Interactive effect of long-term mental stress and cardiac stress reactivity on carotid intima-media thickness: the Cardiovascular Risk in Young Finns study

The present study examined the interaction between vital exhaustion and cardiac reactivity and recovery on preclinical atherosclerosis assessed by carotid intima-media thickness (IMT) in young men and women. We measured heart rate (HR), respiratory sinus arrhythmia (RSA), and pre-ejection period (PEP) in response to mental arithmetic and speech tasks. Vital exhaustion and carotid IMT were also measured. Significant associations were observed for men aged 28-37 years, but not for men aged 22-25 years, nor for women in these age groups. It was shown that, among highly exhausted men in the older age group, lower HR reactivity was related to greater IMT. Our results also imply that, among non-exhausted men in this age group, slow HR and RSA recovery after acute stress predicted higher IMT. These results suggest that long-term stress as assessed by vital exhaustion is a risk only if it has resulted in ineffective cardiac stress reactivity. Autonomic imbalance resulting from chronic stress may be the common mechanism linking vital exhaustion and cardiac responsiveness to an increased risk of atherosclerosis.     

Relationship between chronic stress and carotid intima-media thickness (IMT) in elderly Alzheimer's disease caregivers

The stress associated with providing care for a spouse diagnosed with Alzheimer's disease can have adverse effects on cardiovascular health. One potential explanation is that chronic caregiving stress may contribute to the development of atherosclerosis. The purpose of this study was to determine whether the duration that one has provided care is associated with the degree of atherosclerotic burden, as measured by carotid artery intima-media thickness (IMT). One hundred and ten Alzheimer caregivers [mean age 74?±?8 (SD) years, 69% female] underwent in-home assessment of carotid artery IMT via B-mode ultrasonography. Data regarding medical history, blood pressure, and multiple indicators of caregiving stress were also collected. Multiple regression indicated that duration of care was positively associated with IMT measured in the internal/bifurcation segments of the carotid artery (β?=?0.202, p?=?0.044) independent of risk factors such as age, gender, body mass index, smoking history, sleep quality, hypertension status, and caregiving stressors. Duration of care was positively associated with IMT in the common carotid artery, but the relationship was not significant. These findings provide more evidence of the link between chronic caregiving stress and cardiovascular disease and indicate that enduring the experience of caregiving over a period of years might be associated with atherosclerotic burden.     

Chronic stress, metabolism, and metabolic syndrome

The prevalence of obesity has rapidly escalated and now represents a major public health concern. Although genetic associations with obesity and related metabolic disorders such as diabetes and cardiovascular disease have been identified, together they account for a small proportion of the incidence of disease. Environmental influences such as chronic stress, behavioral and metabolic disturbances, dietary deficiency, and infection have now emerged as contributors to the development of metabolic disease. Although epidemiological data suggest strong associations between chronic stress exposure and metabolic disease, the etiological mechanisms responsible remain unclear. Mechanistic studies of the influence of chronic social stress are now being conducted in both rodent and nonhuman primate models, and phenotypic results are consistent with those in humans. The advantage of these models is that potential neural mechanisms may be examined and interventions to treat or prevent disease may be developed and tested. Further, circadian disruption and metabolic conditions such as diabetes mellitus could increase susceptibility to other stressors or serve as a stressor itself. Here, we review data from leading investigators discussing the interrelationship between chronic stress and development of metabolic disorders.     

What children can tell us about living in danger

Developmental challenges faced by children growing up in situations of chronic danger linked to community violence and communal conflict are reviewed. The concept of post-traumatic stress disorder is expanded to include situations of chronic and on-going traumatic stress associated with dangerous environments--war zones and inner city neighborhoods plagued by violence and crime. Of particular importance is the impact of chronic stress and danger on the child's world view, the child's social map, and the child's moral development. On the basis of field work in 5 war zones, the article points to the importance of adult-led "processing" of the young child's experience to his or her psychological coping and moral development. Some of the contradictions operating in such environments are explored--for example, that "fanatical" ideology may provide short-term support for adults and children but also may serve to prolong communal conflict, impede the necessary processing of experience, and increase vulnerability in the long run.     

