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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.

Wound healing is a critical process involved in the recovery from injury and surgical procedures. Poor healing increases the risk for wound infections or complications, lengthens hospital stays, magnifies patient discomfort, and slows return to activities of daily living. Converging evidence from different research paradigms suggests that psychological stress and other behavioral factors can affect wound healing. A meta-analytical study using diverse wound-healing models and outcomes found that across studies there was an average correlation of −0.42 between psychological stress and wound healing.1 This result suggests that the relationship between stress and wound repair is not only statistically significant but also clinically relevant. This review presents data and methods from observational, experimental, and interventional studies corroborating the impact of stress on wound healing. Potential behavioral and physiologic mechanisms explaining the association between stress and impaired wound healing are also discussed.

Depression has been associated with several circadian rhythm perturbations, suggesting a disruption of the circadian clock system in affective disorders. The interaction of several circadian clock genes generates these daily circadian rhythms.This cross-sectional study evaluated whether circadian gene expression differed between individuals with a history of depression and participants without a similar history. The participants were 60 healthy older adults. Half of the participants had a history of depression. Real-time quantitative polymerase chain reaction was used to measure the circadian gene Clock, BMAL1, Period1, and Period2 messenger RNA levels in peripheral blood leukocytes.Individuals with a history of depression had higher Clock, Period1, and Bmal1 mRNA levels, compared to non-depressed participants.Although circadian gene expression fluctuates throughout the day, clock gene mRNA levels were evaluated only in the morning.These results suggest that disruptions of the molecular mechanisms underlying the circadian clock system may be associated with depression.

KIECOLT-GLASER, J.K., J-P. Gouin, and L. Hantsoo, Close Relationships, Inflammation, and Health. NEUROSCI BIOBEHAV REV XX(X) XXX-XXX, 2009.- Different aspects of personal relationships including social integration, social support, and social conflict have been related to inflammation. This article summarizes evidence linking the quality and quantity of relationships with gene expression, intracellular signaling mechanisms, and inflammatory biomarkers, and highlights the biological and psychological pathways through which close relationships impact inflammatory responses. Relationship conflict and lower social support can effectively modulate proinflammatory cytokine secretion both directly (via CNS/neural/endocrine/immune biobehavioral pathways), and indirectly, by promoting depression, emotional stress responses, and detrimental health behaviors. Accordingly, thorough assessments of health behaviors and attention to key methodological issues are necessary to identify the contributions of relationships to inflammation, and thus we highlight procedural issues to be considered in the design of studies. Despite some notable methodological challenges, the evidence suggests that learning more about how close relationships influence inflammation will provide important new insights into the ways that relationships impact health.

e21578Background: Senescence is an irreversible cell cycle arrest associated with sustained p16INK4a (p16) expression and biological aging. The inability of senescent cells to proliferate suggests ...

Inflammation is the common link among the leading causes of death. Mechanistic studies have shown how various dietary components can modulate key pathways to inflammation including sympathetic activity, oxidative stress, transcription factor nuclear factor kappa B (NF-κB) activation, and proinflammatory cytokine production. Behavioral studies have demonstrated that stressful events and depression can also influence inflammation through these same processes. If the joint contributions of diet and behavior to inflammation were simply additive, they would certainly be important. However, several far more intriguing interactive possibilities are discussed: stress influences food choices; stress can enhance maladaptive metabolic responses to unhealthy meals; and diet can impact mood as well as proinflammatory responses to stressors. Furthermore, because the vagus nerve innervates tissues involved in the digestion, absorption, and metabolism of nutrients, vagal activation can directly and profoundly influence metabolic responses to food, as well as inflammation; in turn, both depression and stress have well-documented negative effects on vagal activation, contributing to the lively interplay between the brain and the gut. As one example, omega-3 fatty acid intake can boost mood and vagal tone, dampen NF-κB activation and responses to endotoxin, and modulate the magnitude of inflammatory responses to stressors. A better understanding of how stressors, negative emotions, and unhealthy meals work together to enhance inflammation will benefit behavioral and nutritional research, as well as the broader biomedical community.

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.

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.

