Search

An extensive body of research defines the default-mode network (DMN) to be one of the critical networks of the human brain, playing a pivotal functional role in processes of internal mentation. Alterations in the connectivity of this network as a function of aging have been found, with reductions associated with functional ramifications for the elderly population. This study examined associations between integrity of the DMN and trait levels of mindfulness disposition, defined by our ability to exert attentional and emotional control in the present moment, and, thereby, bring awareness to immediate experiences. Twenty-five older adults participated in the study and underwent a brief functional magnetic resonance imaging session and filled out questionnaires related to their overall health and mindfulness disposition. Mindfulness disposition was associated with greater connectivity of the DMN, specifically, in the dorsal posterior cingulate cortex and the precuneus. Mindfulness disposition, thus, explains variance in the connectivity of one of the more intrinsic networks of the human brain, known to be critical for promoting self-relevant mental explorations and building cognitive and affective control.

The neuropeptide vasopressin has traditionally been associated with vasoconstriction and water reabsorption by the kidneys. However, data from experimental animal studies also implicate vasopressin in social bonding processes. Preliminary work suggests that vasopressin also plays a role in social behaviors in humans. The goal of this cross-sectional study was to evaluate associations among plasma vasopressin and self-reported interpersonal functioning in a sample of married couples. During a 24-hour admission to a hospital-based research unit, 37 couples completed measures of interpersonal functioning and provided blood samples for neuropeptide analyses. Results showed that vasopressin was associated with markers of interpersonal functioning, but not with general psychological distress. Specifically, greater plasma vasopressin levels were related to a larger social network, fewer negative marital interactions, less attachment avoidance, more attachment security, and marginally greater spousal social support. These results indicate that vasopressin is likely implicated in different relationship maintenance processes in humans.

Summary Background The surveillance and effector functions of the immune system are critically dependent on the appropriate distribution of immune cells in the body. An acute or short-term stress response induces a rapid and significant redistribution of immune cells among different body compartments. Stress-induced leukocyte redistribution may be a fundamental survival response that directs leukocyte subpopulations to specific target organs during stress, and significantly enhances the speed, efficacy and regulation of an immune response. Immune responses are generally enhanced in compartments (e.g., skin) that are enriched with leukocytes, and suppressed in compartments that are depleted of leukocytes during/following stress. The experiments described here were designed to elucidate the: (1) Time-course, trajectory, and subpopulation-specificity of stress-induced mobilization and trafficking of blood leukocytes. (2) Individual and combined actions of the principal stress hormones, norepinephrine (NE), epinephrine (EPI), and corticosterone (CORT), in mediating mobilization or trafficking of specific leukocyte subpopulations. (3) Effects of stress/stress hormones on adhesion molecule, L -selectin (CD62L), expression by each subpopulation to assess its adhesion/functional/maturation status. Methods Male Sprague Dawley rats were stressed (short-term restraint, 2–120 min), or adrenalectomized and injected with vehicle (VEH), NE, EPI, CORT, or their combinations, and blood was collected for measurement of hormones and flow cytometric quantification of leukocyte subpopulations. Results Acute stress induced an early increase/mobilization of neutrophils, lymphocytes, helper T cells (Th), cytolytic T cells (CTL), and B cells into the blood, followed by a decrease/trafficking of all cell types out of the blood, except neutrophil numbers that continued to increase. CD62L expression was increased on neutrophils, decreased on Th, CTL, and natural killer (NK) cells, and showed a biphasic decrease on monocytes & B cells, suggesting that CD62L is involved in mediating the redistribution effects of stress. Additionally, we observed significant differences in the direction, magnitude, and subpopulation specificity of the effects of each hormone: NE increased leukocyte numbers, most notably CD62L−/+ neutrophils and CD62L− B cells. EPI increased monocyte and neutrophil numbers, most notably CD62L−/+ neutrophils and CD62L− monocytes, but decreased lymphocyte numbers with CD62L−/+ CTL and CD62L+ B cells being especially sensitive. CORT decreased monocyte, lymphocyte, Th, CTL, and B cell numbers with CD62L− and CD62L+ cells being equally affected. Thus, naive (CD62L+) vs. memory (CD62L−) T cells, classical (CD62L+) vs. non-classical (CD62L−) monocytes, and similarly distinct functional subsets of other leukocyte populations are differentially mobilized into the blood and trafficked to tissues by stress hormones. Conclusion Stress hormones orchestrate a large-scale redistribution of immune cells in the body. NE and EPI mobilize immune cells into the bloodstream, and EPI and CORT induce traffic out of the blood possibly to tissue surveillance pathways, lymphoid tissues, and sites of ongoing or de novo immune activation. Immune cell subpopulations appear to show differential sensitivities and redistribution responses to each hormone depending on the type of leukocyte (neutrophil, monocyte or lymphocyte) and its maturation/functional characteristics (e.g., non-classical/resident or classical/inflammatory monocyte, naive or central/effector memory T cell). Thus, stress hormones could be administered simultaneously or sequentially to induce specific leukocyte subpopulations to be mobilized into the blood, or to traffic from blood to tissues. Stress- or stress hormone-mediated changes in immune cell distribution could be clinically harnessed to: (1) Direct leukocytes to sites of vaccination, wound healing, infection, or cancer and thereby enhance protective immunity. (2) Reduce leukocyte traffic to sites of inflammatory/autoimmune reactions. (3) Sequester immune cells in relatively protected compartments to minimize exposure to cytotoxic treatments like radiation or localized chemotherapy. (4) Measure biological resistance/sensitivity to stress hormones in vivo. In keeping with the guidelines for Richter Award manuscripts, in addition to original data we also present a model and synthesis of findings in the context of the literature on the effects of short-term stress on immune cell distribution and function.