Elevated content of cortisol in hair of patients with severe chronic pain: a novel biomarker for stress

Hair analysis has been used to reflect long-term systemic exposure to exogenous drugs and toxins. Several studies have demonstrated the feasibility of measuring endogenous steroid hormones, e.g. cortisol, in hair. Recently, a study in macaques showed a significant increase in hair cortisol levels induced by stress. We explored whether hair cortisol levels may be used as a biomarker for long-term stress in humans. Patients with severe chronic pain, aged 18 years or older, receiving opioid treatment for at least one year were recruited. Controls were non-obese (body mass index, BMI < 30 mg/kg(2)) adults. The Perceived Stress Scale (PSS) questionnaire was used to assess perceived stress over the last 4 weeks. A hair sample was obtained from the vertex posterior. Cortisol was measured using an enzyme-linked immunosorbent assay. We included fifteen patients (nine females and six males) and 39 non-obese control subjects (20 females, 19 males). PSS scores (median and range) were significantly higher in chronic pain patients (24: 12-28) than in controls (12: 3-31)(P < 0.001). Hair cortisol contents (median and range) were significantly greater in chronic pain patients (83.1: 33.0-205 g/mg) than in controls (46.1: 27.2-200 pg/mg) (P < 0.01). We conclude that hair cortisol contents are increased in patients with major chronic stress. Measurement of cortisol levels in hair constitutes a novel biomarker of prolonged stress.     

Chronic social stress during adolescence in mice alters fat distribution in late life: prevention by antidepressant treatment

Obesity and visceral fat accumulation are key features of the metabolic syndrome that represents one of the main health problems in western societies due to its neurovascular and cardiovascular complications. Epidemiological studies have identified chronic stress exposure as an important risk factor for the development of obesity and metabolic syndrome, but also psychiatric diseases, especially affective disorders. However, it is still unclear if chronic stress has merely transient or potentially lasting effects on body composition. Here, we investigated the effects of chronic social stress during the adolescent period on body fat composition in mice one year after the cessation of the stressor. We found that stress exposure during the adolescent period decreases subcutaneous fat content, without change in visceral fat, and consequently increases the visceral fat/subcutaneous fat ratio in adulthood. Further, we demonstrated that treatment with a selective serotonin reuptake inhibitor (paroxetine) during stress exposure prevented later effects on body fat distribution. These results from a recently validated chronic stress paradigm in mice provide evidence that stressful experiences during adolescence can alter body fat distribution in adulthood, thereby possibly contributing to an increased risk for metabolic diseases. Antidepressant treatment disrupted this effect underlining the link between the stress hormone system, metabolic homeostasis and affective disorders.     

Mid-life stress is associated with both up- and down-regulation of markers of humoral and cellular immunity

Perception of stress with consequent activation of a neuroendocrine cascade causes changes in immune function that may be bi-directional, with alterations in basal levels of biological parameters outside the optimal range. In this cross-sectional study of 302 healthy persons (males 56.3%, females 43.7%) aged 41-46 years, higher stress levels, as assessed by questionnaire measures of recurrent and recent perceived stress, were associated with a 4-fold greater risk of having a high compared to mid-range serum neopterin concentration, indicating activation of cellular immune mechanisms [adjusted odds ratio, OR; (95% confidence intervals, CI): Low stress=1.00 (reference group); Medium stress=4.13 (1.51, 11.29); High stress=4.63, (1.35, 15.83), p for trend=0.01]. Higher stress levels were associated with a 3-fold greater risk of having signs of humoral immune activation, as indicated by salivary IgA concentration [high compared to mid-range salivary IgA: Low stress=1.00 (reference group); Medium stress=1.06 (0.48, 2.34); High stress=3.62 (1.26, 10.39), p for trend=0.02], but also a 4-fold greater risk of humoral immune depression [low compared to mid-range IgA: Low stress=1.00 (reference group); Medium stress=1.72 (0.74, 3.99); High stress=4.38 (1.47, 13.00), p for trend=0.02]. In conclusion, in this cross-sectional study, higher stress levels were associated with higher serum neopterin and both elevated and depressed salivary IgA levels. These findings emphasise the importance of considering that stress may have bi-directional effects on immune mechanisms, and are consistent with an activational effect of chronic, perceived stress on cellular immunity, and a bi-directional effect on IgA levels, one aspect of humoral immunity.     

