reports, newly positive SPT reactions after the stressor were apparently corrections of previously false-negative SPT reactions. The SPT wheal responses for allergens previously testing negative were enhanced after a stressor. Histamine (positive control) or saline (negative control) SPT responses were not affected.A laboratory stressor affected allergen SPT responses in more anxious patients with allergic rhinitis. In addition to clinical history, assessment of anxiety and current stress at the time of the SPT may provide valuable information about a patient's allergic status and aid in clinical decision making.

Pain and depressive symptoms are commonly experienced by cancer survivors. Lower social support is linked to a variety of negative mental and physical health outcomes among survivors. Immune dysregulation may be one mechanism linking low social support to the development of pain and depressive symptoms over time. Accordingly, the goal of the present study was to examine the relationships among survivors' social support, pain, depressive symptoms, and inflammation.Breast cancer survivors (N=164, stages 0-IIIA) completed two study visits, one before any cancer treatment and the other 6 months after the completion of surgery, radiation, or chemotherapy, whichever came last. Women completed self-report questionnaires assessing social support, pain, and depressive symptoms, and provided a blood sample at both visits.Survivors with lower social support prior to treatment experienced higher levels of pain and depressive symptoms over time than their more socially supported counterparts. Furthermore, women with lower pretreatment social support had higher levels of IL-6 over time, and these elevations in IL-6 predicted marginally larger increases in depressive symptoms.The results of this study suggest that social support at the time of diagnosis predicts the post-treatment development of pain, depressive symptoms, and inflammation. Consequently, early interventions targeting survivors' social networks could improve quality of life during survivorship.

BACKGROUND A number of studies have shown that the chronic stress of caring for persons with dementia can have significant immunological consequences as demonstrated by the down-regulation/dysregulation of the cellular immune response. METHODS Utilizing flow cytometry to measure the percentages and absolute numbers of CD-4(+) and CD-8(+) T lymphocytes producing the cytokines indicative of Th-1, Tc1 and Th-2, and Tc2 cells, we compared spousal caregivers and control subjects. The expression of interleukin-2 (IL-2), interferon gamma (IFN-gamma), and interleukin-10 (IL-10) in the cytoplasm of CD-4(+) and CD-8(+) lymphocytes was assessed. RESULTS Neither stress nor age was significantly related to the percentage or number of IFNgamma(+)/CD-8(+), IL-2(+)/CD-8(+) cells, or IFNgamma(+), IL-2(+), CD-4(+) cells. However, the percentage of IL-10(+) cells was higher in lymphocytes obtained from caregivers than control subjects. In addition, the significant interaction between stress and aging for IL-10(+)/CD-4(+) and IL-10(+)/CD-8(+) cells demonstrated that the difference between caregivers and control subjects was age dependent; the difference between caregivers and control subjects was substantially larger in younger individuals than in older individuals. CONCLUSIONS The data are consistent with previous reports on acute stress and suggest that there may also be a shift from a Th-1 to a Th-2 response associated with a chronic stressor such as caregiving. This shift could have implications for an individual's responses to pathogens.

Objective: Influenza and pneumonia account for significant morbidity and mortality, particularly in older individuals. Previous studies have shown that spousal caregivers of patients with dementia have poorer antibody and virus specific T cell responses to an influenza virus vaccine relative to noncaregiving control subjects. This study tested the hypothesis that stress can also significantly inhibit the IgG antibody response to a pneumococcal bacterial vaccine. Method: We measured antibody titers of current caregivers, former caregivers, and control subjects after vaccination with a pneumococcal bacterial vaccine. Results: Caregivers showed deficits relative to controls and former caregivers in their antibody responses to vaccination. Although the groups did not differ before vaccination or in the rise in antibody 2 weeks or 1 month after vaccination, current caregivers had lower antibody titers 3 and 6 months after vaccination than either former caregivers or controls. Conclusions: These data, the first evidence that chronic stress can inhibit the stability of the IgG antibody response to a bacterial vaccine for pneumonia, provide additional evidence of health risks associated with dementia caregiving. Key words: stress, immune response, vaccinations.