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.

An unhappy marriage increases disease and mortality risks. Discordant couples exhibit stronger links to their partner’s autonomic fluctuations–that is, stronger covariation–than do satisfied couples, but whether this physiological signature plays a role in marriage’s health effects is unknown. To examine associations between couples’ heart rate variability (HRV) covariation during conflict and their inflammation levels, 43 married couples engaged in a marital problem discussion while wearing heart rate monitors and provided blood samples throughout the day. Multilevel models treated log-transformed interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS) stimulated IL-6 and TNF-alpha, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) as outcomes, accounting for morning baseline HRV levels, age, gender, trunk fat, marital satisfaction, hostility observed during the problem discussion, and study design features. Couples whose moment-to-moment HRV changes tracked more closely together during conflict had higher serum IL-6 ( p = 0.04), LPS-stimulated IL-6 ( p = 0.02), VCAM- 1 ( p = 0.01), and at a trend level, LPS-stimulated TNF-alpha ( p = 0.06) across the day. Thought to result in part from couples’ exchange of negative emotion during disagreement, stronger HRV covariation predicted a heightened inflammatory profile beyond the roles of general marital quality and observed negativity. These data highlight partners’ conflict-related HRV linkage as a novel social-biological mechanism explaining marital discord’s connection to inflammation-related disease.

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.

The current study examined the role of perceived social isolation in moderating the effects of oxytocin on cardiac autonomic control in humans. Intranasal administration of 20 IU oxytocin resulted in a significant increase in autonomic (parasympathetic and sympathetic) cardiac control. Specifically, oxytocin increased high frequency heart rate variability, a relatively pure measure of parasympathetic cardiac control, and decreased pre-ejection period, a well-validated marker of enhanced sympathetic cardiac control. Derived metrics of autonomic co-activity and reciprocity revealed that oxytocin significantly increased overall autonomic cardiac control. Furthermore, the effects of oxytocin on cardiac autonomic control were significantly associated with loneliness ratings. Higher levels of loneliness were associated with diminished parasympathetic cardiac reactivity to intranasal oxytocin. The effects of OT on autonomic cardiac control were independent of any effects on circulating pro-inflammatory cytokine or stress hormone levels. Thus, lonely individuals may be less responsive to the salubrious effects of oxytocin on cardiovascular responsivity.