Chronic stress-induced alterations in mouse colonic 5-HT and defecation responses are strain dependent

Mood disorders and chronic stress are frequently associated with gastrointestinal (GI) symptoms including diarrhoea or constipation. Locally produced serotonin [5-hydroxytryptamine (5-HT)] regulates GI motility and is a key factor in the pathophysiology of stress-associated GI disorders. We aimed to establish whether chronic stress can differentially affect faecal output and colon 5-HT concentration in two inbred mouse strains: BALB/c and C57BL/6 which differ in their ability to cope with stress. Adult male BALB/c and C57BL/6 mice were restrained for 2?h daily for 10 days. Defecation was monitored during each stress session. Twenty-four hours after the last session of stress, plasma corticosterone concentration was higher than control in both strains, indicative of a physiological effect of chronic stress; however, stress-induced diarrhoea was more persistent in C57BL/6 mice. Basal concentration of colon 5-HT was higher in C57BL/6 mice, and stress elicited an increase in colon 5-HT only in this strain. Finally, na?ve BALB/c mice had a higher sensitivity (incidence of diarrhoea) to 5-HT (0.33?mg/kg, i.p.) than C57BL/6 mice. Our results suggest that differential defecation responses to stress may be associated with colon 5-HT concentration, which may in turn reflect the individual sensitivity to 5-HT. In addition, C57BL/6 mice emerge as a relevant model for studying GI alterations induced by chronic stress.     

The Community Child Health Network Life Stress Interview: a brief chronic stress measure for community health research

Background and Objectives: Chronic stress is implicated in many theories as a contributor to a wide range of physical and mental health problems. The current study describes the development of a chronic stress measure that was based on the UCLA Life Stress Interview (LSI) and adapted in collaboration with community partners for use in a large community health study of low-income, ethnically diverse parents of infants in the USA (Community Child Health Network [CCHN]). We describe the instrument, its purpose and adaptations, implementation, and results of a reliability study in a subsample of the larger study cohort. Design and Methods: Interviews with 272 mothers were included in the present study. Chronic stress was assessed using the CCHN LSI, an instrument designed for administration by trained community interviewers to assess four domains of chronic stress, each rated by interviewers. Results: Significant correlations ranging from small to moderate in size between chronic stress scores on this measure, other measures of stress, biomarkers of allostatic load, and mental health provide initial evidence of construct and concurrent validity. Reliability data for interviewer ratings are also provided. Conclusions: This relatively brief interview (15 minutes) is available for use and may be a valuable tool for researchers seeking to measure chronic stress reliably and validly in future studies with time constraints.     

Lipid reactivity to stress: I. Comparison of chronic and acute stress responses in middle-aged airline pilots.

Lipids increase during psychological stress, but no studies have compared the effects of acute and chronic stressors on lipid responsivity in the same individuals. One hundred middle-aged men (n = 92) and women (n = 8) were examined during high chronic occupational stress, low chronic stress, and acute laboratory stressors. In addition to measures of perceived stress and affect, an extensive battery of lipid and lipoprotein measures was undertaken at each time point. Most lipid parameters were significantly increased during the chronic and acute stressors, although the responses to the different stressors were not consistently associated. For example, significant correlations among the chronic and acute stress responses were apparent for the apoproteins, but not for total, low density lipoprotein, or high density lipoprotein cholesterol. The factors and processes regulating these variables during stress may be different during acute and chronic stressors.     

Relationships Among Perceived Racial Stress, Intolerance of Uncertainty, and Worry in a Black Sample

The purpose of this study was to explore the relationships among chronic worry, perceived racial stress, and intolerance of uncertainty in a sample of adults who racially identify as Black. Intolerance of uncertainty has been associated with worry and generalized anxiety disorder in predominantly White samples. Given that racial stress is likely to increase worry, perhaps through the mechanism of intolerance of uncertainty, intolerance of uncertainty was hypothesized to mediate the relationship between perceived racial stress and chronic worry. A nonclinical sample of 77 Black undergraduate students at an urban university completed a series of questionnaires assessing the constructs of interest. Both perceived racial stress and intolerance of uncertainty were significantly correlated with chronic worry in this sample. Moreover, intolerance of uncertainty fully mediated the relationship between perceived racial stress and worry for these Black individuals. These findings are discussed in terms of directions for future research and implications for clinical interventions for Black individuals who are both exposed to racial stress and suffer from chronic worry.     