Marital stress has been associated with immune dysregulation, including increased production of interleukin-6 (IL-6). Attachment style, one’s expectations about the availability and responsiveness of others in intimate relationships, appears to influence physiological stress reactivity and thus could influence inflammatory responses to marital conflict. Thirty-five couples were invited for two 24-hour admissions to a hospital research unit. The first visit included a structured social support interaction, while the second visit comprised the discussion of a marital disagreement. A mixed effect within-subject repeated measure model indicated that attachment avoidance significantly influenced IL-6 production during the conflict visit but not during the social support visit. Individuals with higher attachment avoidance had on average an 11% increase in total IL-6 production during the conflict visit as compared to the social support visit, while individuals with lower attachment avoidance had, on average, a 6% decrease in IL-6 production during the conflict visit as compared to the social support visit. Furthermore, greater attachment avoidance was associated with a higher frequency of negative behaviors and a lower frequency of positive behaviors during the marital interaction, providing a mechanism by which attachment avoidance may influence inflammatory responses to marital conflict. In sum, these results suggest that attachment avoidance modulates marital behavior and stress-induced immune dysregulation.

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 h 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.

Objective: To examine whether greater cognitive engagement during a marital conflict discussion, as evidenced by use of words that suggest thinking and meaning-making, results in attenuated proinflammatory cytokine increases to stress and wounding. Design: Husbands and wives (N 84 individuals) were observed during two separate 24-hr visits: each visit included a wounding procedure, which was followed by a nonconflictive marital discussion (first visit) and a conflictive marital discussion (second visit). Main Outcome Measures: Serum proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor- (TNF-). Results: Individuals who used more cognitive processing words during the conflict discussion (but not the nonconflictive discussion) showed smaller increases in serum IL-6 and TNF- over 24 hours; they also had lower levels of both cytokines 24 hours after baseline controlling for demographics, hostility, depressed mood, positive and negative interactions, and marital quality. Effects of word use were not mediated by ruminative thoughts after conflict. Although both men and women benefited from their own cognitive engagement, only husbands’ IL-6 patterns were affected by spouses’ engagement. Conclusion: In accord with research demonstrating the value of cognitive processing in emotional disclosure, this research suggests that productive communication patterns may help mitigate the adverse effects of relationship conflict on inflammatory dysregulation.

Increased levels of proinflammatory cytokines, TNF-alpha and IL-6, predict mortality and morbidity. In cardiovascular disease patients, they are observed in atherosclerotic lesions and serum. Factors behind the increased levels of these cytokines are multifaceted and may include latent herpesviruses, such as Epstein-Barr virus (EBV) that can be reactivated by stress. Previously, we showed that the EBV-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase), a protein synthesized in the early phase of virus replication, can induce human monocytes/macrophages to produce TNF-alpha and IL-6. In this study, we modeled the interactions that take place between macrophages and endothelial cells in vivo using human umbilical vein endothelial cells (HUVEC). HUVEC were stimulated by soluble factors induced by EBV dUTPase-treated monocyte-derived macrophages (MDM) that resulted in the upregulation of VCAM-1 and ICAM-1. These changes were related to MDM production of TNF-alpha following the activation of NF-kappaB. In a previous study, chronically stressed dementia caregivers had elevations in plasma IL-6 levels, a risk for cardiovascular disease. We found a relationship between plasma IL-6 levels and neutralizing antibody titers to EBV dUTPase suggesting that one source of the plasma IL-6 observed in our previous study could be related to the effect of EBV-encoded dUTPase on macrophages. The results suggest that EBV-encoded dUTPase can enhance production of proinflammatory cytokines by monocytes/macrophages in contact with endothelial cells of blood vessels, and may play a role in cardiovascular pathology and chronic inflammation.

Caregivers of Alzheimer’s disease patients endure chronic stress associated with a decline of immune function. To assess the psychological and immunological changes of caregivers, we compared depressive symptoms, PBMC composition, in vitro activation-induced proliferation and cytokine production, and telomere length and telomerase activity of 82 individuals (41 caregivers and 41 age- and gender-matched controls). We found depressive symptoms were significantly higher in caregivers than in controls (p < 0.001). Correspondingly, caregivers had significantly lower T cell proliferation but higher production of immune-regulatory cytokines (TNF-α and IL-10) than controls in response to stimulation in vitro. We examined the impact of these changes on cellular replicative lifespan and found that caregivers had significantly shorter telomere lengths in PBMC than controls (6.2 and 6.4 kb, respectively, p < 0.05) with similar shortening in isolated T cells and monocytes and that this telomere attrition in caregivers was not due to an increase of shorter telomere possessing T cell subsets in PBMC. Finally, we showed that basal telomerase activity in PBMC and T cells was significantly higher in caregivers than in controls (p < 0.0001), pointing to an unsuccessful attempt of cells to compensate the excessive loss of telomeres in caregivers. These findings demonstrate that chronic stress is associated with altered T cell function and accelerated immune cell aging as suggested by excessive telomere loss.