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.

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.

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.

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.

For the past two decades, research appearing in the pages of Brain, Behavior, and Immunity (BBI), as well as other journals, has significantly deepened our understanding of the complexities of endocrine regulation of immunity in states of health and disease. This mini-review discusses contributions that endocrinology has made to the field of psycho-neuroimmunology (PNI), as well as discoveries that PNI researchers have made of the pervasive interactions between the endocrine and immune systems. We highlight the endocrine-immune interface, emphasizing similarities between the immune and endocrine systems as well as hormone/cytokine interactions. Differing endocrine-immune responses to acute and chronic psychosocial stress have been clarified during this time frame with the use of novel stress and endocrine sampling paradigms. Furthermore, investigations examining the role of cytokine involvement in acquired glucocorticoid resistance in illnesses like depression have expanded our understanding of the complexity of the endocrine-immune response to psychosocial stress. We have selected literature, with a focus on human studies, to illustrate these principals. We conclude with a discussion of the clinical relevance of endocrine-immune investigations and thoughts about the next decade of endocrine research in PNI.

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.

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.

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 Two studies using cross-sectional designs explored four possible mechanisms by which loneliness may have deleterious effects on health: health behaviors, cardiovascular activation, cortisol levels, and sleep. Methods In Study 1, we assessed autonomic activity, salivary cortisol levels, sleep quality, and health behaviors in 89 undergraduate students selected based on pretests to be among the top or bottom quintile in feelings of loneliness. In Study 2, we assessed blood pressure, heart rate, salivary cortisol levels, sleep quality, and health behaviors in 25 older adults whose loneliness was assessed at the time of testing at their residence. Results Total peripheral resistance was higher in lonely than nonlonely participants, whereas cardiac contractility, heart rate, and cardiac output were higher in nonlonely than lonely participants. Lonely individuals also reported poorer sleep than nonlonely individuals. Study 2 indicated greater age-related increases in blood pressure and poorer sleep quality in lonely than nonlonely older adults. Mean salivary cortisol levels and health behaviors did not differ between groups in either study. Conclusions Results point to two potentially orthogonal predisease mechanisms that warrant special attention: cardiovascular activation and sleep dysfunction. Health behavior and cortisol regulation, however, may require more sensitive measures and large sample sizes to discern their roles in loneliness and health.

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.

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.

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.

Peripheral blood mononuclear cells (PBMCs), including rare circulating stem and progenitor cells (CSPCs), have important yet poorly understood roles in the maintenance and repair of blood vessels and perfused organs. Our hypothesis was that the identities and functions of CSPCs in cardiovascular health could be ascertained by analyzing the patterns of their co-expressed markers in unselected PBMC samples. Because gene microarrays had failed to detect many stem cell-associated genes, we performed quantitative real-time PCR to measure the expression of 45 primitive and tissue differentiation markers in PBMCs from healthy and hypertensive human subjects. We compared these expression levels to the subjects' demographic and cardiovascular risk factors, including vascular stiffness. The tested marker genes were expressed in all of samples and organized in hierarchical transcriptional network modules, constructed by a bottom-up approach. An index of gene expression in one of these modules (metagene), defined as the average standardized relative copy numbers of 15 pluripotency and cardiovascular differentiation markers, was negatively correlated (all p

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.