Effects of acute, repeated and chronic variable stress on in vivo tyrosine hydroxylase activity and on alpha(2)-adrenoceptor sensitivity in the rat brain

We assessed the effects of a single tail pinch and two chronic stress regimes, repeated and variable, on in vivo tyrosine hydroxylase activity and on alpha2-adrenoceptor sensitivity in two brain regions. After administering a 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, tyrosine hydroxylase activity, measured as the accumulation of DOPA, and noradrenaline (NA) content were determined by using high-performance liquid chromatography. A single tail pinch for 5 min induced an enhancement of DOPA content in hippocampus (28%) and hypothalamus (67%) which was still present 24 h later. This increase could account for the lack of changes in NA content in both regions after the application of this stressor. However, tyrosine hydroxylase activity was unmodified 24 h after exposure to both repeated (5 min of tail pinch, twice daily, for 14 days) and chronic variable stress (one of 5 different stressors, once daily, for 14 days) although there was an enhancement of NA levels in hippocampus (45 and 54%, respectively) and hypothalamus (24.5 and 36%, respectively). The sensitivity of the alpha2-adrenoceptors which regulate [3H]-NA release in hippocampal and hypothalamic synaptosomes was not modified by the acute or chronic stress protocols assayed. The results show that both paradigms of chronic stress had similar effects on the noradrenergic indices evaluated.     

Environmental enrichment protects against the effects of chronic stress on cognitive and morphological measures of hippocampal integrity

Chronic stress has detrimental effects on hippocampal integrity, while environmental enrichment (EE) has beneficial effects when initiated early in development. In this study, we investigated whether EE initiated in adulthood would mitigate chronic stress effects on cognitive function and hippocampal neuronal architecture, when EE started one week before chronic stress began, or two weeks after chronic stress onset. Adult male Sprague Dawley rats were chronically restrained (6h/d) or assigned as non-stressed controls and subdivided into EE or non-EE housing. After restraint ended, rats were tested on a radial arm water maze (RAWM) for 2-d to assess spatial learning and memory. The first study showed that when EE began prior to 3-weeks of chronic stress, EE attenuated chronic stress-induced impairments in acquisition, which corresponded with the prevention of chronic stress-induced reductions in CA3 apical dendritic length. A second study showed that when EE began 2-weeks after the onset of a 5-week stress regimen, EE blocked chronic stress-induced impairments in acquisition and retention at 1-h and 24-h delays. RAWM performance corresponded with CA3 apical dendritic complexity. Moreover, rats in EE housing (control or stress) exhibited similar corticosterone profiles across weeks, which differed from the muted corticosterone response to restraint by the chronically stressed pair-housed rats. These data support the interpretation that chronic stress and EE may act on similar mechanisms within the hippocampus, and that manipulation of these factors may yield new directions for optimizing brain integrity and resilience under chronic stress or stress related neuropsychological disorders in the adult.     

Hormonal and behavioural abnormalities induced by stress in utero: an animal model for depression

Prenatal stress in rats can exert profound influence on the off spring's development, inducing abnormalities such as increased "anxiety", "emotionality" or "depression-like" behaviours.Prenatal stress has long-term effects on the development of the hypothalamo-pituitary-adrenal(HPA) axis and forebrain cholinergic systems. These long-term neuroendocrinological effects are mediated, at least in part, by stress-induced maternal corticosterone increase during pregnancy and stress-induced maternal anxiety during the postnatal period. We have shown a significant phase advance in the circadian rhythms of corticosterone secretion and locomotor activity in prenatally-stressed (PNS) rats. When subjected to an abrupt shift in the light-dark(LD) cycle, PNS rats resynchronized their activity rhythm more slowly than control rats. In view of the data suggesting abnormalities in the circadian timing system in these animals, we have investigated the effects of prenatal stress on the sleep-wake cycle in adult male rats. PNS rats exhibited various changes in sleep-wake parameters, including a dramatic increase in the amount of paradoxical sleep. Taken together, our results indicate that prenatal stress can induce increased responses to stress and abnormal circadian rhythms and sleep in adult rats.Various clinical observations in humans suggest a possible pathophysiological link between depression and disturbances in circadian rhythmicity. Circadian abnormalities in depression can be related to those found in PNS rats. Interestingly, we have recently shown that the increased immobility in the forced swimming test observed in PNS rats can be corrected by chronic treatment with the antidepressant tianeptine, or with melatonin or S23478, a melatonin agonist. Those results reinforce the idea of the usefulness of PNS rats as an appropriate animal model to study human depression and support a new antidepressant-like effect of melatonin and the melatonin agonist S23478.     