Depression is the most common psychiatric illness, and both major depression and subthreshold depressive symptoms carry substantial health risks (1, 2). A number of well-controlled prospective studies have linked depressive symptoms with coronary heart disease (CHD), the leading cause of death in the United States (3); moreover, the nearly 60-fold variance in the annual prevalence of major depression across countries is very similar to the pattern for cardiovascular disease, which shows a strong comorbidity for depression (4, 5). Epidemiological studies have demonstrated significant inverse relationships between annual fish consumption and prevalence of major depression (4). Fish oil is the prime source for two key omega-3 (n-3) polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA). Several laboratories have provided evidence that depressed patients have, on average, lower plasma levels of n-3 PUFAs than nondepressed controls; furthermore, there are relationships within these populations between severity of depressive symptoms and lower plasma levels of the n-3 PUFAs (3–6). What is more, all but one of four randomized controlled trials reported significant improvement in the treatment of depression following n-3 PUFA supplementation compared to nonsupplemented controls (6). Significant relationships between lower n-3 PUFA plasma levels and greater negative mood have also been documented in nonpsychiatric populations (7). Omega-6 (n-6) PUFAs are also implicated in depression, with higher n-6:n-3 ratios observed in depressed patients compared to nondepressed controls (3–6). Arachidonic acid (AA) derived n-6 eicosanoids (primarily from refined vegetable oils such as corn, sunflower, and safflower) increase the production of proinflammatory cytokines, operating as precursors of the proinflammatory eicosanoids of the prostaglandin (PG)2-series (5). In contrast, the n-3 PUFAs, found most abundantly in fish, fish oil, walnuts, wheat germ, and flaxseed can curb the production of AA-derived eicosanoids (5, 8). Thus it is not surprising that both higher levels of n-3 PUFAs as well as lower n-6:n-3 ratios are associated with lower proinflammatory cytokine production (9). The fatty acid composition of the modern Western diet has changed dramatically during the last century, and these changes are thought to be related to increases in inflammatory-related diseases, including depression and cardiovascular disease (6, 10). For example, the early hunter-gatherer diet had an n-6:n-3 ratio of 2:1 to 3:1 (11). However, during the last century, the typical Western diet underwent fundamental alterations with the enormous growth in refined vegetable oil use, a central n-6 source that replaced n-3 PUFAs from fish, wild game, nuts, seeds, and green leafy vegetables (5, 11); in the contemporary North American diet, the n-6:n-3 ratio is 15:1 to 17:1 (12, 13). In fact, the heightened n-6:n-3 ratio in the Western diet since 1913 has been suggested as a central stimulus for the sharply increased incidence of major depression (4, 5). The n-6:n-3 ratio is related to serotonergic as well as catecholaminergic neurotransmission (14), providing mechanistic pathways that help explain the relationships with negative mood. Alterations in serotonin (5-HT) receptor numbers and function provoked by changes in PUFAs have been used to link fatty acids with contemporary theories of depression (5, 15). Moreover, immune activation may interact with 5-HT functioning to promote depression (5), because PUFAs influence the synthesis of proinflammatory cytokines. Furthermore, both syndromal depression and depressive symptoms can enhance production of proinflammatory cytokines, including interleukins 1 and 6 (IL-1 and IL-6) and tumor necrosis factor alpha (TNF-α) (2, 16–21). Brief laboratory stressors can also provoke transient increases in proinflammatory cytokines (1, 22, 23). Moreover, stress and depression may effectively “prime” inflammatory responses, promoting larger cytokine increases in reaction to subsequent stressors and/or pathogens (19, 24–27). Thus, chronic or longer-term stress and depression can elevate both acute and chronic proinflammatory cytokine production (16, 20, 23, 28). Importantly, these are bi-directional relationships; cytokines have substantial effects on the central nervous system (CNS), producing and enhancing negative moods, as well as physical symptoms such as lethargy and fatigue (18). Indeed, there is evidence that cytokines play a role in the neuroendocrine and behavioral features of depressive disorders (18). In a provocative study relevant to the present investigation, students who had higher n-6:n-3 ratios (above the mean) before exams demonstrated greater TNF-α production by lipopolysaccharide (LPS) and mitogen-stimulated peripheral blood leukocytes (PBLs) during exams than those with lower ratios (29). These data suggest that the n-6:n-3 ratio may influence the proinflammatory response to stressors; because TNF-α and IL-6 are produced by a variety of types of cells, serum cytokine levels may better reflect the overall inflammatory profile than stimulated PBLs or ex vivo production (8). Indeed, the aging and depression literatures have focused on proinflammatory cytokine levels assessed in serum (2, 30). Accordingly, we were interested in how depressive symptoms and the n-6:n-3 ratio would be related to serum TNF-α, IL-6, and the IL-6 soluble receptor (sIL-6r). We studied an older population because proinflammatory cytokine production is elevated following menopause or andropause even in the absence of infection, trauma, or stress (31). Both higher n-6:n-3 ratios and higher levels of depressive symptoms have been associated with greater production of proinflammatory cytokines; however, in accord with the student examination study (29), we expected that higher n-6:n-3 ratios and higher levels of depressive symptoms would predict higher levels of TNF-α, IL-6, and sIL-6r than either alone.

