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1.  Neuroendocrine Effects of Stress on Immunity in the Elderly: Implications for Inflammatory Disease 
Synopsis
Age-related changes in immune function leave older adults at risk for a host of inflammatory diseases. Immune-mediated inflammatory processes are regulated by neuroendocrine hormones, including glucocorticoids, dehydroepiandrosterone (DHEA), and the catecholamines, epinephrine and norepinephrine. This regulation, however, becomes impaired in older adults in light of age-related changes in endocrine function. Chronic stress shows similarly harmful effects on neuroendocrine and immune function and may, therefore, combine with age to further increase disease risk in older adults. This article highlights evidence for the impact of age and stress on neuroendocrine regulation of inflammatory processes that may substantially increase risk for inflammatory disease at older ages.
doi:10.1016/j.iac.2010.09.005
PMCID: PMC2989743  PMID: 21094926
stress; HPA axis; inflammation; inflammatory disease; aging; older adults
2.  Chronic Low Back Pain, Sleep Disturbance, and Interleukin-6 
The Clinical journal of pain  2011;27(1):35-41.
Objectives
Sleep disturbance is a common co-morbidity of chronic pain. Inflammatory processes are dysregulated in sleep disturbance and also contribute to pain sensitivity. Thus, inflammation may play an important role in bi-directional associations between pain and sleep. Little is known about concurrent relationships among chronic pain, sleep, and inflammation. The aim of our study was to examine associations among sleep disturbance and circulating levels of the inflammatory cytokine, interleukin-6 (IL-6), in individuals with and without chronic low back pain.
Methods
Gender and age-matched adults with chronic low back pain (CLBP; n = 25) or without chronic pain (controls; n = 25) completed measures of sleep quality in the past month and depressive symptoms in the past week, and provided a blood draw for IL-6. The next morning, participants reported their sleep quality the previous night and their current experience of morning pain.
Results
Individuals with CLBP had more sleep disturbance than controls. Circulating IL-6 levels were similar for the two groups; however, in adults with CLBP, poorer sleep quality was associated with higher IL-6 levels, and both sleep and IL-6 related to pain reports. Unlike CLBP participants, controls showed normal, age-related increases in IL-6 levels, whereas sleep quality was unrelated to IL-6 levels. Depressive symptoms could not fully explain the observed associations.
Discussion
Inflammatory processes may play a significant role in cycles of pain and sleep disturbance. Clinical interventions that improve sleep and reduce concomitant inflammatory dysregulation hold promise for chronic pain management.
PMCID: PMC3058637  PMID: 21188850
chronic back pain; sleep disturbance; inflammatory cytokines; interleukin-6
3.  Moderating Effects of Moderate-Intensity Physical Activity in the Relationship Between Depressive Symptoms and Interleukin-6 in Primary Care Patients 
Psychosomatic medicine  2011;73(3):265-269.
Objective
To determine whether the relationship between interleukin (IL)-6 and depressive symptoms is moderated by participation in moderate-intensity physical activity in a sample of primary care patients. Elevated inflammation has been associated with a number of poor health outcomes. Depressive symptoms may be related to higher levels of the inflammatory marker IL-6; however, previous findings are inconsistent, possibly due to unidentified moderating factors.
Methods
A total of 107 participants, aged ≥40 years, were recruited in Rochester, New York, in 2006 to 2007. Depressive symptoms were measured by the Center for Epidemiologic Studies Depression Scale-Revised, participation in moderate-intensity physical activity was measured using a modified version of the Community Health Activities Model Program for Seniors Activity Questionnaire for Older Adults, and serum IL-6 concentrations were determined using standard enzyme-linked immunosorbent assay protocols and high-sensitivity, anti-cytokine antibody pairs. A hierarchical multiple regression analysis was conducted.
Results
The correlation between IL-6 and depressive symptoms was nonsignificant (r = .086, p = .40). The association between IL-6 and depressive symptoms was moderated by participation in moderate-intensity physical activity (p = .02). Among those who did not engage in moderate-intensity physical activity, higher levels of depressive symptoms were significantly associated with higher levels of IL-6 (r = .28, p = .05), whereas this association was not significant among those who did participate in moderate-intensity physical activity (r = −.13, p = .38).
Conclusion
Participation in moderate-intensity physical activity may buffer the risk of higher inflammation often associated with higher levels of depressive symptoms.
doi:10.1097/PSY.0b013e3182108412
PMCID: PMC3775592  PMID: 21364200
exercise; depressive symptoms; interleukin-6; inflammation; physical activity; depression
4.  Sleep Disturbance and Older Adults' Inflammatory Responses to Acute Stress 
Objectives
Poor sleep diminishes mental and physical health. The objective of this study was to examine associations between sleep disturbance and interleukin-6 (IL-6) responses to acute mental stress in older adults.
Design
Observational study of community-dwelling, healthy older adults.
Setting
Participants completed the study in a clinical research laboratory of a mid-sized university.
Participants
Generally healthy, community-dwelling men and women 50 years of age and older.
Measurements
IL-6 and negative affect at rest and following a series of challenging cognitive tests; sleep quality; depressive symptoms; perceived stress; loneliness.
Results
Participants categorized as poor sleepers based on Pittsburgh Sleep Quality Index scores had significantly larger IL-6 responses to the cognitive stressors compared to good sleepers. The association between poor sleep and heightened IL-6 response to acute stress was not explained by other psychosocial factors previously linked to immune dysregulation, including depressive symptoms, perceived stress, and loneliness.