Chronic stress modulates the use of spatial and stimulus-response learning strategies in mice and man

Acute stress modulates multiple memory systems in favor of caudate nucleus-dependent stimulus-response and at the expense of hippocampus-dependent spatial learning and memory. We examined in mice and humans whether chronic stress has similar consequences. Male C57BL/6J mice that had been repeatedly exposed to rats ("rat stress") used in a circular hole board task significantly more often a stimulus-response strategy (33%) than control mice (0%). While velocity was increased, differences in latency to exit hole, distance moved or number of holes visited were not observed. Increased velocity and performance during retention trials one day later indicates altered emotionality and motivation to explore in rat stressed mice. Forty healthy young men and women were split into "high chronic stress" and "low chronic stress" groups based on their answers in a chronic stress questionnaire ("Trier Inventory of Chronic Stress"-TICS) and trained in a 2D task. A test trial immediately after training revealed that participants of the "high chronic stress" group used the S-R strategy significantly more often (94%) than participants of the "low chronic stress" group (52%). Verbal self-reports confirmed the strategy derived from participants' choice in the test trial. Learning performance was unaffected by the chronic stress level. We conclude that one consequence of chronic stress is the shift to more rigid stimulus-response learning, that is accompanied by changes in motivational factors in mice.     

Gender differences in acute and chronic stress in Wistar Kyoto (WKY) rats

While females are considered more susceptible to depressive behavior, this assertion is not strongly supported by the experimental literature. Since stress contributes to depressive behavior, male and female Wistar Kyoto (WKY) rats were exposed to either one session (acute stress) or 5 sessions (chronic stress) of restraint plus cold in order to study depressive behavior in male and female rats. After their respective treatment exposure, rats were tested in the open field test (OFT) and for retention of a passive-avoidance (P-A) task. One stress session resulted in significant immobility in the OFT for males, whereas 5 sessions were required to produce similar immobility in female rats. Acute stress interfered with the retention of the P-A response for males, while both acute and chronic stress produced poor P-A responses in female rats. Food consumption decresed, progressively, as a function of stress sessions, in female rats, whereas feeding in males returned to control levels after five stress days. Both acute and chronic stress exacerbated the stress ulcer response in male rats, but not in female rats. Chronic, but not acute, stress resulted in an increase in serotonin transporter mRNA levels in the dorsal raphe nucleus of both male and, female rats. The general consensus from these data suggested that female rats were more vulnerable to chronic stress and consequently supported the notion that females may be more susceptible to stress induced behavioral depression.     

The role of the anterodorsal thalami nuclei in the regulation of adrenal medullary function, beta-adrenergic cardiac receptors and anxiety responses in maternally deprived rats under stressful conditions

Maternal separation can interfere with growth and development of the brain and represents a significant risk factor for adult psychopathology. In rodents, prolonged separation from the mother affects the behavioral and endocrine responses to stress for the lifetime of the animal. Limbic structures such as the anterodorsal thalamic nuclei (ADTN) play an important role in the control of neuroendocrine and sympathetic-adrenal function. In view of these findings we hypothesized that the function of the ADTN may be affected in an animal model of maternal deprivation. To test this hypothesis female rats were isolated 4.5 h daily, during the first 3 weeks of life and tested as adults. We evaluated plasma epinephrine (E) and norepinephrine (NE), cardiac adrenoreceptors and anxiety responses after maternal deprivation and variable chronic stress (VCS) in ADTN-lesioned rats. Thirty days after ADTN lesion, in non-maternally deprived rats basal plasma NE concentration was greater and cardiac beta-adrenoreceptor density was lower than that in the sham-lesioned group. Maternal deprivation induced a significant increase in basal plasma NE concentration, which was greater in lesioned rats, and cardiac beta-adrenoreceptor density was decreased in lesioned rats. After VCS plasma catecholamine concentration was much greater in non-maternally deprived rats than in maternally-deprived rats; cardiac beta-adrenoreceptor density was decreased by VCS in both maternally-deprived and non-deprived rats, but more so in non-deprived rats, and further decreased by the ADTN lesion. In the plus maze test, the number of open arm entries was greater in the maternally deprived and in the stressed rats. Thus, sympathetic-adrenal medullary activation produced by VCS was much greater in non-deprived rats, and was linked to a down regulation of myocardial beta-adrenoceptors. The ADTN are not responsible for the reduced catecholamine responses to stress in maternally-deprived rats. Maternal deprivation or chronic stress also induced a long term anxiolytic effect, which was also not affected by ADTN lesion.     