Depression and inflammation fuel one another. Inflammation plays a key role in depression’s pathogenesis for a subset of depressed individuals; depression also primes larger cytokine responses to stressors and pathogens that do not appear to habituate. Accordingly, treatment decisions may be informed by attention to questions of ‘how’ (pathways) and ‘for whom’ (predispositions) these links exist, which are the focus of the current article. When combined with predisposing factors (moderators such as childhood adversity and obesity), stressors and pathogens can lead to exaggerated or prolonged inflammatory responses. The resulting sickness behaviors (e.g., pain, disturbed sleep), depressive symptoms, and negative health behaviors (e.g., poor diet, a sedentary lifestyle) may act as mediating pathways that lead to further unrestrained inflammation and depression. Depression, childhood adversity, stressors, and diet can all influence the gut microbiome and promote intestinal permeability, another pathway to enhanced inflammatory responses. Larger, more frequent, or more prolonged inflammatory responses could have negative mental and physical health consequences. In clinical practice, inflammation provides a guide to potential targets for symptom management by signaling responsiveness to certain therapeutic strategies. For example, a theme across research with cytokine antagonists, omega-3 polyunsaturated fatty acids, celecoxib, and exercise is that anti-inflammatory interventions have a substantially greater impact on mood among individuals with heightened inflammation. Thus, when inflammation and depression co-occur, treating them in tandem may enhance recovery and reduce risk of recurrence. The bidirectional links among depression, inflammation, and disease suggest that effective depression treatments could have a far-reaching impact on mood, inflammation, and health.

Chronically elevated systemic inflammation has a dramatic impact on health for older individuals. As stress-related responses, both hostility and pain perception may contribute to inflammation which in turn may maintain negative emotion and pain over time. We used structural equation modeling to examine the degree to which trait hostility and pain were uniquely associated with C-reactive protein (CRP) and serum IL-6 levels over a 6-year span in a sample of older adults. The sample included 113 present or former caregivers of a spouse with dementia and 101 non-caregivers. After accounting for depression, health behaviours, and other risk factors, which were also assessed longitudinally, pain and, to a lesser extent, hostility were uniquely associated with plasma levels of CRP but not IL-6. When examined separately, the association between pain and CRP was significant only for caregivers, while the association between hostility and CRP was comparable for the two groups. These findings suggest that hostility may play a role in a cycle of inflammation among older adults, and that pain may be particularly problematic for those under chronic stress. Our results also shed light on inflammation as a mechanism underlying the effects of hostility on cardiovascular disease morbidity and mortality.

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.

To examine the independent and interactive contribution of positive and negative behaviors during marital conflict to changes in adrenocorticotropic hormone (ACTH) and cortisol, behavioral and endocrine data were collected from 90 newlywed couples during a 30-minute conflict task. Positive and negative behaviors were coded by the Marital Interaction Coding System. High levels of husbands' positive behavior and high couple negativity were related to steeper ACTH and cortisol declines in wives. Low levels of wives' positive behavior and high couple negativity were related to flatter declines in wives' cortisol. Supportiveness during highly negative interactions contributed to steeper ACTH and cortisol declines in wives, suggesting that constructively engaging in discussions promotes adaptive physiological responses to interpersonal conflict.