The effects of octreotide (up to 5 yr) as primary treatment in 26 patients with acromegaly were compared with those in 81 patients with acromegaly who received octreotide as secondary or adjunctive therapy after previous surgery and/or pituitary radiation. These patients were part of a multicenter study that took place between 1989-1995. The study was divided into 3 phases beginning with a 1-month placebo-controlled treatment period followed by a 1-month washout period. In the second phase, patients were randomized to treatment with either 100 or 250 micrograms octreotide, sc, every 8 h for 6 months. Octreotide was then discontinued for 1 month and reinitiated at the lower dose for a total mean treatment duration of 39 months. The dose was titrated by each investigator to improve each patient's individual response, which included improvement in symptoms and signs of acromegaly as well as reduction of GH and insulin-like growth factor I (IGF-I) into the normal range. In the second phase of the study, in which patients were randomized to either 100 or 250 micrograms octreotide, three times daily, mean integrated GH and IGF-I concentrations after 3 and 6 months were equivalent in the primary and secondary treatment groups. During long term open label treatment, mean GH fell from 32.7 +/- 5.2 to 6.0 +/- 1.7 micrograms/L 2 h after octreotide injection in the primary therapy group and remained suppressed for a mean period of 24 months (range, 3-60 months). The mean final daily dose was 777 micrograms. In the patients receiving secondary treatment, mean GH fell from 30.2 +/- 7.6 to 5.6 +/- 1.1 micrograms/L after 3 months and remained suppressed for the remainder of the study (average dose, 635 micrograms daily). Mean IGF-I concentrations fell from 5.2 +/- 0.5 x 10(3) U/L (primary treatment group) and 4.7 +/- 0.4 x 10(3) U/L (secondary treatment group) to a mean of 2.2 +/- 0.3 x 10(3) U/L in both groups after 3 months of open label treatment and remained suppressed. IGF-I was reduced into the normal range during at least half of the study visits in 68% of the primary treatment group and in 62% of the secondary treatment group. Patients whose GH levels fell to at least 2 SD below the baseline mean GH were considered responders. There was no significant difference in the percentage of responders in the primary and secondary treatment groups (70% vs. 61%), nor was there a statistical difference in the mean GH concentrations between the groups. Symptoms of headache, increased perspiration, fatigue, and joint pain were reported at baseline by 46%, 73%, 69%, and 85%, respectively, of patients in the primary therapy group and improved during 3 yr of octreotide treatment in 50-100%. Similarly, these acromegaly-related symptoms were reported by 62%, 58%, 78%, and 60% of patients in the secondary therapy group, and improvement was noted in 62-88%. Pituitary magnetic resonance imaging scans were available in 13 of 26 patients in the primary treatment group before and after 6 months of octreotide treatment. Tumor shrinkage was observed in 6 of 13 patients, with reduction in tumor volume greater than 25% in only 3. Of 6 patients with documented tumor shrinkage, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 5 patients. The degree of tumor shrinkage did not correlate with the percent reduction in IGF-I or GH. In summary, octreotide was equally effective in 26 previously untreated acromegalic patients (primary treatment group) and 81 patients previously treated with either surgery or pituitary radiation (secondary treatment group). These observations call into question the current practice of surgical resection of all newly diagnosed GH-secreting pituitary adenomas regardless of the likelihood of cure. (AB