Conclusions
Findings add to the growing evidence for poor sleep as an independent risk factor for poor mental and physical health. Older adults may be particularly vulnerable to effects of sleep disturbance due to significant age-related changes in both sleep and inflammatory regulation.
doi:10.1097/JGP.0b013e31824361de
PMCID: PMC3588882  PMID: 22327621
sleep disturbance; stress; interleukin-6
5.  Social isolation, C-reactive protein, and coronary heart disease mortality among community-dwelling adults 
Social science & medicine (1982)  2011;72(9):1482-1488.
Social isolation confers increased risk for coronary heart disease (CHD) events and mortality. In two recent studies, low levels of social integration among older adults were related to higher levels of C-reactive protein (CRP), a marker of inflammation, suggesting a possible biological link between social isolation and CHD. The current study examined relationships among social isolation, CRP, and 15-year CHD death in a community sample of US adults aged 40 years and older without a prior history of myocardial infarction. A nested case-cohort study was conducted from a parent cohort of community-dwelling adults from the southeastern New England region of the United States (N = 2,321) who were interviewed in 1989 and 1990. CRP levels were measured from stored sera provided by the nested case-cohort (n = 370), which included all cases of CHD death observed through 2005 (n = 48), and a random sample of non-cases. We found that the most socially isolated individuals had two-and-a-half times the odds of elevated CRP levels compared to the most socially integrated. In separate logistic regression models, both social isolation and CRP predicted later CHD death. The most socially isolated continued to have more than twice the odds of CHD death compared to the most socially integrated in a model adjusting for CRP and more traditional CHD risk factors. The current findings support social isolation as an independent risk factor of both high levels of CRP and CHD death in middle-aged adults without a prior history of myocardial infarction. Prospective study of inflammatory pathways related to social isolation and mortality are needed to fully delineate whether and how CRP or other inflammatory markers contribute to mechanisms linking social isolation to CVD health.
doi:10.1016/j.socscimed.2011.03.016
PMCID: PMC3090468  PMID: 21492978
USA; social isolation; social integration; social support; inflammation; C-reactive protein; coronary heart disease; mortality
6.  Is the association between optimistic cardiovascular risk perceptions and lower rates of cardiovascular disease mortality explained by biomarkers of systemic inflammation or endothelial function? A case-cohort study 
Background
More optimistic perceptions of cardiovascular disease risk are associated with substantively lower rates of cardiovascular death among men. It remains unknown whether this association represents causality (i.e. perception leads to actions/conditions that influence cardiovascular disease occurrence) or residual confounding by unmeasured factors that associate with risk perceptions and with physiological processes that promote cardiovascular disease (i.e. inflammation or endothelial dysfunction).
Purpose
To evaluate whether previously unmeasured biological markers of inflammation or endothelial dysregulation confound the observed association between cardiovascular disease risk perceptions and cardiovascular disease outcomes;
Methods
We conducted a nested case-cohort study among community-dwelling men from Southeastern New England (USA) who were interviewed between 1989 and 1990 as part of the Pawtucket Heart Health Program. We measured C-reactive protein (CRP) and Vascular Endothelial Growth Factor (VEGF) levels from stored sera for a random sample of the parent cohort (control sample, n = 127) and all cases of cardiovascular death observed through 2005 (case sample, n = 44). We evaluated potential confounding using stratified analyses and logistic regression modeling.
Results
Optimistic ratings of risk associated with lower odds of dying from cardiovascular causes among men (OR = 0.39, 95% CI = 0.17, 0.91). Neither CRP nor VEGF confounded these findings.
Conclusions
The strong cardio-protective association between optimistic ratings of cardiovascular disease risk and lower rates of cardiovascular mortality among men is not confounded by baseline biomarkers of systemic inflammation or endothelial dysfunction.
doi:10.1186/1751-0759-4-11
PMCID: PMC2949755  PMID: 20858244
7.  How Stress and Anxiety Can Alter Immediate and Late Phase Skin Test Responses in Allergic Rhinitis 
Psychoneuroendocrinology  2009;34(5):670.
Summary
Allergic rhinitis (AR) is the fifth most common chronic disease, and the association between allergic disorders and anxiety is well-documented. To investigate how anxiety and stressors modulate skin prick test (SPT) responses and associated inflammatory responses, 28 men and women with AR were selected by clinical history and skin test responses. The participants were admitted twice to a hospital research unit for 4 hours in a crossover trial. Changes in SPT wheals were assessed before and after a standardized laboratory speech stressor, as well as again the following morning; skin responses assessed twice during a lab session without a stressor and again the following morning served as the contrast condition. Anxiety heightened the magnitude of allergen-induced wheals following the stressor. As anxiety increased, SPT wheal diameters increased after the stressor, compared to a slight decrease following the control task. Anxiety also substantially enhanced the effects of stress on late phase responses: even skin tests performed the day after the stressor reflected the continuing impact of the speech stressor among the more anxious participants. Greater anxiety was associated with more IL-6 production by Con A-stimulated leukocytes following the stressor compared to the control visit. The data suggest that stress and anxiety can enhance and prolong AR symptoms.
doi:10.1016/j.psyneuen.2008.11.010
PMCID: PMC2819057  PMID: 19150180
Allergies; psychoneuroimmunology; stress; anxiety; allergic rhinitis; skin tests

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