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.

Chronic stress is typically associated with suppression of the immune system, including impaired responses to infectious disease and delayed wound healing. Recent work suggests that stress and depression can enhance production of proinflammatory cytokines, substances that regulate the body's immune response to infection and injury. We provide a broad framework relating stress and depression to a range of diseases whose onset and course may be influenced by proinflammatory cytokines, particularly the cytokine interleukin-6 (IL-6). IL-6 has been linked to a spectrum of chronic diseases associated with aging. Production of proinflammatory cytokines that influence these and other conditions can be directly stimulated by chronic stress and depression. We suggest that a key pathway through which chronic stress and depression influence health outcomes involves proinflammatory cytokines. We discuss the evidence for relationships between psychosocial factors and proinflammatory cytokines, and important health implications of these findings.

Folk wisdom has long suggested that stressful events take a toll on health. The field of psychoneuroimmunology (PNI) is now providing key mechanistic evidence about the ways in which stressors--and the negative emotions that they generate--can be translated into physiological changes. PNI researchers have used animal and human models to learn how the immune system communicates bidirectionally with the central nervous and endocrine systems and how these interactions impact on health.

Antibodies to several Epstein-Barr virus (EBV)-encoded enzymes are observed in patients with different EBV-associated diseases. The reason for these antibody patterns and the role these proteins might play in the pathophysiology of disease, separate from their role in virus replication, is unknown. In this series of studies, we found that purified EBV deoxyuridine triphosphate nucleotidohydrolase (dUTPase) can inhibit the replication of human peripheral blood mononuclear cells in vitro and upregulate the production of TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10. It also enhanced the ability of natural killer cells to lyse target cells. The EBV dUTPase also significantly inhibited the replication of mitogen-stimulated lymphocytes and the synthesis of IFN-gamma by cells isolated from lymph nodes and spleens obtained from mice inoculated with the protein. It also produced sickness behaviors known to be induced by some of the cytokines that were studied in the in vitro experiments. These symptoms include an increase in body temperature, a decrease in body mass and in physical activity. The data provide a new perspective on how an early nonstructural EBV-encoded protein can cause immune dysregulation and produce clinical symptoms observed in patients with chronic fatigue syndrome (CFS) separate from its role in virus replication and may serve as a new approach to help identify one of the etiological agents for CFS. The data also provide additional insight into the pathophysiology of EBV infection, inflammation, and cancer.

We investigated the impact of relative marital power on 72 newlywed couples’ endocrinological responses to marital conflict. Marital power was determined by comparing spouses’ reports of dependent love for one another. Less powerful spouses displayed elevated adrenocorticotropic hormone (ACTH) responses to a conflict discussion. Shared power appeared to have a beneficial effect on wives’ but not husbands’ ACTH responses. Spouses’ cortisol levels declined over time, except for wives who were less powerful and for husbands who shared power with their wives. Conflict behaviors did not differ as a function of this marital power index. These data suggest that relative levels of general emotional power in relationships may play an important role in spouses’ physiological responses to marital conflict.

We investigated linkages between spousal support satisfaction and affective, cortisol, and blood pressure responses to conflict in two samples, 85 newlyweds and 31 older couples, married an average of 42 years. Couples were admitted to a hospital research unit and provided self-reports regarding the support received from their spouses. After a baseline period, couples engaged in a 30-min conflict discussion during which time blood was drawn for cortisol assessment. After the conflict, newlyweds' blood pressure was measured. Among newlywed wives, greater spousal support satisfaction was associated with smaller changes in negative affect and cortisol responses to conflict. Notably, newlywed wives and husbands demonstrated lower blood pressure after conflict when spousal support satisfaction was higher. In contrast, older husbands (but not wives) exhibited greater cortisol responses when spousal support satisfaction was lower. These relationships provide a window on mechanisms linking marriage and health for men and women across the life span.