We compared virus-specific antibody and T-cell responses to influenza virus vaccination in 32 caregivers of Alzheimer's disease (AD) patients and matched control subjects. Caregivers showed a poorer antibody response and virus-specific T-cell response following vaccination compared to the control subjects as measured by fourfold increases in antibody titers to the vaccine and lower levels of virus-induced IL-2 levels in vitro. We performed a second study in which forty-eight medical students were inoculated with a series of three injections of the hepatitis-B (HEP-B) vaccine to coincide with the third day of three, three-day examination blocks. Twelve of the 48 medical students seroconverted after the first injection; these students were characterized by falling into the lower stressed/lower anxiety group of students. Students who reported greater social support and lower anxiety and stress demonstrated a higher antibody response to the vaccine and a more vigorous T-cell response to HEP-B surface antigen at the end of the third examination experience. The differences in antibody and T-cell responses to HEP-B and influenza virus vaccinations provide a demonstration of how stress may be able to alter both the cellular and humoral immune responses to vaccines and novel pathogens in both younger and older adults.

This study investigated whether the stress of caregiving alters cellular immune responses to acute psychological stressors. Twenty-seven women caring for a spouse with a progressive dementia (high chronic stress) and 37 controls matched for age and family income performed a 12-min laboratory stressor. Cellular immune function was assessed by both functional and quantitative measures taken before (low acute stress), immediately after (high acute stress), and 30 min after (recovery from stress) exposure to the laboratory stressors. The laboratory challenges were associated with diminished proliferative responses but elevated natural killer (NK) cell cytotoxicity; however, subsequent analyses suggested that this elevated cytotoxicity was largely attributable to an increase in the number of NK cells in peripheral blood. The results suggest that although the stress of caregiving diminishes cellular immune function, caregiving appears to have little effect on cellular immune responses to or recovery from brief psychological challenges.

Objective: Postmenopausal status increases some aspects of women's physiological responses to psychological stress; however, the influences of chronic hormone replacement with estrogen and progestogen on these responses are not known. We investigated possible effects of long-term estrogen replacement therapy (ERT). both with and without progestogen, on physiological reactivity to brief laboratory stressors. Method: We studied three groups of postmenopausal women: 16 on estrogen alone, 14 on estrogen and progestogen, and 25 control participants receiving no replacement therapy. Cardiovascular, neuroendocrine, and immune data were collected at baseline and after speech and math tasks. Results: In all groups, the stressors reduced vagal cardiac control (indexed by respiratory sinus arrhythmia); increased heart rate and plasma epinephrine, adrenocorticotropic hormone, and cortisol levels; and altered T lymphocyte response (measured by mitogen-induced cell proliferation), natural killer cell lysis, and circulating leukocyte subsets. Women on either type of ERT had higher total cortisol levels (reflecting an estrogen effect on cortisol binding globulin) and greater mitogen-induced blastogenesis across measurement periods than controls. They also showed greater vagal withdrawal and less decline in mitogen-stimulated blastogenesis in response to the stressors. Combined estrogen and progestogen was associated with higher epinephrine and lower circulating total lymphocytes, T cells, and CD4+ T cells across measurement periods, and with intermediate levels of vagal withdrawal in response to the stressors. Conclusions: Long-term ERT was associated with enhanced parasympathetic responsiveness to stress, suggesting possible reduced demand for potentially detrimental sympathetic activation; and with higher overall levels and smaller stress-induced reductions of mitogen-stimulated blastogenesis, suggesting

Background A relation between stress and symptoms of rhinitis has not been established. Objective: To determine if participants' reporting of allergy flares correlated with perceived emotional stress, depression, mood, and a biomarker of stress (cortisol). Methods This study was a secondary analysis of 179 university employees who participated in a study evaluating the influence of several lifestyle interventions on health symptoms and inflammation. Perceived stress and depressive symptom questionnaires were obtained before each 2-week study period. Online diary entries documenting same-day allergy flares, stressful events, perceived stress, mood, and salivary cortisol levels were collected daily during 2 14-day blocks. Results Thirty-nine percent of subjects (n = 69) self-reported allergy symptoms. This allergy flare group had higher perceived stress scores than the group without allergy symptoms. Perceived stress, but not depressive symptoms, positively correlated with allergy flares evaluated during 2 independent 14-day periods. There also was a positive relation between negative mood scores and allergy flares over the course of the study. Cortisol had no association with allergy symptom flares. Conclusion These findings suggest that individuals with persistent emotional stress have more frequent allergy flares. Furthermore, those with more flares have greater negative mood.