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

We evaluated the influence of continual estrogen replacement therapy (ERT) as presently practiced by postmenopausal women with conjugated estrogens and medroxyprogesterone acetate (MPA) on the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and cellular immunity. Thirty-nine postmenopausal women were evaluated (12 on no replacement, 14 on estrogen only, and 13 on estrogen and MPA). In the women receiving only conjugated estrogens, increased GH levels and decreased IGF-1 levels were found, which replicated previous research and probably reflected estrogen inhibition of hepatic IGF-1 production with a secondary increase in GH release because of reduced feedback inhibition. In women taking both MPA and estrogen, GH was increased and the previously observed estrogen induced decrease in IGF-1 levels was inhibited. In order to determine the influence of ERT on psycho-social stress-induced GH release, math (mental stress) and speech (social stress) challenges were utilized, and they produced significant increases in heart rate in all three groups. The heart rate following stress was significantly enhanced by estrogen replacement. These stressors also led to increased GH secretion in the women taking estrogen and MPA, but not in the other two groups. Gonadal steroids and GH can influence cellular immunity. We observed that ERT in both groups was associated with significantly enhanced lymphocyte responsiveness to the T-cell mitogens phytohemaglutinin (PHA) and Conconavalin A (Con A), and basal GH levels were correlated with the PHA response in the estrogen only group. ERT did not influence natural killer (NK) cell activity. We also found significant differences in the steady-state expression of latent Epstein-Barr virus (EBV) with increased antibody titers in the women in the estrogen only group and lower antibody titers in the MPA plus estrogen group. GH levels were correlated with EBV antibody titers in the estrogen plus MPA group. This study supports the hypothesis that GH and immune modulation can be influenced by ERT in postmenopausal woman. Given the extant literature on the immune-enhancing effects of GH, these data suggest that ERT may slow the decline of GH secretion with aging, an event that has been implicated in immunosenescence.

In longitudinal research investigators often measure multiple variables at multiple points in time and are interested in investigating individual differences in patterns of change on those variables. In the vast majority of applications, researchers focus on studying change in one variable at a time. In this article we consider methods for studying relations1.1ips between patterns of change on different variables. We show how the multilevel modeling framework, which is often used to study univariate change, can be extended to the multivariate case to yield estimates of covariances of parameters representing aspects of change on different variables. We illustrate this approach using data from a study of physiological response to marital conflict in older married couples, showing a substantial correlation between rate of linear change on different stress-related hormones during conflict. We also consider how similar issues can be studied using extensions of latent curve models to the multivariate case, and we show how such models are related to multivariate multilevel models.

Growing evidence suggests that lower subjective social status (SSS), which reflects where a person positions himself on a social ladder in relation to others, is independently related to poor health. People who rate themselves lower in status also experience more frequent stressors and report higher stress than those who rate themselves higher in status, and chronic stress can enhance an individual's response to subsequent stressors. To address whether SSS predicted stress-induced interleukin-6 (IL-6) changes, we assessed 138 healthy adults at rest and following the Trier Social Stress Test (TSST). Participants completed the TSST at two study visits, separated by 4 months. People who placed themselves lower on the social ladder had larger IL-6 responses from baseline to 45 minutes post-stressor (p = 0.01) and from baseline to 2 hours post-stressor (p = 0.03) than those who placed themselves higher on the social ladder. Based on a ratio of subjective threat and coping ratings of the stress task, participants who viewed themselves as lower in status also tended to rate the speech task as more threatening and less manageable than those who viewed themselves as higher in status (p = 0.05). These data suggest that people with lower perceived status experience greater physiological and psychological burden from brief stressors compared to those with higher perceived status. Accordingly, responses to stressors may be a possible mechanistic link among SSS, stress, and health.

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.

“Pituitary” peptides are produced in both endocrine and immune cells. Acute and chronic stress can alter pituitary peptide secretion and might also influence neuroendocrine gene expression in human immune cells. We reasoned that, in Alzheimer caregivers, the chronic stress of caregiving would impact on the sympathetic-adrenal-medullary and hypothalamicpituitary-adrenal axis possibly leading to alterations in GH mRNA in their peripheral blood mononuclear cells (PBMCs). Therefore, we evaluated 10 caregivers and 10 controls subjects using a math and speech stress protocol to determine their neuroendocrine profile and to evaluate any relationship with mononuclear cell GH mRNA levels simultaneously acquired and then evaluated by a quantitative competitive RT-PCR technique. We found a significant (p

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.