Marriage is the central relationship for most adults and has beneficial effects for health. At the same time, troubled marriages have negative health consequences. This review outlines the physiological pathways through which marital relationships influence health based on a stress/social support model. In addition, we review recent findings suggesting that unhappy marriages are associated with morbidity and mortality. We then turn to studies of marital interaction that include assessment of physiological pathways through which marital functioning influences health: the cardiovascular, endocrine, and immune systems. Across these studies, negative and hostile behaviors during marital conflict discussions are related to elevations in cardiovascular activity, alterations in hormones related to stress, and dysregulation of immune function. Using recent conceptualizations of the physiological impact of chronic stress, we illustrate how physiological changes associated with marital functioning in these studies have long-term implications for health outcomes. Finally, we discuss future implications of current research for understanding the relationships among marital functioning, physiology, and health.

We report long-term temporal consistency of stress-related neuroendocrine and cardiovascular variables in mid-aged and older women who performed mental math and speech stress tasks two times approximately 1 year apart. Epinephrine, norepinephrine, ACTH, cortisol, cardiac preejection period (PEP), respiratory sinus arrhythmia, heart rate (HR), blood pressure, and respiration rate were measured at baseline, after or during stressors, and 30 min posttask. Although there were exceptions, year-to-year Spearman coefficients showed mostly moderate to high consistency (rs approximately equal to .5-.8) for baseline, stressor, and posttask values. For reactivity, HR and PEP were most consistent (rs approximately equal to .65); consistency for other variables was moderate to low (rs approximately equal to .1-.4). Means of most variables changed from year to year. Results support the use of baseline, stressor, and posttask values in longitudinal studies.

Objective: The increased morbidity and mortality associated with depression is substantial. In this paper, we review evidence suggesting that depression contributes to disease and death through immune dysregulation. Method: This review focuses on recent human studies addressing the impact of depression on immune function, and the health consequences of those changes. Results: There is growing evidence that depression can directly stimulate the production of proinflammatory cytokines that influence a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, periodontal disease, frailty, and functional decline. Additionally, depression can down-regulate the cellular immune response; as a consequence, processes such as prolonged infection and delayed wound healing that fuel sustained proinflammatory cytokine production may be promoted by depression. Conclusions: These direct and indirect processes pose the greatest health risks for older adults who already show age-related increases in proinflammatory cytokine production. Thus, aging interacts with depression to enhance risks for morbidity and mortality.

Attachment theory provides a framework for understanding individual differences in chronic interpersonal stress. Attachment anxiety, a type of relationship insecurity characterized by worry about rejection and abandonment, is a chronic interpersonal stressor. Stress impacts cellular immunity, including herpes-virus reactivation. We investigated whether attachment anxiety was related to the expression of a latent herpesvirus, Epstein–Barr virus (EBV), when individuals were being tested for breast or colon cancer and approximately 1 year later. Participants (N = 183) completed a standard attachment questionnaire and provided blood to assess EBV viral capsid antigen (VCA) IgG antibody titers. Individuals with more attachment anxiety had higher EBV VCA IgG antibody titers than those with less attachment anxiety. The strength of the association between attachment anxiety and antibody titers was the same at both assessments. This study is the first to show an association between latent herpesvirus reactivation and attachment anxiety. Because elevated herpesvirus antibody titers reflect poorer cellular immune system control over the latent virus, these data suggest that high attachment anxiety is associated with cellular immune dysregulation.