Gender differences in acute and chronic stress in Wistar Kyoto (WKY) rats.

While females are considered more susceptible to depressive behavior, this assertion is not strongly supported by the experimental literature. Since stress contributes to depressive behavior, male and female Wistar Kyoto (WKY) rats were exposed to either one session (acute stress) or 5 sessions (chronic stress) of restraint plus cold in order to study depressive behavior in male and female rats. After their respective treatment exposure, rats were tested in the open field test (OFT) and for retention of a passive-avoidance (P-A) task. One stress session resulted in significant immobility in the OFT for males, whereas 5 sessions were required to produce similar immobility in female rats. Acute stress interfered with the retention of the P-A response for males, while both acute and chronic stress produced poor P-A responses in female rats. Food consumption decreased progressively, as a function of stress sessions, in female rats, whereas feeding in males returned to control levels after five stress days. Both acute and chronic stress exacerbated the stress ulcer response in male rats, but not in female rats. Chronic, but not acute, stress resulted in an increase in serotonin transporter mRNA levels in the dorsal raphe nucleus of both male and female rats. The general consensus from these data suggested that female rats were more vulnerable to chronic stress and consequently supported the notion that females may be more susceptible to stress-induced behavioral depression. Key Words: WKY rats, acute and chronic stress, gender, passive avoidance, open field behavior, stress-ulcer, adrenal weight, serotonin, dorsal raphe nucleus     

Effects of social isolation and environmental enrichment on atherosclerosis in ApoE-/- mice

Social support and a stimulating environment have been suggested to reduce stress reactions and cardiovascular risk. The aim of this study was to assess the role of environmental enrichment and social interaction for development of atherosclerosis in atherosclerosis prone mice. Male ApoE-/- mice were divided into four groups and followed during 20 weeks: (i) enriched environment (E, n=12), (ii) deprived environment (ED, n=12), (iii) enriched environment with exercise (E-Ex, n=12) and (iv) socially deprived by individual housing (SD, n=10). Plasma lipid and cytokine concentrations were measured. Atherosclerosis was quantified in cross-sections of innominate artery and en face in thoracic aorta. Plaque area was significantly increased in SD mice in the innominate artery (P<0.05 vs. all other groups), but not in the thoracic aorta. Plasma lipids were increased in SD mice (P<0.001 vs. all for total cholesterol, P<0.05 vs. E and P<0.01 vs. ED for triglycerides). Plasma concentration of granulocyte-colony stimulating factor (G-CSF) was decreased in SD mice compared to E mice (P<0.05). Thus, social isolation increased atherosclerosis and plasma lipids in ApoE-/- mice. Reduction in plasma G-CSF levels may hamper endothelial regeneration in the atherosclerotic process. While environmental enrichment did not affect atherosclerosis, social isolation accelerated atherosclerosis.     

Stress and Disease: A Structural and Functional Analysis

Chronic stress, a validated health risk factor, remains an ambiguous construct in spite of years of research. We propose that chronic stress is best understood as a series of acute stress responses, and that these responses become maladaptive when they occur frequently or are of long duration. We focus on the factors that contribute to chronic stress: whether the presence of a stressor, real or imagined, is long‐lived and/or frequent (repeated activation), the degree to which the stressor is perceived as a threat even when no longer present (low or slow adaptation), and the extent to which the duration of responding is prolonged (delayed or failure to return to homeostasis). Importantly, we examine how perseverative cognitions (such as rumination and worry) contribute to chronic stress by creating and sustaining acute stress responses, largely via influencing activation, adaptation, and return to homeostasis. Finally, we discuss the implications of our stress model: that interventions can be ideographically tailored to address how an individual is experiencing chronic stress; that researchers may be better able to identify specific characteristics of chronic stress that relate most strongly to poor health; and that moderators of chronic stress may function through these contributing factors rather than via general effects on the system.