Although evidence suggests that loneliness may increase risk for health problems, the mechanisms responsible are not well understood. Immune dysregulation is one potential pathway: Elevated proinflammatory cytokines such as interleukin-6 (IL-6) increase risk for health problems. In our first study ( N = 134), lonelier healthy adults exposed to acute stress exhibited greater synthesis of tumor necrosis factor-alpha (TNF-α) and IL-6 by peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharide (LPS) than their less lonely counterparts. Similarly, in the second study ( N = 144), lonelier posttreatment breast-cancer survivors exposed to acute stress exhibited greater synthesis of IL-6 and interleukin-1 beta (IL-1β) by LPS-stimulated PBMCs than their counterparts who felt more socially connected. However, loneliness was unrelated to TNF-α in Study 2, although the result was in the expected direction. Thus, two different populations demonstrated that lonelier participants had more stimulated cytokine production in response to stress than less lonely participants, which reflects a proinflammatory phenotype. These data provide a glimpse into the pathways through which loneliness may affect health.

To determine whether a chronic stressor (caregiving for a spouse with a progressive dementia) is associated with an impaired immune response to influenza virus vaccination, we compared 32 caregivers' vaccine responses with those of 32 sex-, age-, and socioeconomically matched control subjects. Caregivers showed a poorer antibody response following vaccination relative to control subjects as assessed by two independent methods, ELISA and hemagglutination inhibition. Caregivers also had lower levels of in vitro virus-specific-induced interleukin 2 levels and interleukin 1beta; interleukin 6 did not differ between groups. These data demonstrate that down-regulation of the immune response to influenza virus vaccination is associated with a chronic stressor in the elderly. These results could have implications for vulnerability to infection among older adults.

Childhood abuse leads to greater morbidity and mortality in adulthood. Dysregulated physiological stress responses may underlie the greater health risk among abused individuals.This study evaluated the impact of childhood abuse on inflammatory responses to naturalistically occurring daily stressors.In this cross-sectional study of 130 older adults, recent daily stressors and childhood abuse history were evaluated using the Daily Inventory of Stressful Events and the Childhood Trauma Questionnaire. Blood samples provided data on circulating interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP).Childhood abuse history moderated IL-6 levels but not TNF-α and CRP responses to daily stressors. Individuals with a childhood abuse history who experienced multiple stressors in the past 24 h had IL-6 levels 2.35 times greater than those of participants who reported multiple daily stressors but no early abuse history.Childhood abuse substantially enhances IL-6 responses to daily stressors in adulthood.

Summary Cigarette smoking continues to be the most preventable cause of illness and death and has been linked to the development and prognosis of cancer. Current smokers have higher levels of inflammation than nonsmokers, and inflammation can remain elevated in former smokers even years following cessation. Inflammation can also be enhanced by stress. This study examined cortisol and inflammatory responses to a laboratory stressor in breast cancer survivors who formerly smoked compared to their counterparts who had never smoked. Participants included 89 women (age = 51.6 ± 8.9 years) who had completed treatment for stage 0–IIIA breast cancer within the past three years and were at least two months post surgery, radiation or chemotherapy, whichever occurred last. Cortisol and interleukin-6 (IL-6) were evaluated in response to a standardized laboratory speech and mental arithmetic stressor. Former (n = 25) and never (n = 64) smokers did not differ by cancer stage, cancer treatment, comorbidities, time since cancer treatment, depression, or stress. Despite having similar cortisol responses to the stressor, former smokers had exaggerated IL-6 responses two hours post-stressor compared to never smokers. This effect persisted after controlling for age, BMI, time since treatment, education, and antidepressant use. An exaggerated and prolonged inflammatory response to stress could be one mechanism underlying the persistent inflammation observed in former smokers.