Cacioppo et al 1 elegantly outline potential contributions of social neuroscience to psychiatry. Their interdisciplinary approach could be enhanced by incorporating a nutritional perspective. Indeed, although the human brain represents only about 2% of human body mass, it accounts for ∼20% of the total resting metabolic rate 2. As a consequence of the brain's intense energy requirements, metabolic aberrations can have substantial consequences for its function. In this commentary we focus on the progress and potential of social nutritional neuroscience, an area of growing interest and importance, for psychiatry. In traditional terms, nutritional neuroscience focuses on the effects that various dietary components have on neurochemistry, neurobiology, behavior, and cognition. Social nutritional neuroscience takes a broader view that incorporates key bidirectional influences: social processes and behavior impact diet, both of which affect neurochemistry and neurobiology. These resulting dietary and biological changes may subsequently alter social and behavioral processes, ultimately creating a feedback loop. Studies addressing the dietary and biological consequences of depression help demonstrate the importance of viewing these relationships as a two-way street. Depression can have a substantial effect on food intake. Appetite changes are a notable feature of major depressive disorder. In fact, one of the diagnostic criteria for this disorder in the DSM-5 is diet-relevant: weight gain/loss or hyperphagia/hypophagia. Depression also influences dietary preferences3: for example, some people increase comfort food intake when depressed 4. Depression and diet can impact the same physiological systems. Mechanistic studies have shown how depression can modulate key pathways to inflammation including sympathetic activity, oxidative stress, transcription factor nuclear factor kappa B (NF-κB) activation, and pro-inflammatory cytokine production 5. Diet affects inflammation and modifies brain function through these same processes 3,5. Both depression and stress also have well-documented negative effects on vagal activation. Because the vagus nerve innervates tissues involved in the digestion, absorption, and metabolism of nutrients, vagal activation can directly and profoundly influence metabolic responses to food, as well as inflammation, contributing to the lively interplay between the brain and the gut 5. Diet and immune alterations may promote depression. Growing evidence suggests that people with poorer quality diets have a higher likelihood of being depressed than people with better quality diets 6. Furthermore, pro-inflammatory cytokine administration induces “sickness behaviors”, i.e., behavioral changes that resemble the somatic symptoms evident in depression, like anhedonia and lethargy 7. Accordingly, depression may start a negative cascade whereby depression promotes dysregulated food consumption and physiological responses which, in turn, further enhance depression. The bi-directional links among depression, diet, and biological responses are nicely illustrated by the relationship between depression and obesity, which is clearly linked to both diet and dysregulated physiological responses. For example, clinical depression and obesity often travel together 8. The risk for developing depression over time is 55% in obese persons, and depressed people have a 58% increased risk of becoming obese 8. In addition, a large prospective study showed that older depressed adults gained visceral fat over five years, while non-depressed adults lost visceral fat 9. Importantly, this association did not reflect changes in overall obesity, suggesting that depressive symptoms were specifically associated with changes in visceral fat, a central and important contributor to inflammation. Functioning as an endocrine organ, adipose tissue secretes a number of different peptide hormones and cytokines that influence brain function, metabolism and behavior 3. While a poor diet increases risk for depression, a healthy diet may be protective. In a prospective study with over 10,000 participants, those who ate a Mediterranean diet that was rich in monounsaturated fats, fish, fruit, nuts, and vegetables had a lower risk for depression four years later than people who consumed diets with fewer of these foods and higher amounts of saturated fats 10. Healthy diets may also reduce anxiety symptoms, in addition to depressive symptoms 6. After summarizing key issues in social neuroscience and its potential contribution to psychiatry, Cacioppo et al 1 concluded that neuroimaging and genetic research that focuses on specific component processes underlying social living is needed. In the field of social nutritional neuroscience, similar neuroimaging and genetic research would be valuable. In fact, an interdisciplinary approach that incorporates both social neuroscience and social nutritional neuroscience could foster unique and provocative questions that would further our understanding of psychiatric disorders. A broader emphasis on the role of behavior as a key driver in nutritional neuroscience could also open up new vistas and prospects for future research.

Stressful events enhance risk for weight gain and adiposity. Ghrelin and leptin, two hormones that are implicated in appetite regulation, may link stressful events to weight gain; a number of rodent studies suggest that stressors increase ghrelin production. The present study investigated the links among daily stressors, ghrelin and leptin, and dietary intake in humans.Women (n=50) completed three study appointments that were scheduled at least 2 weeks apart. At each visit, women arrived fasting and ate a standardized breakfast and lunch. Blood samples were collected 45min after each meal. Women completed a self-report version of the Daily Inventory of Stressful Events (DISE) at each appointment. Two composites were created from the DISE data, reflecting the number of stressors that did and did not involve interpersonal tension.Women who experienced more stressors involving interpersonal tension had higher ghrelin and lower leptin levels than those who experienced fewer interpersonal stressors. Furthermore, women who experienced more interpersonal stressors had a diet that was higher in calories, fat, carbohydrates, protein, sugar, sodium, and fiber, and marginally higher in cholesterol, vegetables (but not fruits), vitamin A, and vitamin C. Stressors that did not involve interpersonal tension were unrelated to ghrelin and leptin levels or any of the dietary components examined.These data suggest that ghrelin and leptin may link daily interpersonal stressors to weight gain and obesity.

Cancer survivors often report cognitive problems. Furthermore, decreases in physical activity 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.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.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 0.001).These findings suggest that yoga can effectively reduce breast cancer survivors' cognitive complaints and prompt further research on mind-body and physical activity interventions for improving cancer-related cognitive problems.

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.

A competent immune response is central to good health. There is good evidence that both aging and psychological stress can dysregulate immune function, resulting in changes in various aspects of the immune response that are large enough to have consequences for health. Older adults appear to show even greater immunological impairments associated with stress or depression than younger adults. Thus, the data suggest that aging interacts with stress and depression to enhance risks for morbidity and mortality among older adults.

This review focuses on the pathway leading from the marital relationship to physical health. Evidence from 64 articles published in the past decade, particularly marital interaction studies, suggests that marital functioning is consequential for health; negative dimensions of marital functioning have indirect influences on health outcomes through depression and health habits, and direct influences on cardiovascular, endocrine, immune, neurosensory, and other physiological mechanisms. Moreover, individual difference variables such as trait hostility augment the impact of marital processes on biological systems. Emerging themes in the past decade include the importance of differentiating positive and negative dimensions of marital functioning, the explanatory power of behavioral data, and gender differences in the pathways from the marital relationship to physiological functioning. Contemporary models of gender that emphasize self-processes, traits, and roles furnish alternative perspectives on the differential costs and benefits of marriage for men's and women's health.

This cross-sectional study investigated whether active and avoidance coping methods were differentially related to immune function depending on stress level. Perceived stress and coping method were assessed in 173 healthy older adults and related to the number and percentage of CD3+, CD4+, and CD8+ T lymphocytes as well as the proliferative response of peripheral blood leukocytes to phytohemagluttinin (PHA) and concanavalin A (Con A). Both active and avoidance coping significantly interacted with perceived stress on proliferative responses to both mitogens. Higher levels of active coping were significantly related to a more vigorous proliferative response to PHA and Con A, particularly at high stress levels. At low stress levels, active coping was not significantly related to proliferative responses, whereas avoidance coping was significantly associated with a greater proliferative response to Con A. These results suggest that the relationships between certain coping methods and immune function depend on perceived stress level.

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.

How do stressful events and negative emotions influence the immune system, and how big are the effects? This broad question has been intensely interesting to psychoneuroimmunology researchers over the last 3 decades. Many promising lines of work underscore the reasons why this question is still so important and pivotal to understanding and other advances. New multidisciplinary permutations provide fresh vistas and emphasize the importance of training psychologists more broadly so that they will be central and essential players in the advancement of biomedical science.

There is substantial evidence from both healthy populations as well as individuals with cancer linking psychological stress with immune downregulation. This discussion highlights natural killer (NK) cells, because of the role that they may play in malignant disease. In addition, distress or depression is also associated with two important processes for carcinogenesis: poorer repair of damaged DNA, and alterations in apoptosis. Conversely, the possibility that psychological interventions may enhance immune function and survival among cancer patients clearly merits further exploration, as does the evidence suggesting that social support may be a key psychological mediator. These studies and others suggest that psychological or behavioural factors may influence the incidence or progression of cancer through psychosocial influences on immune function and other physiological pathways.

It is now well established that psychological stress can downregulate the cellular immune response. Communication between the central nervous system and the immune system occurs via a complex network of bidirectional signals linking the nervous, endocrine, and immune systems. Stress disrupts the homeostasis of this network, which in turn, alters immune function. In this review, we discuss the role of stress in modulating cellular immune function and the potential health implications of this downregulation.

The invitation to present the Norman Cousins Memorial Lecture to the Psychoneuroimmunology Research Society is a distinct honor; this recognition is clearly shared by my primary collaborator, Ronald Glaser, who has had equal responsibility for the design of our studies and whose laboratory generated most of the immunological data I will describe. We have addressed a number of questions since we initiated our joint research program in 1982: How do commonplace, everyday stressors affect the immune response? What are the health consequences of stress-related immunological changes? Does a chronic stressor promote persistent immunological dysregulation? Does age pose an additional risk factor? I will address each of these topics briefly; however, as a clinical psychologist, the studies of greatest interest to me are those that have examined the links between close personal relationships and immune responses and, in turn, how these elements are translated into important health outcomes. Thus, these issues will be my primary focus.

We review the methods in the ranking of clinical psychology doctoral programs provided by Stewart, Roberts, and Roy (2007). Using our own program as an example, we identify several areas of concern (e.g., authorship credits, criteria applied, faculty attrition). The inaccuracies identified for our program ranking, in combination with methodological concerns highlighted by previous commentaries, suggest that the validity of the rankings can be called into question.

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.